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Almohmadi NH, Al-Kuraishy HM, Al-Gareeb AI, Albuhadily AK, Abdelaziz AM, Jabir MS, Alexiou A, Papadakis M, Batiha GES. Glutamatergic dysfunction in neurodegenerative diseases focusing on Parkinson's disease: Role of glutamate modulators. Brain Res Bull 2025; 225:111349. [PMID: 40252703 DOI: 10.1016/j.brainresbull.2025.111349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/02/2025] [Accepted: 04/15/2025] [Indexed: 04/21/2025]
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder resulting from the degeneration of dopamenergic neurons in the substantia nigra pars compacta (SNpc). Research has predominantly centered on understanding the dysfunction of dopaminergic neurotransmission in PD. Recently, more studies discussed the potential role of other neurotransmitters in PD neuropathology. One of the most important non-dopaminergic neurotransmitters involved in the pathogenesis of PD is glutamate, which is widely involved in glutamatergic neurotransmission in different brain regions, including SNpc. The development and progression of PD neuropathology and levodopa-induced dyskinesias (LID) are associated with glutamate neurotoxicity. Therefore, this review seeks to explore the possible involvement of glutamatergic signaling in PD development and assess the therapeutic potential of glutamate receptor antagonists in treating the disorder.
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Affiliation(s)
- Najlaa Hamed Almohmadi
- Clinical Nutrition Department, College of Applied Medical Sciences, Umm Al-Qura University, Makkah 24381, Saudi Arabia.
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq.
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq; Jabir ibn Hayyan Medical University Al-Ameer Qu, Po. Box (13), Kufa, Najaf, Iraq.
| | - Ali K Albuhadily
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq.
| | - Ahmed M Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Arish Branch, Arish 45511, Egypt.
| | - Majid S Jabir
- Department of Applied Science, University of Technology-Iraq, Baghdad, Iraq.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia; University Centre for Research & Development, Chandigarh University, Mohali, India; Department of Research & Development, Funogen, Athens, Greece.
| | - Marios Papadakis
- University Hospital Witten-Herdecke, University of Witten, Herdecke, Heusnerstrasse 40, Wuppertal 42283, Germany.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhur University, Damanhur, AlBeheira 22511, Egypt.
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Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chem Biol Interact 2025; 413:111489. [PMID: 40147618 DOI: 10.1016/j.cbi.2025.111489] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 02/23/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Richard Valko
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Jan Liska
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University, 811 08, Bratislava, Slovakia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic
| | - Kamil Kuca
- Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 5005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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Liu X, Hebron ML, Stevenson M, Moussa C. A Novel Small Molecule Enhances Stable Dopamine Delivery to the Brain in Models of Parkinson's Disease. Int J Mol Sci 2025; 26:4251. [PMID: 40362491 PMCID: PMC12072186 DOI: 10.3390/ijms26094251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 05/15/2025] Open
Abstract
Levodopa is the gold standard symptomatic treatment for Parkinson's disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson's patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson's disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels.
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Affiliation(s)
- Xiaoguang Liu
- Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA; (M.L.H.); (M.S.)
| | | | | | - Charbel Moussa
- Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA; (M.L.H.); (M.S.)
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Alves Fernandes TA, Tourville A, Ciss I, Ribeiro Silva R, Andretto de Mattos B, Dos Santos Pereira M, Oblaza M, Brunel JM, Ferrié L, Raisman-Vozari R, Figadère B, Del-Bel E, Michel PP. Oxytetracycline and its Non-Antibiotic Derivative DOT Protect Midbrain Dopamine Neurons from Iron-Driven Oxidative Damage. Neurotox Res 2025; 43:16. [PMID: 40119187 DOI: 10.1007/s12640-025-00742-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/14/2025] [Accepted: 03/17/2025] [Indexed: 03/24/2025]
Abstract
This study aimed to investigate the neuroprotective potential of the tetracycline (TC) antibiotic oxytetracycline (OT) and its non-antibiotic derivative 4-dedimethylamino 12a-deoxy-oxytetracycline (DOT), in experimental conditions that mimic the gradual loss of dopamine (DA) neurons in Parkinson's disease (PD). Specifically, we established a model system of mouse midbrain cultures where DA neurons progressively die when exposed to an iron-containing medium. We found that OT (EC50 = 0.25µM) and DOT (EC50 = 0.34µM) efficiently protected DA neurons from degeneration, with these effects observable until advanced stages of neurodegeneration. The reference antibiotic TC doxycycline (DOX) also exhibited protective effects in this context. Importantly, DA neurons rescued by OT, DOT, and DOX retained their capacity to accumulate and release DA, indicating full functional integrity. Additionally, molecules with iron-chelating properties (apotransferrin, desferoxamine), as well as inhibitors of lipid peroxidation and ferroptosis (Trolox, Liproxstatin-1), could replicate the rescue of DA neurons provided by OT, DOT, and DOX. Live-cell imaging studies showed that test TCs and other neuroprotective molecules prevented the emission of intracellular reactive oxygen species and the associated disruption of the mitochondrial membrane potential. However, neither OT, DOT, nor DOX could protect DA neurons from selective mitochondrial poisoning by 1-methyl-4-phenylpyridinium. This suggests that test TCs may be protective against iron-mediated damage through a mechanism not directly involving mitochondria. Overall, we demonstrate that OT and DOT possess promising properties that could be useful for combating PD neurodegeneration. However, the absence of antimicrobial activity makes DOT a better candidate drug compared to its parent compound OT.
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Affiliation(s)
- Thaís Antonia Alves Fernandes
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
- Department of Basic and Oral Biology, Ribeirão Preto School of Dentistry, University of São Paulo (USP), Ribeirão Preto, SP, 14049-904, Brazil
- Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Aurore Tourville
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
| | - Ismaila Ciss
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
- Université Paris-Saclay, BioCIS, CNRS, Orsay, 91190, France
| | - Rafaela Ribeiro Silva
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
| | - Bianca Andretto de Mattos
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
- Department of Basic and Oral Biology, Ribeirão Preto School of Dentistry, University of São Paulo (USP), Ribeirão Preto, SP, 14049-904, Brazil
- Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Maurício Dos Santos Pereira
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
- Stanley Center, Broad Institute, Cambridge, MA, 02142, USA
| | - Maxime Oblaza
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
- Université Paris-Saclay, BioCIS, CNRS, Orsay, 91190, France
| | - Jean-Michel Brunel
- Aix Marseille Univ, Inserm, Membranes et Cibles Thérapeutiques, Service de Santé des Armées, Marseille, 13385, France
| | - Laurent Ferrié
- Université Paris-Saclay, BioCIS, CNRS, Orsay, 91190, France
| | - Rita Raisman-Vozari
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France
| | - Bruno Figadère
- Université Paris-Saclay, BioCIS, CNRS, Orsay, 91190, France
| | - Elaine Del-Bel
- Department of Basic and Oral Biology, Ribeirão Preto School of Dentistry, University of São Paulo (USP), Ribeirão Preto, SP, 14049-904, Brazil.
| | - Patrick Pierre Michel
- Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, 75013, France.
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Sampson TR, Tansey MG, West AB, Liddle RA. Lewy body diseases and the gut. Mol Neurodegener 2025; 20:14. [PMID: 39885558 PMCID: PMC11783828 DOI: 10.1186/s13024-025-00804-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/21/2025] [Indexed: 02/01/2025] Open
Abstract
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.
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Affiliation(s)
- Timothy R Sampson
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30329, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
| | - Malú Gámez Tansey
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, 32610, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA
- Normal Fixel Institute of Neurological Diseases, Gainesville, FL, 32608, USA
| | - Andrew B West
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Center for Neurodegeneration and Neurotherapeutic Research, Department of Pharmacology and Cancer Biology, Durham, NC, 27710, USA.
| | - Rodger A Liddle
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Institute for Brain Sciences, Duke University, Durham, NC, 27710, USA.
- Department of Medicine, Duke University and Department of Veterans Affairs Health Care System, Durham, NC, 27710, USA.
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Wei J, Liu C, Qin D, Ren F, Duan J, Chen T, Wu A. Targeting inflammation and gut microbiota with antibacterial therapy: Implications for central nervous system health. Ageing Res Rev 2024; 102:102544. [PMID: 39419400 DOI: 10.1016/j.arr.2024.102544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
The complex symbiotic relationship between inflammation, the gut microbiota, and the central nervous system (CNS) has become a pivotal focus of contemporary biomedical research. Inflammation, as a physiological defense mechanism, plays a dual role as both a protective and pathological factor, and is intricately associated with gut microbiota homeostasis, often termed the "second brain." The gutbrain axis (GBA) exemplifies this multifaceted interaction, where gut health exerts significantly regulatory effects on CNS functions. Antibacterial therapies represent both promising and challenging strategies for modulating inflammation and gut microbiota composition to confer CNS benefits. However, while such therapies may exert positive modulatory effects on the gut microbiota, they also carry the potential to disrupt microbial equilibrium, potentially exacerbating neurological dysfunction. Recent advances have provided critical insights into the therapeutic implications of antibacterial interventions; nevertheless, the application of these therapies in the context of CNS health warrants a judicious and evidence-based approach. As research progresses, deeper investigation into the microbial-neural interface is essential to fully realize the potential of therapies targeting inflammation and the gut microbiota for CNS health. Future efforts should focus on refining antibacterial interventions to modulate the gut microbiota while minimizing disruption to microbial balance, thereby reducing risks and enhancing efficacy in CNS-related conditions. In conclusion, despite challenges, a more comprehensive understanding of the GBA, along with precise modulation through targeted antibacterial therapies, offers significant promise for advancing CNS disorder treatment. Continued research in this area will lead to innovative interventions and improved patient outcomes.
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Affiliation(s)
- Jing Wei
- Eye School of Chengdu University of TCM, Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, China; School of Pharmaceutical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua 418000, China.
| | - Chunmeng Liu
- Eye School of Chengdu University of TCM, Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, China.
| | - Dalian Qin
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Department of Cardiology, the Affiliated Hospital of Southwest Medical University and Key Laboratory of Medical Electrophysiology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
| | - Fang Ren
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China.
| | - Junguo Duan
- Eye School of Chengdu University of TCM, Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, China.
| | - Ting Chen
- School of Pharmaceutical Sciences, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, Hunan University of Medicine, Huaihua 418000, China.
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Department of Cardiology, the Affiliated Hospital of Southwest Medical University and Key Laboratory of Medical Electrophysiology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Hamilton AM, Krout IN, White AC, Sampson TR. Microbiome-based therapeutics for Parkinson's disease. Neurotherapeutics 2024; 21:e00462. [PMID: 39393983 PMCID: PMC11585879 DOI: 10.1016/j.neurot.2024.e00462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/18/2024] [Accepted: 09/26/2024] [Indexed: 10/13/2024] Open
Abstract
Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.
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Affiliation(s)
- Adam M Hamilton
- Department of Cell Biology, Emory University School of Medicine, Atlanta GA 30322, USA
| | - Ian N Krout
- Department of Cell Biology, Emory University School of Medicine, Atlanta GA 30322, USA
| | - Alexandria C White
- Department of Cell Biology, Emory University School of Medicine, Atlanta GA 30322, USA
| | - Timothy R Sampson
- Department of Cell Biology, Emory University School of Medicine, Atlanta GA 30322, USA.
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8
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Bido S, Nannoni M, Muggeo S, Gambarè D, Ruffini G, Bellini E, Passeri L, Iaia S, Luoni M, Provinciali M, Giannelli SG, Giannese F, Lazarevic D, Gregori S, Broccoli V. Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease. Sci Transl Med 2024; 16:eadm8563. [PMID: 39167665 DOI: 10.1126/scitranslmed.adm8563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 04/23/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024]
Abstract
Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson's disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8+ T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.
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Affiliation(s)
- Simone Bido
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Melania Nannoni
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Sharon Muggeo
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Diana Gambarè
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Giorgia Ruffini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Edoardo Bellini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Laura Passeri
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Silvia Iaia
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Mirko Luoni
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- CNR Institute of Neuroscience, 20129 Milan, Italy
| | - Martino Provinciali
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Serena Gea Giannelli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Francesca Giannese
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Dejan Lazarevic
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Silvia Gregori
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Vania Broccoli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- CNR Institute of Neuroscience, 20129 Milan, Italy
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9
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Ploper D, Pernicone AO, Tomas-Grau RH, Manzano VE, Socías SB, Teran MDM, Budeguer Isa V, Sosa-Padilla B, González-Lizárraga F, Avila CL, Guayán ML, Chaves S, Cruz H, Vera Pingitore E, Varela O, Chehín R. Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease. ACS Chem Neurosci 2024; 15:2795-2810. [PMID: 38991155 DOI: 10.1021/acschemneuro.4c00169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024] Open
Abstract
The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.
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Affiliation(s)
- Diego Ploper
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Agustín O Pernicone
- Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Universidad de Buenos Aires, Pabellón 2, C1428EHA Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigación en Hidratos de Carbono (CIHIDECAR), Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
| | - Rodrigo H Tomas-Grau
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Verónica E Manzano
- Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Universidad de Buenos Aires, Pabellón 2, C1428EHA Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigación en Hidratos de Carbono (CIHIDECAR), Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
| | - Sergio B Socías
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - María Del Milagro Teran
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Valentina Budeguer Isa
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Bernardo Sosa-Padilla
- Instituto de Química del Noroeste Argentino (INQUINOA) (CONICET), Universidad Nacional de Tucumán (UNT), Ayacucho 471, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Florencia González-Lizárraga
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - César L Avila
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - María Laura Guayán
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Silvina Chaves
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Hernán Cruz
- Instituto de Química Física, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Lorenzo 456, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Esteban Vera Pingitore
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
| | - Oscar Varela
- Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Universidad de Buenos Aires, Pabellón 2, C1428EHA Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigación en Hidratos de Carbono (CIHIDECAR), Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
| | - Rosana Chehín
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina
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10
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Rodrigues MS, do Nascimento NB, Farias HR, Schons T, Machado AG, Behenck E, Mesquita A, Krolow Bast R, Budni J, Engblom D, de Bem AF, de Oliveira J. Microglia contribute to cognitive decline in hypercholesterolemic LDLr -/- mice. J Neurochem 2024; 168:1565-1586. [PMID: 37694813 DOI: 10.1111/jnc.15952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/12/2023]
Abstract
Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr-/-) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr-/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr-/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr-/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr-/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr-/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr-/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr-/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.
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Affiliation(s)
- Matheus Scarpatto Rodrigues
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Natalia Baltazar do Nascimento
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Hemelin Resende Farias
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Taina Schons
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Alessandra Gonçalves Machado
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Eduarda Behenck
- Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - Ariadni Mesquita
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Rachel Krolow Bast
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Josiani Budni
- Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil
| | - David Engblom
- Center for Social and Affective Neuroscience (CSAN), Linköping University, Linköping, Sweden
| | | | - Jade de Oliveira
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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11
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Bourzam A, Hamdi Y, Bahdoudi S, Duraisamy K, El Mehdi M, Basille-Dugay M, Dlimi O, Kharrat M, Vejux A, Lizard G, Ghrairi T, Lefranc B, Vaudry D, Boutin JA, Leprince J, Masmoudi-Kouki O. Octadecaneuropeptide, ODN, Promotes Cell Survival against 6-OHDA-Induced Oxidative Stress and Apoptosis by Modulating the Expression of miR-34b, miR-29a, and miR-21in Cultured Astrocytes. Cells 2024; 13:1188. [PMID: 39056770 PMCID: PMC11487398 DOI: 10.3390/cells13141188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/03/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Astrocytes specifically synthesize and release endozepines, a family of regulatory peptides including octadecaneuropeptide (ODN). We have previously reported that ODN rescues neurons and astrocytes from 6-OHDA-induced oxidative stress and cell death. The purpose of this study was to examine the potential implication of miR-34b, miR-29a, and miR-21 in the protective activity of ODN on 6-OHDA-induced oxidative stress and cell death in cultured rat astrocytes. Flow cytometry analysis showed that 6-OHDA increased the number of early apoptotic and apoptotic dead cells while treatment with the subnanomolar dose of ODN significantly reduced the number of apoptotic cells induced by 6-OHDA. 6-OHDA-treated astrocytes exhibited the over-expression of miR-21 (+118%) associated with a knockdown of miR-34b (-61%) and miR-29a (-49%). Co-treatment of astrocytes with ODN blocked the 6-OHDA-stimulated production of ROS and NO and stimulation of Bax and caspase-3 gene transcription. Concomitantly, ODN down-regulated the expression of miR-34b and miR-29a and rescued the 6-OHDA-associated reduced expression of miR21, indicating that ODN regulates their expression during cell death. Transfection with miR-21-3p inhibitor prevented the effect of 6-OHDA against cell death. In conclusion, our study indicated that (i) the expression of miRNAs miR-34b, miR-29a, and miR-21 is modified in astrocytes under 6-OHDA injury and (ii) that ODN prevents this deregulation to induce its neuroprotective action. The present study identified miR-21 as an emerging candidate and as a promising pharmacological target that opens new neuroprotective therapeutic strategies in neurodegenerative diseases, especially in Parkinson's disease.
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Affiliation(s)
- Amine Bourzam
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
- LR18ES03 Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
| | - Yosra Hamdi
- LR18ES03 Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
| | - Seyma Bahdoudi
- LR18ES03 Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
| | - Karthi Duraisamy
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Mouna El Mehdi
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Magali Basille-Dugay
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Omayma Dlimi
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Maher Kharrat
- Human Genetics Laboratory (LR99ES10), Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
| | - Anne Vejux
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, Institut Agro, Université de Bourgogne, 21000 Dijon, France
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), Université de Bourgogne, Inserm, 21000 Dijon, France
| | - Gérard Lizard
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), Université de Bourgogne, Inserm, 21000 Dijon, France
| | - Taoufik Ghrairi
- LR18ES03 Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
| | - Benjamin Lefranc
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - David Vaudry
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Jean A Boutin
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Jérôme Leprince
- Laboratory of Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Inserm UMR 1239, University Rouen Normandie, 76000 Rouen, France
| | - Olfa Masmoudi-Kouki
- LR18ES03 Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
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12
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Aktas B, Aslim B, Ozdemir DA. A neurotherapeutic approach with Lacticaseibacillus rhamnosus E9 on gut microbiota and intestinal barrier in MPTP-induced mouse model of Parkinson's disease. Sci Rep 2024; 14:15460. [PMID: 38965287 PMCID: PMC11224381 DOI: 10.1038/s41598-024-65061-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 06/17/2024] [Indexed: 07/06/2024] Open
Abstract
The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson's disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.
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Affiliation(s)
- Busra Aktas
- Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur, 15200, Turkey.
| | - Belma Aslim
- Department of Biology, Faculty of Science, Gazi University, Ankara, 06500, Turkey
| | - Deniz Ates Ozdemir
- Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, 06230, Turkey
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13
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Strohm AO, Majewska AK. Physical exercise regulates microglia in health and disease. Front Neurosci 2024; 18:1420322. [PMID: 38911597 PMCID: PMC11192042 DOI: 10.3389/fnins.2024.1420322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
There is a well-established link between physical activity and brain health. As such, the effectiveness of physical exercise as a therapeutic strategy has been explored in a variety of neurological contexts. To determine the extent to which physical exercise could be most beneficial under different circumstances, studies are needed to uncover the underlying mechanisms behind the benefits of physical activity. Interest has grown in understanding how physical activity can regulate microglia, the resident immune cells of the central nervous system. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise.
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Affiliation(s)
- Alexandra O. Strohm
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Ania K. Majewska
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, United States
- Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY, United States
- Center for Visual Science, University of Rochester Medical Center, Rochester, NY, United States
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14
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Cheng G, Hardy M, Hillard CJ, Feix JB, Kalyanaraman B. Mitigating gut microbial degradation of levodopa and enhancing brain dopamine: Implications in Parkinson's disease. Commun Biol 2024; 7:668. [PMID: 38816577 PMCID: PMC11139878 DOI: 10.1038/s42003-024-06330-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 05/14/2024] [Indexed: 06/01/2024] Open
Abstract
Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa-alone or combined with carbidopa-to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.
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Affiliation(s)
- Gang Cheng
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Micael Hardy
- Aix-Marseille Univ, CNRS, ICR, UMR 7273, Marseille, 13013, France
| | - Cecilia J Hillard
- Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Jimmy B Feix
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Balaraman Kalyanaraman
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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15
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Gallagher E, Hou C, Zhu Y, Hsieh CJ, Lee H, Li S, Xu K, Henderson P, Chroneos R, Sheldon M, Riley S, Luk KC, Mach RH, McManus MJ. Positron Emission Tomography with [ 18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy. Int J Mol Sci 2024; 25:4943. [PMID: 38732162 PMCID: PMC11084161 DOI: 10.3390/ijms25094943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of aSyn aggregation in the synucleinopathies; however, noninvasive methods for detecting oxidative stress in living animals have proven elusive. In this study, we used the reactive oxygen species (ROS)-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace to detect increases in oxidative stress in the widely-used A53T mouse model of synucleinopathy. A53T-specific elevations in [18F]ROStrace signal emerged at a relatively early age (6-8 months) and became more widespread within the brain over time, a pattern which paralleled the progressive development of aSyn pathology and oxidative damage in A53T brain tissue. Systemic administration of lipopolysaccharide (LPS) also caused rapid and long-lasting elevations in [18F]ROStrace signal in A53T mice, suggesting that chronic, aSyn-associated oxidative stress may render these animals more vulnerable to further inflammatory insult. Collectively, these results provide novel evidence that oxidative stress is an early and chronic process during the development of synucleinopathy and suggest that PET imaging with [18F]ROStrace holds promise as a means of detecting aSyn-associated oxidative stress noninvasively.
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Affiliation(s)
- Evan Gallagher
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Catherine Hou
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Yi Zhu
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
| | - Chia-Ju Hsieh
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Hsiaoju Lee
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Shihong Li
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Kuiying Xu
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Patrick Henderson
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
| | - Rea Chroneos
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
| | - Malkah Sheldon
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
| | - Shaipreeah Riley
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
| | - Kelvin C. Luk
- Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert H. Mach
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (C.H.); (R.H.M.)
| | - Meagan J. McManus
- Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (E.G.)
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16
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Tanaka K, Choudhury ME, Kikuchi S, Takeda I, Umakoshi K, Miyaue N, Mikami K, Takenaga A, Yagi H, Shinabe R, Matsumoto H, Yano H, Nagai M, Takeba J, Tanaka J. A dopamine D1-like receptor-specific agonist improves the survival of septic mice. iScience 2024; 27:109587. [PMID: 38623339 PMCID: PMC11016908 DOI: 10.1016/j.isci.2024.109587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/08/2024] [Accepted: 03/25/2024] [Indexed: 04/17/2024] Open
Abstract
In this study, a murine sepsis model was developed using the cecum ligation and puncture (CLP) technique. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in the brain increased 6 h after CLP but decreased 24 h later when elevated endogenous dopamine levels in the brain were sustained. Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride reduced dopamine levels in the striatum and increased mortality in septic mice. Dopamine D1-like receptors were significantly expressed in the brain, but not in the lungs. Intraperitoneally administered SKF-81297 (SKF), a blood-brain barrier-permeable D1-like receptor agonist, prevented CLP-induced death of septic mice with ameliorated acute lung injury and cognitive dysfunction and suppressed TNF-α and IL-1β expression. The D1-like receptor antagonist SCH-23390 abolished the anti-inflammatory effects of SKF. These data suggest that D1-like receptor-mediated signals in the brain prevent CLP-induced inflammation in both the brain and the periphery.
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Affiliation(s)
- Koichi Tanaka
- Advanced Emergency and Critical Care Center, Ehime Prefectural Central Hospital, Kasugamachi, Matsuyama, Ehime 790-0024, Japan
- Department of Aeromedical Services for Emergency and Trauma Care, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Mohammed E. Choudhury
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Satoshi Kikuchi
- Department of Emergency Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Ikuko Takeda
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
- Division of Multicellular Circuit Dynamics, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan
| | - Kensuke Umakoshi
- Advanced Emergency and Critical Care Center, Ehime Prefectural Central Hospital, Kasugamachi, Matsuyama, Ehime 790-0024, Japan
| | - Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Kanta Mikami
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Ayane Takenaga
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Harumichi Yagi
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Rintaro Shinabe
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Hironori Matsumoto
- Department of Emergency Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Hajime Yano
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Jun Takeba
- Department of Aeromedical Services for Emergency and Trauma Care, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
| | - Junya Tanaka
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan
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17
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Giri PM, Banerjee A, Ghosal A, Layek B. Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications. Int J Mol Sci 2024; 25:3995. [PMID: 38612804 PMCID: PMC11011898 DOI: 10.3390/ijms25073995] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/29/2024] [Accepted: 03/30/2024] [Indexed: 04/14/2024] Open
Abstract
Neurodegenerative disorders (NDs) have become increasingly common during the past three decades. Approximately 15% of the total population of the world is affected by some form of NDs, resulting in physical and cognitive disability. The most common NDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although NDs are caused by a complex interaction of genetic, environmental, and lifestyle variables, neuroinflammation is known to be associated with all NDs, often leading to permanent damage to neurons of the central nervous system. Furthermore, numerous emerging pieces of evidence have demonstrated that inflammation not only supports the progression of NDs but can also serve as an initiator. Hence, various medicines capable of preventing or reducing neuroinflammation have been investigated as ND treatments. While anti-inflammatory medicine has shown promising benefits in several preclinical models, clinical outcomes are often questionable. In this review, we discuss various NDs with their current treatment strategies, the role of neuroinflammation in the pathophysiology of NDs, and the use of anti-inflammatory agents as a potential therapeutic option.
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Affiliation(s)
- Paras Mani Giri
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Anurag Banerjee
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Arpita Ghosal
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Buddhadev Layek
- Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58105, USA
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18
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Bobotis BC, Halvorson T, Carrier M, Tremblay MÈ. Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping. Front Cell Neurosci 2024; 18:1317125. [PMID: 38425429 PMCID: PMC10902073 DOI: 10.3389/fncel.2024.1317125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/15/2024] [Indexed: 03/02/2024] Open
Abstract
The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in the maintenance and regulation of neuronal network dynamics. Research on microglia, the resident innate immune cells of the CNS, has advanced considerably in recent years, and our understanding of their diverse functions continues to grow. Microglia play critical roles in the formation and regulation of neuronal synapses, myelination, responses to injury, neurogenesis, inflammation, and many other physiological processes. In parallel with advances in microglial biology, cutting-edge techniques for the characterization of microglial properties have emerged with increasing depth and precision. Labeling tools and reporter models are important for the study of microglial morphology, ultrastructure, and dynamics, but also for microglial isolation, which is required to glean key phenotypic information through single-cell transcriptomics and other emerging approaches. Strategies for selective microglial depletion and modulation can provide novel insights into microglia-targeted treatment strategies in models of neuropsychiatric and neurodegenerative conditions, cancer, and autoimmunity. Finally, fate mapping has emerged as an important tool to answer fundamental questions about microglial biology, including their origin, migration, and proliferation throughout the lifetime of an organism. This review aims to provide a comprehensive discussion of these established and emerging techniques, with applications to the study of microglia in development, homeostasis, and CNS pathologies.
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Affiliation(s)
- Bianca Caroline Bobotis
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology, Victoria, BC, Canada
| | - Torin Halvorson
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
- British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Micaël Carrier
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec City, QC, Canada
- Axe neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology, Victoria, BC, Canada
- Axe neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
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19
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Iglesias LP, Soares N, Asth L, Moreira FA, Aguiar DC. Minocycline as a potential anxiolytic drug: systematic review and meta-analysis of evidence in murine models. Behav Pharmacol 2024; 35:4-13. [PMID: 38375658 DOI: 10.1097/fbp.0000000000000754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Minocycline is a tetracycline antibiotic with off-label use as an anti-inflammatory drug. Because it can cross the blood-brain barrier, minocycline has been proposed as an alternative treatment for psychiatric disorders, in which inflammation plays an important role. However, its beneficial effects on anxiety disorders are unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy of minocycline as an anxiolytic drug in preclinical models. We performed a PubMed search according to the PRISMA guidelines and PICOS strategy. The risk of bias was evaluated using the SYRCLE tool. We included studies that determined the efficacy of minocycline in animal models of anxiety that may involve exposures (e.g. stressors, immunomodulators, injury). Data extracted included treatment effect, dose range, route of administration, and potential mechanisms for the anxiolytic effect. Meta-analysis of twenty studies showed that minocycline reduced anxiety-like behavior in rodents previously exposed to stress or immunostimulants but not in exposure-naïve animals. This effect was not associated with the dose administered or treatment duration. The mechanism for the anxiolytic activity of minocycline may depend on its anti-inflammatory effects in the brain regions involving anxiety. These suggest that minocycline could be repurposed as a treatment for anxiety and related disorders and warrants further evaluation.
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Affiliation(s)
- Lia P Iglesias
- Graduate School in Neuroscience, Universidade Federal de Minas Gerais (UFMG)
| | - Nicia Soares
- Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Laila Asth
- Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Fabricio A Moreira
- Graduate School in Neuroscience, Universidade Federal de Minas Gerais (UFMG)
- Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Daniele C Aguiar
- Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
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20
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Patel B, Greenland JC, Williams-Gray CH. Clinical Trial Highlights: Anti-Inflammatory and Immunomodulatory Agents. JOURNAL OF PARKINSON'S DISEASE 2024; 14:1283-1300. [PMID: 39331111 PMCID: PMC11492043 DOI: 10.3233/jpd-240353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/28/2024]
Abstract
Inflammation and immune dysregulation have been linked to the pathogenesis and progression of Parkinson's disease (PD), and represent an attractive target for therapeutic intervention, given the potential for repurposing of existing anti-inflammatory and immunomodulatory agents. Despite the fact that initial studies of drugs with secondary anti-inflammatory effects did not yield positive results, agents specifically targeting immune and inflammatory pathways may hold more promise. This article will briefly review the evidence base for targeting the immune system and neuroinflammation in PD, and discuss in detail the recently completed and currently active trials of primary anti-inflammatory/immunomodulatory drugs in PD.
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Affiliation(s)
- Bina Patel
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Julia C. Greenland
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Caroline H. Williams-Gray
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
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21
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Zhang ZX, Zhou YJ, Gu P, Zhao W, Chen HX, Wu RY, Zhou LY, Cui QZ, Sun SK, Zhang LQ, Zhang K, Xu HJ, Chai XQ, An SJ. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson's disease and neuronal damage through inhibition of microglia. Neural Regen Res 2023; 18:2291-2300. [PMID: 37056150 PMCID: PMC10328268 DOI: 10.4103/1673-5374.368300] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 11/19/2022] [Accepted: 12/06/2022] [Indexed: 04/15/2023] Open
Abstract
Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson's disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson's disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson's disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson's disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.
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Affiliation(s)
- Zhong-Xia Zhang
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Yong-Jie Zhou
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ping Gu
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Wei Zhao
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Hong-Xu Chen
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ruo-Yu Wu
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Lu-Yang Zhou
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Qing-Zhuo Cui
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Shao-Kang Sun
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Lin-Qi Zhang
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ke Zhang
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Hong-Jun Xu
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Xi-Qing Chai
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Sheng-Jun An
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
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22
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Roy R, Paul R, Bhattacharya P, Borah A. Combating Dopaminergic Neurodegeneration in Parkinson's Disease through Nanovesicle Technology. ACS Chem Neurosci 2023; 14:2830-2848. [PMID: 37534999 DOI: 10.1021/acschemneuro.3c00070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023] Open
Abstract
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.
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Affiliation(s)
- Rubina Roy
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar 788011, Assam, India
| | - Rajib Paul
- Department of Zoology, Pandit Deendayal Upadhyaya Adarsha Mahavidyalaya (PDUAM), Eraligool, Karimganj 788723, Assam, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad 382355, Gandhinagar, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar 788011, Assam, India
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23
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Aktas B. Gut Microbial Alteration in MPTP Mouse Model of Parkinson Disease is Administration Regimen Dependent. Cell Mol Neurobiol 2023; 43:2815-2829. [PMID: 36708421 PMCID: PMC9883829 DOI: 10.1007/s10571-023-01319-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/18/2023] [Indexed: 01/29/2023]
Abstract
Parkinson Disease (PD) is one of the most common neurodegenerative disorders characterized by loss of dopaminergic neurons involved in motor functions. Growing evidence indicates that gut microbiota communicates with the brain known as the gut-brain axis (GBA). Mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used in animal studies to investigate the GBA in PD. Various MPTP administration regimens are performed in PD mouse models involving one to multiple injections in 1 day or one injection per day for several days. The aim of this study is to investigate if the impact of MPTP on gut microbiota differs depending on the administration regimen. C57BL/6 mice were treated with acute or subchronic regimens of MPTP. Motor functions were assessed by open-field, catalepsy, and wire hanging tests. The cecum and the brain samples were obtained for microbiota and gene expression analyses, respectively. MPTP administration regimens differed in their ability to alter the gut microbiota. Firmicutes and Bacteroidota were both increased in subchronic mice while did not change and decreased, respectively, in acute mice. Verrucomicrobiota was elevated in acute MPTP mice but dropped in subchronic MPTP mice. Muribaculaceae was the predominant genus in all groups but acute mice. In acute mice, Akkermansia was increased and Colidextribacter was decreased; however, they showed an opposite trend in subchronic mice. These data suggest that MPTP mouse model cause a gut microbiota dysbiosis in an administration regimen dependent manner, and it is important to take consideration of mouse model to investigate the GBA in neurodegenerative diseases including PD.
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Affiliation(s)
- Busra Aktas
- Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University Burdur, 15030, Burdur, Turkey.
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24
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Shayan M, Mehri S, Razavi BM, Hosseinzadeh H. Minocycline as a Neuroprotective Agent in Arsenic-Induced Neurotoxicity in PC12 Cells. Biol Trace Elem Res 2023; 201:2955-2962. [PMID: 35939230 DOI: 10.1007/s12011-022-03376-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/30/2022] [Indexed: 11/02/2022]
Abstract
Arsenic is a naturally occurring metalloid that exists in water, soil, food, and air. Humans can be exposed to arsenic through occupational, medical, or nutritional routes. Both acute and chronic forms of toxicity with severe outcomes are likely following arsenic exposure. Neurotoxicity is one of the serious manifestations of arsenic toxicity. In our study, the effect of minocycline, a widely used antimicrobial agent with antioxidant aspects and the ability to cross the blood-brain barrier, was evaluated against arsenic-induced neurotoxicity. PC12 cell line was used as the cellular model of this study. Cells were pre-treated with minocycline (50 nM-1 µM) for 2 h, and then incubated for 24 h after adding sodium arsenite (10 µM). The MTT assay and fluorimetry were performed to study cytotoxicity and reactive oxygen species generation, respectively. Finally, Western blotting was done to determine the levels of caspase-8, Bax, Bcl-2, and caspase-3. Once exposed to arsenic, the cell viability was significantly reduced, the intracellular oxidative balance was significantly disrupted, and the levels of proteins caspase-8, Bax/Bcl-2, and caspase-3 were significantly increased. Minocycline not only attenuated arsenic-induced cytotoxicity and reduced oxidative stress, but also led to lower levels of caspase-8, Bax/Bcl-2, and caspase-3 proteins compared with the arsenic-treated cells. Minocycline can significantly protect cells against arsenic-induced neurotoxicity by antioxidant and anti-apoptosis properties via both intrinsic and extrinsic caspase-dependent apoptotic pathways; therefore, at this point, it's worth considering it as a promising agent for the treatment of arsenic toxicity.
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Affiliation(s)
- Mersedeh Shayan
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soghra Mehri
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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25
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Zhang W, Ding L, Chen H, Zhang M, Ma R, Zheng S, Gong J, Zhang Z, Xu H, Xu P, Zhang Y. Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte-microglia C3-C3aR pathway. Cell Death Dis 2023; 14:285. [PMID: 37087484 PMCID: PMC10122675 DOI: 10.1038/s41419-023-05807-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/24/2023]
Abstract
Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human α-synuclein overexpression (AAV-hα-Syn). This scenario was further validated in A53T α-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, α-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte-microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated α-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.
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Affiliation(s)
- Wenlong Zhang
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Liuyan Ding
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Huaqing Chen
- Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, 518055, China
| | - Mengran Zhang
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
- School of Life Sciences, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, 310024, China
| | - Runfang Ma
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
- School of Life Sciences, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, 310024, China
| | - Shaohui Zheng
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
- School of Life Sciences, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, 310024, China
| | - Junwei Gong
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhiling Zhang
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Huaxi Xu
- Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
| | - Yunlong Zhang
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
- School of Life Sciences, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, 310024, China.
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26
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Shayan M, Mehri S, Razavi BM, Hosseinzadeh H. Minocycline Protects PC12 Cells Against Cadmium-Induced Neurotoxicity by Modulating Apoptosis. Biol Trace Elem Res 2023; 201:1946-1954. [PMID: 35661325 DOI: 10.1007/s12011-022-03305-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/28/2022] [Indexed: 11/25/2022]
Abstract
Cadmium (Cd) is a well-known heavy metal and a neurotoxic agent. Minocycline (Mino) is an anti-microbial agent with a lipophilic structure that crosses the blood-brain barrier and enters the cerebral tissue. In recent studies, Mino has been introduced as an antioxidant and anti-apoptotic chemical compound, and therefore, it was examined as a protective candidate against Cd-induced neurotoxicity. In this study, PC12 cells were exposed to Cd alone, or after being pre-treated with Mino. Initially, the cell viability and oxidative stress were analyzed using the MTT assay and fluorimetry, respectively. Then, Cd-induced apoptosis and Mino anti-apoptotic effect were evaluated in both intrinsic and extrinsic pathways using western blot analysis. Exposing PC12 cells to Cd for 24 h decreased cell viability and increased production of reactive oxygen species in comparison with the control group. Cd (35 μM) also elevated the level of caspase-8, Bax/Bcl-2, and caspase-3 proteins in the cells. Mino pre-treatment for 2 h (100 nM) increased the number of viable cells and decreased the production of reactive oxygen species, and the level of all apoptotic markers in comparison to Cd-treated cells. Considering all the evidence, it appears that Mino holds promising antioxidant and anti-apoptotic activity and can protect cells against Cd-induced oxidative stress and prevent apoptotic cell death.
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Affiliation(s)
- Mersedeh Shayan
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soghra Mehri
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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27
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Li N, Yao CY, Diao J, Liu XL, Tang EJ, Huang QS, Zhou YM, Hu YG, Li XK, Long JY, Xiao H, Li DW, Du N, Li YF, Luo P, Cai TJ. The role of MAPK/NF-κB-associated microglial activation in T-2 toxin-induced mouse learning and memory impairment. Food Chem Toxicol 2023; 174:113663. [PMID: 36775139 DOI: 10.1016/j.fct.2023.113663] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/10/2022] [Accepted: 02/09/2023] [Indexed: 02/12/2023]
Abstract
T-2 toxin is a mycotoxin with multiple toxic effects and has emerged as an important food pollutant. Microglia play a significant role in the toxicity of various neurotoxins. However, whether they participate in the neurotoxicity of T-2 toxin has not been reported. To clarify this point, an in vivo mouse model of T-2 toxin (4 mg/kg) poisoning was established. The results of Morris water maze and open-field showed that T-2 toxin induced learning and memory impairment and locomotor inhibition. Meanwhile, T-2 toxin induced microglial activation, while inhibiting microglia activation by minocycline (50 mg/kg) suppressed the toxic effect of the T-2 toxin. To further unveil the potential mechanisms involved in T-2 toxin-induced microglial activation, an in vitro model of T-2 toxin (0, 2.5, 5, 10 ng/mL) poisoning was established using BV-2 cells. Transcriptomic sequencing revealed lots of differentially expressed genes related to MAPK/NF-κB pathway. Western blotting results further confirmed that T-2 toxin (5 ng/mL) induced the activation of MAPKs and their downstream NF-κB. Moreover, the addition of inhibitors of NF-κB and MAPKs reversed the microglial activation induced by T-2 toxin. Overall, microglial activation may contribute a considerable role in T-2 toxin-induced behavioral abnormalities, which could be MAPK/NF-κB pathway dependent.
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Affiliation(s)
- Na Li
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China; Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Chun-Yan Yao
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Jun Diao
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; Chongqing Jiulongpo District Center for Disease Control and Prevention, Chongqing, 400050, China
| | - Xiao-Ling Liu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - En-Jie Tang
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qing-Song Huang
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China; Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yu-Meng Zhou
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yue-Gu Hu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiu-Kuan Li
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China; Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Jin-Yun Long
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China; Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Hua Xiao
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Da-Wei Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Ning Du
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Ya-Fei Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Peng Luo
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China.
| | - Tong-Jian Cai
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China; Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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28
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Poggini S, Banqueri M, Ciano Albanese N, Golia MT, Ibáñez FG, Limatola C, Furhmann M, Lalowski M, Tremblay ME, Maggi L, Kaminska B, Branchi I. Minocycline treatment improves cognitive and functional plasticity in a preclinical mouse model of major depressive disorder. Behav Brain Res 2023; 441:114295. [PMID: 36641083 DOI: 10.1016/j.bbr.2023.114295] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/06/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.
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Affiliation(s)
- Silvia Poggini
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Maria Banqueri
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Naomi Ciano Albanese
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy; PhD program in Behavioral Neurosciences, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
| | - Maria Teresa Golia
- Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
| | - Fernando González Ibáñez
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Centre de recherche du CHU de Québec, Université Laval, Québec, Canada
| | - Cristina Limatola
- Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
| | | | - Maciej Lalowski
- Helsinki Institute for Life Science (HiLIFE) and Faculty of Medicine, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki FI-00014, Finland
| | - Marie-Eve Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Centre de recherche du CHU de Québec, Université Laval, Québec, Canada
| | - Laura Maggi
- Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
| | - Bozena Kaminska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Igor Branchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
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29
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Basurco L, Abellanas MA, Ayerra L, Conde E, Vinueza-Gavilanes R, Luquin E, Vales A, Vilas A, Martin-Uriz PS, Tamayo I, Alonso MM, Hernaez M, Gonzalez-Aseguinolaza G, Clavero P, Mengual E, Arrasate M, Hervás-Stubbs S, Aymerich MS. Microglia and astrocyte activation is region-dependent in the α-synuclein mouse model of Parkinson's disease. Glia 2023; 71:571-587. [PMID: 36353934 PMCID: PMC10100513 DOI: 10.1002/glia.24295] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/16/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration.
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Affiliation(s)
- Leyre Basurco
- Departamentode Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain.,Programa de Neurociencias, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Miguel Angel Abellanas
- Departamentode Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain.,Programa de Neurociencias, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Leyre Ayerra
- Departamentode Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain.,Programa de Neurociencias, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Enrique Conde
- Programa de Inmunología, CIMA-Universidad de Navarra, Pamplona, Spain
| | | | - Esther Luquin
- Departamento de Patología, Anatomía y Fisiología, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain
| | - Africa Vales
- Programa de Terapia Génica, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Amaya Vilas
- Programa de Oncohematología, CIMA-Universidad de Navarra, Pamplona, Spain
| | | | - Ibon Tamayo
- Programa de Biología Computacional, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Marta M Alonso
- Programa de Tumores Sólidos, CIMA-Universidad de Navarra, Pamplona, Spain.,Neurociencias y Salud Mental, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
| | - Mikel Hernaez
- Programa de Biología Computacional, CIMA-Universidad de Navarra, Pamplona, Spain
| | - Gloria Gonzalez-Aseguinolaza
- Programa de Terapia Génica, CIMA-Universidad de Navarra, Pamplona, Spain.,Neurociencias y Salud Mental, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
| | - Pedro Clavero
- Servicio de Neurología, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Elisa Mengual
- Departamento de Patología, Anatomía y Fisiología, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain
| | - Montserrat Arrasate
- Programa de Neurociencias, CIMA-Universidad de Navarra, Pamplona, Spain.,Neurociencias y Salud Mental, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
| | - Sandra Hervás-Stubbs
- Programa de Inmunología, CIMA-Universidad de Navarra, Pamplona, Spain.,Neurociencias y Salud Mental, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
| | - Maria S Aymerich
- Departamentode Bioquímica y Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain.,Programa de Neurociencias, CIMA-Universidad de Navarra, Pamplona, Spain.,Programa de Tumores Sólidos, CIMA-Universidad de Navarra, Pamplona, Spain.,Neurociencias y Salud Mental, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain
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30
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Mathur S, Gawas C, Ahmad IZ, Wani M, Tabassum H. Neurodegenerative disorders: Assessing the impact of natural vs drug-induced treatment options. Aging Med (Milton) 2023; 6:82-97. [PMID: 36911087 PMCID: PMC10000287 DOI: 10.1002/agm2.12243] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/15/2023] [Accepted: 01/29/2023] [Indexed: 02/24/2023] Open
Abstract
Neurodegenerative illnesses refer to the gradual, cumulative loss of neural activity. Neurological conditions are considered to be the second leading cause of mortality in the modern world and the two most prevalent ones are Parkinson's disease and Alzheimer's disease. The negative side effects of pharmaceutical use are a major global concern, despite the availability of many different treatments for therapy. We concentrated on different types of neurological problems and their influence on targets, in vitro, in vivo, and in silico methods toward neurological disorders, as well as the molecular approaches influencing the same, in the first half of the review. The bulk of the second half of the review focuses on the many categories of treatment possibilities, including natural and artificial. Nevertheless, herbal treatment solutions are piquing scholarly attention due to their anti-oxidative properties and accessibility. However, more quality investigations and innovations are undoubtedly needed to back up these conclusions.
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Affiliation(s)
- Sakshi Mathur
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil VidyapeethPuneMaharashtraIndia
| | - Chaitali Gawas
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil VidyapeethPuneMaharashtraIndia
| | | | - Minal Wani
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil VidyapeethPuneMaharashtraIndia
| | - Heena Tabassum
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil VidyapeethPuneMaharashtraIndia
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31
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SAJI R, UCHIO R, FUWA A, OKUDA-HANAFUSA C, KAWASAKI K, MUROYAMA K, MUROSAKI S, YAMAMOTO Y, HIROSE Y. Turmeronols (A and B) from Curcuma longa have anti-inflammatory effects in lipopolysaccharide-stimulated BV-2 microglial cells by reducing NF-κB signaling. BIOSCIENCE OF MICROBIOTA, FOOD AND HEALTH 2023; 42:172-179. [PMID: 37404570 PMCID: PMC10315188 DOI: 10.12938/bmfh.2022-071] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/10/2023] [Indexed: 07/06/2023]
Abstract
Turmeronols (A and B), bisabolane-type sesquiterpenoids found in turmeric, reduce inflammation outside the brain in animals; however, their effects on neuroinflammation, a common pathology of various neurodegenerative diseases, are not understood. Inflammatory mediators produced by microglial cells play a key role in neuroinflammation, so this study evaluated the anti-inflammatory effects of turmeronols in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Pretreatment with turmeronol A or B significantly inhibited LPS-induced nitric oxide (NO) production; mRNA expression of inducible NO synthase; production of interleukin (IL)-1β, IL-6, and tumor necrosis factor α and upregulation of their mRNA expression; phosphorylation of nuclear factor-κB (NF-κB) p65 proteins and inhibitor of NF-κB kinase (IKK); and nuclear translocation of NF-κB. These results suggest that these turmeronols may prevent the production of inflammatory mediators by inhibiting the IKK/NF-κB signaling pathway in activated microglial cells and can potentially treat neuroinflammation associated with microglial activation.
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Affiliation(s)
- Ryosuke SAJI
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Ryusei UCHIO
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Arisa FUWA
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Chinatsu OKUDA-HANAFUSA
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Kengo KAWASAKI
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Koutarou MUROYAMA
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Shinji MUROSAKI
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Yoshihiro YAMAMOTO
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
| | - Yoshitaka HIROSE
- Research & Development Institute, House Wellness Foods
Corporation, 3-20 Imoji, Itami-shi, Hyogo 664-0011, Japan
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32
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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33
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Morén C, Treder N, Martínez-Pinteño A, Rodríguez N, Arbelo N, Madero S, Gómez M, Mas S, Gassó P, Parellada E. Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia. Antioxidants (Basel) 2022; 11:2275. [PMID: 36421461 PMCID: PMC9686909 DOI: 10.3390/antiox11112275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 09/15/2023] Open
Abstract
Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmitter-systems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychotic-symptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages.
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Affiliation(s)
- Constanza Morén
- Barcelona Clínic Schizophrenia Unit (BCSU), Institute of Neuroscience, Psychiatry and Psychology Service, Hospital Clínic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
- Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- U722 Group, Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, Carlos III Health Institute, 28029 Madrid, Spain
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
| | - Nina Treder
- Faculty of Psychology and Neuroscience, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Albert Martínez-Pinteño
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
| | - Natàlia Rodríguez
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
| | - Néstor Arbelo
- Barcelona Clínic Schizophrenia Unit (BCSU), Institute of Neuroscience, Psychiatry and Psychology Service, Hospital Clínic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
| | - Santiago Madero
- Barcelona Clínic Schizophrenia Unit (BCSU), Institute of Neuroscience, Psychiatry and Psychology Service, Hospital Clínic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
| | - Marta Gómez
- Barcelona Clínic Schizophrenia Unit (BCSU), Institute of Neuroscience, Psychiatry and Psychology Service, Hospital Clínic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
- Department of Psychiatry, Servizo Galego de Saúde (SERGAS), 36001 Pontevedra, Spain
| | - Sergi Mas
- Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
| | - Patricia Gassó
- Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
| | - Eduard Parellada
- Barcelona Clínic Schizophrenia Unit (BCSU), Institute of Neuroscience, Psychiatry and Psychology Service, Hospital Clínic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
- Clinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, 08036 Barcelona, Spain
- G04 Group, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, 28029 Madrid, Spain
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Silva DF, Empadinhas N, Cardoso SM, Esteves AR. Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation. Antioxidants (Basel) 2022; 11:2141. [PMID: 36358513 PMCID: PMC9686748 DOI: 10.3390/antiox11112141] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 04/18/2025] Open
Abstract
Inflammation and oxidative stress characterize a number of chronic conditions including neurodegenerative diseases and aging. Inflammation is a key component of the innate immune response in Alzheimer's disease and Parkinson's disease of which oxidative stress is an important hallmark. Immune dysregulation and mitochondrial dysfunction with concomitant reactive oxygen species accumulation have also been implicated in both diseases, both systemically and within the Central Nervous System. Mitochondria are a centrally positioned signalling hub for inflammatory responses and inflammatory cells can release reactive species at the site of inflammation often leading to exaggerated oxidative stress. A growing body of evidence suggests that disruption of normal gut microbiota composition may induce increased permeability of the gut barrier leading to chronic systemic inflammation, which may, in turn, impair the blood-brain barrier function and promote neuroinflammation and neurodegeneration. The gastrointestinal tract is constantly exposed to myriad exogenous substances and microbial pathogens, which are abundant sources of reactive oxygen species, oxidative damage and pro-inflammatory events. Several studies have demonstrated that microbial infections may also affect the balance in gut microbiota composition (involving oxidant and inflammatory processes by the host and indigenous microbiota) and influence downstream Alzheimer's disease and Parkinson's disease pathogenesis, in which blood-brain barrier damage ultimately occurs. Therefore, the oxidant/inflammatory insults triggered by a disrupted gut microbiota and chronic dysbiosis often lead to compromised gut barrier function, allowing inflammation to "escape" as well as uncontrolled immune responses that may ultimately disrupt mitochondrial function upwards the brain. Future therapeutic strategies should be designed to "restrain" gut inflammation, a goal that could ideally be attained by microbiota modulation strategies, in alternative to classic anti-inflammatory agents with unpredictable effects on the microbiota architecture itself.
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Affiliation(s)
- Diana Filipa Silva
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Nuno Empadinhas
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Sandra Morais Cardoso
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Ana Raquel Esteves
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
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The Interplay between Gut Microbiota and Parkinson's Disease: Implications on Diagnosis and Treatment. Int J Mol Sci 2022; 23:ijms232012289. [PMID: 36293176 PMCID: PMC9603886 DOI: 10.3390/ijms232012289] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
The bidirectional interaction between the gut microbiota (GM) and the Central Nervous System, the so-called gut microbiota brain axis (GMBA), deeply affects brain function and has an important impact on the development of neurodegenerative diseases. In Parkinson’s disease (PD), gastrointestinal symptoms often precede the onset of motor and non-motor manifestations, and alterations in the GM composition accompany disease pathogenesis. Several studies have been conducted to unravel the role of dysbiosis and intestinal permeability in PD onset and progression, but the therapeutic and diagnostic applications of GM modifying approaches remain to be fully elucidated. After a brief introduction on the involvement of GMBA in the disease, we present evidence for GM alterations and leaky gut in PD patients. According to these data, we then review the potential of GM-based signatures to serve as disease biomarkers and we highlight the emerging role of probiotics, prebiotics, antibiotics, dietary interventions, and fecal microbiota transplantation as supportive therapeutic approaches in PD. Finally, we analyze the mutual influence between commonly prescribed PD medications and gut-microbiota, and we offer insights on the involvement also of nasal and oral microbiota in PD pathology, thus providing a comprehensive and up-to-date overview on the role of microbial features in disease diagnosis and treatment.
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Tomas-Grau R, González-Lizárraga F, Ploper D, Avila CL, Socías SB, Besnault P, Tourville A, Mella RM, Villacé P, Salado C, Rose C, Seon-Méniel B, Brunel JM, Ferrié L, Raisman-Vozari R, Michel PP, Figadère B, Chehín R. Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound. Cells 2022; 11:cells11172759. [PMID: 36078167 PMCID: PMC9454755 DOI: 10.3390/cells11172759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 12/09/2022] Open
Abstract
The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-SynPFF) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-SynPFF less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson's disease and other synucleinopathies.
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Affiliation(s)
- Rodrigo Tomas-Grau
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
| | - Florencia González-Lizárraga
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
| | - Diego Ploper
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
| | - César L. Avila
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
| | - Sergio B. Socías
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
| | - Pierre Besnault
- Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France
| | - Aurore Tourville
- Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France
| | - Rosa M. Mella
- Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain
| | - Patricia Villacé
- Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain
| | - Clarisa Salado
- Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain
| | - Clémence Rose
- BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France
| | | | - Jean-Michel Brunel
- UMR_MD1 “Membranes et Cibles Thérapeutiques”, U1261 INSERM, Aix-Marseille Université, 13385 Marseille, France
| | - Laurent Ferrié
- BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France
| | - Rita Raisman-Vozari
- Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France
| | - Patrick P. Michel
- Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France
| | - Bruno Figadère
- BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France
- Correspondence: (B.F.); (R.C.)
| | - Rosana Chehín
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina
- Correspondence: (B.F.); (R.C.)
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Antibiotic Consumption Patterns in European Countries Are Associated with the Prevalence of Parkinson’s Disease; the Possible Augmenting Role of the Narrow-Spectrum Penicillin. Antibiotics (Basel) 2022; 11:antibiotics11091145. [PMID: 36139924 PMCID: PMC9494973 DOI: 10.3390/antibiotics11091145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/19/2022] [Accepted: 08/21/2022] [Indexed: 11/19/2022] Open
Abstract
Parkinson’s disease: Parkinson’s disease (PD) is the second-most common neurodegenerative disease, affecting at least 0.3% of the worldwide population and over 3% of those over 80 years old. According to recent research (2018), in 2016, 6.1 million (95% uncertainty interval (UI) 5.0–7.3) individuals had Parkinson’s disease globally, compared with 2.5 million (2.0–3.0) in 1990. The pandemic-like spreading of PD is considered a slow-moving disaster. Most recent studies indicated the possible role of an altered microbiome, dysbiosis, in the development of PD, which occurs long before the clinical diagnosis of PD. Antibiotics are considered as major disruptors of the intestinal flora and we have hypothesized that, as different classes of antibiotics might induce different dysbiosis, certain classes of antibiotics could trigger the PD-related dysbiosis as well. Comparative analyses were performed between the average yearly antibiotic consumption of 30 European countries (1997–2016) and the PD prevalence database (estimated for 2016). We divided the time frame of antibiotic consumption of 1997–2016 into four subsections to estimate the possible time lapse between antibiotic exposure and the prevalence, prevalence change, and PD-related death rates estimated for 2016. Our results indicated that countries with high consumption of narrow-spectrum penicillin experienced a higher increase in PD prevalence than the others. Countries reporting a decline in PD from 1990 to 2016 demonstrated a reduction in the consumption of narrow-spectrum penicillin in this period.
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Stykel MG, Ryan SD. Nitrosative stress in Parkinson's disease. NPJ Parkinsons Dis 2022; 8:104. [PMID: 35953517 PMCID: PMC9372037 DOI: 10.1038/s41531-022-00370-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 07/26/2022] [Indexed: 12/13/2022] Open
Abstract
Parkinson’s Disease (PD) is a neurodegenerative disorder characterized, in part, by the loss of dopaminergic neurons within the nigral-striatal pathway. Multiple lines of evidence support a role for reactive nitrogen species (RNS) in degeneration of this pathway, specifically nitric oxide (NO). This review will focus on how RNS leads to loss of dopaminergic neurons in PD and whether RNS accumulation represents a central signal in the degenerative cascade. Herein, we provide an overview of how RNS accumulates in PD by considering the various cellular sources of RNS including nNOS, iNOS, nitrate, and nitrite reduction and describe evidence that these sources are upregulating RNS in PD. We document that over 1/3 of the proteins that deposit in Lewy Bodies, are post-translationally modified (S-nitrosylated) by RNS and provide a broad description of how this elicits deleterious effects in neurons. In doing so, we identify specific proteins that are modified by RNS in neurons which are implicated in PD pathogenesis, with an emphasis on exacerbation of synucleinopathy. How nitration of alpha-synuclein (aSyn) leads to aSyn misfolding and toxicity in PD models is outlined. Furthermore, we delineate how RNS modulates known PD-related phenotypes including axo-dendritic-, mitochondrial-, and dopamine-dysfunctions. Finally, we discuss successful outcomes of therapeutics that target S-nitrosylation of proteins in Parkinson’s Disease related clinical trials. In conclusion, we argue that targeting RNS may be of therapeutic benefit for people in early clinical stages of PD.
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Affiliation(s)
- Morgan G Stykel
- The Department of Molecular and Cellular Biology, The University of Guelph, Guelph, ON N1G 2W1, ON, Canada
| | - Scott D Ryan
- The Department of Molecular and Cellular Biology, The University of Guelph, Guelph, ON N1G 2W1, ON, Canada. .,Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA.
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Lim JJ, Hyun S. Minocycline treatment improves proteostasis during Drosophila aging via autophagy mediated by FOXO and Hsp70. Biomed Pharmacother 2022; 149:112803. [PMID: 35286967 DOI: 10.1016/j.biopha.2022.112803] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 11/02/2022] Open
Abstract
Minocycline is a semi-synthetic tetracycline derivative antibiotic that has been examined for its non-antibiotic properties, such as anti-inflammatory, tumor-suppressive, and neuroprotective effects. In this study, we found that feeding minocycline to Drosophila improves proteostasis during organismal aging. Poly-ubiquitinated protein aggregates increase in the flight muscles as flies age, which are reduced in response to minocycline feeding. Minocycline feeding increases the expression of several autophagy genes and the activity of the autophagy/lysosomal pathway in Drosophila muscles. Interestingly, mutant flies lacking either FOXO or Hsp70 showed increased levels of poly-ubiquitinated protein aggregates with reduced autophagy/lysosomal activity, which was not reversed by minocycline feeding. Our findings suggest that minocycline may improve proteostasis in aging tissues via FOXO-Hsp70 axis, which highlights the multifaceted effects of minocycline as a therapeutic agent in age-associated features.
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Affiliation(s)
- Jin Ju Lim
- Department of Life Science, Chung-Ang University, Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
| | - Seogang Hyun
- Department of Life Science, Chung-Ang University, Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea.
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40
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GM1 ganglioside modifies microglial and neuroinflammatory responses to α-synuclein in the rat AAV-A53T α-synuclein model of Parkinson's disease. Mol Cell Neurosci 2022; 120:103729. [DOI: 10.1016/j.mcn.2022.103729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 11/18/2022] Open
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Guo T, Chen L. Gut microbiota and inflammation in Parkinson’s disease: Pathogenetic and therapeutic insights. EUR J INFLAMM 2022. [DOI: 10.1177/1721727x221083763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss and α-synuclein (α-syn) aggregation. With the acceleration of population aging process, the incidence of PD is expected to increase, putting a heavy burden on the whole society. Recent studies have found the alterations of gut microbiota (GM) in PD patients and the clinical relevance of these changes, indicating the underlying relationship between GM and PD. Additionally, elevated inflammatory responses originating from the gut play a crucial role in the initiation and progression of PD, which is closely associated with GM. In this review, we will summarize recent studies on the correlation between GM and PD, and discuss the possible pathogenesis of PD mediated by GM and subsequent inflammatory cascades. We will also focus on the promising GM-based therapeutic strategies of PD, including antibiotics, probiotics and/or prebiotics, fecal microbiota transplantation, and dietary interventions, aiming to provide some new therapeutic insights for PD.
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Affiliation(s)
- Tong Guo
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Li Chen
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, China
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Wang SK, Cepko CL. Targeting Microglia to Treat Degenerative Eye Diseases. Front Immunol 2022; 13:843558. [PMID: 35251042 PMCID: PMC8891158 DOI: 10.3389/fimmu.2022.843558] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 01/31/2022] [Indexed: 12/29/2022] Open
Abstract
Microglia have been implicated in many degenerative eye disorders, including retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, uveitis, and retinal detachment. While the exact roles of microglia in these conditions are still being discovered, evidence from animal models suggests that they can modulate the course of disease. In this review, we highlight current strategies to target microglia in the eye and their potential as treatments for both rare and common ocular disorders. These approaches include depleting microglia with chemicals or radiation, reprogramming microglia using homeostatic signals or other small molecules, and inhibiting the downstream effects of microglia such as by blocking cytokine activity or phagocytosis. Finally, we describe areas of future research needed to fully exploit the therapeutic value of microglia in eye diseases.
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Affiliation(s)
- Sean K. Wang
- Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Constance L. Cepko
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
- Howard Hughes Medical Institute, Chevy Chase, MD, United States
- *Correspondence: Constance L. Cepko,
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Linetsky E, Abd Elhadi S, Bauer M, Gallant A, Namnah M, Weiss S, Segal D, Sharon R, Arkadir D. Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease. Front Neurol 2022; 12:716126. [PMID: 35046880 PMCID: PMC8761891 DOI: 10.3389/fneur.2021.716126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 12/10/2021] [Indexed: 11/13/2022] Open
Abstract
Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of α-synuclein fibrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible benefit, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identifier: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efficacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6/14 participants on mannitol. None of the clinical or biochemical efficacy secondary outcome measures significantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These findings should be considered in the design of future efficacy trials.
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Affiliation(s)
- Eduard Linetsky
- Department of Neurology, Faculty of Medicine, Hadassah Medical Organization, Hebrew University, Jerusalem, Israel
| | - Suaad Abd Elhadi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Max Bauer
- Department of Neurology, Faculty of Medicine, Hadassah Medical Organization, Hebrew University, Jerusalem, Israel
| | - Akiva Gallant
- Department of Neurology, Faculty of Medicine, Hadassah Medical Organization, Hebrew University, Jerusalem, Israel
| | - Montaser Namnah
- Department of Neurology, Faculty of Medicine, Hadassah Medical Organization, Hebrew University, Jerusalem, Israel
| | | | - Daniel Segal
- Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv, Israel
| | - Ronit Sharon
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, Israel
| | - David Arkadir
- Department of Neurology, Faculty of Medicine, Hadassah Medical Organization, Hebrew University, Jerusalem, Israel
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Abstract
The notion that autoimmune responses to α-synuclein may be involved in the pathogenesis of this disorder stems from reports that mutations in α-synuclein or certain alleles of the major histocompatibility complex (MHC) are associated with the disease and that dopaminergic and norepinephrinergic neurons in the midbrain can present antigenic epitopes. Here, we discuss recent evidence that a defined set of peptides derived from α-synuclein act as antigenic epitopes displayed by specific MHC alleles and drive helper and cytotoxic T cell responses in patients with PD. Moreover, phosphorylated α-synuclein may activate T cell responses in a less restricted manner in PD. While the roles for the acquired immune system in disease pathogenesis remain unknown, preclinical animal models and in vitro studies indicate that T cells may interact with neurons and exert effects related to neuronal death and neuroprotection. These findings suggest that therapeutics that target T cells and ameliorate the incidence or disease severity of inflammatory bowel disorders or CNS autoimmune diseases such as multiple sclerosis may be useful in PD.
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Klann EM, Dissanayake U, Gurrala A, Farrer M, Shukla AW, Ramirez-Zamora A, Mai V, Vedam-Mai V. The Gut-Brain Axis and Its Relation to Parkinson's Disease: A Review. Front Aging Neurosci 2022; 13:782082. [PMID: 35069178 PMCID: PMC8776990 DOI: 10.3389/fnagi.2021.782082] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/18/2021] [Indexed: 02/02/2023] Open
Abstract
Parkinson's disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome-gut-brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome-gut-brain axis might play in the underlying pathological mechanisms of Parkinson's disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson's disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome-gut-brain axis in the context of Parkinson's disease.
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Affiliation(s)
- Emily M. Klann
- Department of Epidemiology, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL, United States
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, United States
| | - Upuli Dissanayake
- Department of Epidemiology, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL, United States
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, United States
| | - Anjela Gurrala
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Matthew Farrer
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Aparna Wagle Shukla
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
| | - Adolfo Ramirez-Zamora
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
| | - Volker Mai
- Department of Epidemiology, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL, United States
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, United States
| | - Vinata Vedam-Mai
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
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Markulin I, Matasin M, Turk VE, Salković-Petrisic M. Challenges of repurposing tetracyclines for the treatment of Alzheimer's and Parkinson's disease. J Neural Transm (Vienna) 2022; 129:773-804. [PMID: 34982206 DOI: 10.1007/s00702-021-02457-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022]
Abstract
The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.
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Affiliation(s)
- Iva Markulin
- Community Health Centre Zagreb-Centre, Zagreb, Croatia
| | | | - Viktorija Erdeljic Turk
- Division of Clinical Pharmacology, Department of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Melita Salković-Petrisic
- Department of Pharmacology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.
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Hogg E, Frank S, Oft J, Benway B, Rashid MH, Lahiri S. Urinary Tract Infection in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2022; 12:743-757. [PMID: 35147552 PMCID: PMC9108555 DOI: 10.3233/jpd-213103] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/26/2022] [Indexed: 11/27/2022]
Abstract
Urinary tract infection (UTI) is a common precipitant of acute neurological deterioration in patients with Parkinson's disease (PD) and a leading cause of delirium, functional decline, falls, and hospitalization. Various clinical features of PD including autonomic dysfunction and altered urodynamics, frailty and cognitive impairment, and the need for bladder catheterization contribute to an increased risk of UTI. Sepsis due to UTI is a feared consequence of untreated or undertreated UTI and a leading cause of morbidity in PD. Emerging research suggests that immune-mediated brain injury may underlie the pathogenesis of UTI-induced deterioration of PD symptoms. Existing strategies to prevent UTI in patients with PD include use of topical estrogen, prophylactic supplements, antibiotic bladder irrigation, clean catheterization techniques, and prophylactic oral antibiotics, while bacterial interference and vaccines/immunostimulants directed against common UTI pathogens are potentially emerging strategies that are currently under investigation. Future research is needed to mitigate the deleterious effects of UTI in PD.
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Affiliation(s)
- Elliot Hogg
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Samuel Frank
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jillian Oft
- Department of Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Brian Benway
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Shouri Lahiri
- Departments of Neurology, Neurosurgery, and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Saleh M, Markovic M, Olson KE, Gendelman HE, Mosley RL. Therapeutic Strategies for Immune Transformation in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2022; 12:S201-S222. [PMID: 35871362 PMCID: PMC9535567 DOI: 10.3233/jpd-223278] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 06/20/2022] [Indexed: 12/16/2022]
Abstract
Dysregulation of innate and adaptive immunity can lead to alpha-synuclein (α-syn) misfolding, aggregation, and post-translational modifications in Parkinson's disease (PD). This process is driven by neuroinflammation and oxidative stress, which can contribute to the release of neurotoxic oligomers that facilitate dopaminergic neurodegeneration. Strategies that promote vaccines and antibodies target the clearance of misfolded, modified α-syn, while gene therapy approaches propose to deliver intracellular single chain nanobodies to mitigate α-syn misfolding, or to deliver neurotrophic factors that support neuronal viability in an otherwise neurotoxic environment. Additionally, transformative immune responses provide potential targets for PD therapeutics. Anti-inflammatory drugs represent one strategy that principally affects innate immunity. Considerable research efforts have focused on transforming the balance of pro-inflammatory effector T cells (Teffs) to favor regulatory T cell (Treg) activity, which aims to attenuate neuroinflammation and support reparative and neurotrophic homeostasis. This approach serves to control innate microglial neurotoxic activities and may facilitate clearance of α-syn aggregates accordingly. More recently, changes in the intestinal microbiome have been shown to alter the gut-immune-brain axis leading to suppressed leakage of bacterial products that can promote peripheral inflammation and α-syn misfolding. Together, each of the approaches serves to interdict chronic inflammation associated with disordered immunity and neurodegeneration. Herein, we examine research strategies aimed at improving clinical outcomes in PD.
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Affiliation(s)
- Maamoon Saleh
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA
| | - Milica Markovic
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA
| | - Katherine E. Olson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA
| | - Howard E. Gendelman
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA
| | - R. Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA
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Yadav RK, Mehan S, Sahu R, Kumar S, Khan A, Makeen HA, Al Bratty M. Protective effects of apigenin on methylmercury-induced behavioral/neurochemical abnormalities and neurotoxicity in rats. Hum Exp Toxicol 2022; 41:9603271221084276. [PMID: 35373622 DOI: 10.1177/09603271221084276] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Methylmercury (MeHg) is a neurotoxin that induces neurotoxicity and cell death in neurons. MeHg increases oligodendrocyte death, glial cell activation, and motor neuron demyelination in the motor cortex and spinal cord. As a result, MeHg plays an important role in developing neurocomplications similar to amyotrophic lateral sclerosis (ALS). Recent research has implicated c-JNK and p38MAPK overactivation in the pathogenesis of ALS. Apigenin (APG) is a flavonoid having anti-inflammatory, antioxidant, and c-JNK/p38MAPK inhibitory activities. The purpose of this study is to determine whether APG possesses neuroprotective effects in MeHg-induced neurotoxicity in adult rats associated with ALS-like neuropathological alterations. In the current study, the neurotoxin MeHg causes an ALS-like phenotype in Wistar rats after 21 days of oral administration at a dose of 5 mg/kg. Prolonged administration of APG (40 and 80 mg/kg) improved neurobehavioral parameters such as learning memory, cognition, motor coordination, and grip strength. This is mainly associated with the downregulation of c-JNK and p38MAPK signaling as well as the restoration of myelin basic protein within the brain. Furthermore, APG inhibited neuronal apoptotic markers (Bax, Bcl-2, and caspase-3), restored neurotransmitter imbalance, decreased inflammatory markers (TNF- and IL-1), and alleviated oxidative damage. As a result, the current study shows that APG has neuroprotective potential as a c-JNK and p38MAPK signaling inhibitor against MeHg-induced neurotoxicity in adult rats. Based on these promising findings, we suggested that APG could be a potential new therapeutic approach over other conventional therapeutic approaches for MeHg-induced neurotoxicity in neurobehavioral, molecular, and neurochemical abnormalities.
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Affiliation(s)
- Rajeshwar Kumar Yadav
- Neuropharmacology Division, Department of Pharmacology, 75126ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, 75126ISF College of Pharmacy, Moga, Punjab, India
| | - Rakesh Sahu
- Neuropharmacology Division, Department of Pharmacology, 75126ISF College of Pharmacy, Moga, Punjab, India
| | - Sumit Kumar
- Neuropharmacology Division, Department of Pharmacology, 75126ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, 123285Jazan University, Jazan, Saudi Arabia
| | - Hafiz Antar Makeen
- Department of Clinical Pharmacy, College of Pharmacy, 123285Jazan University, Jazan, Saudi Arabia
| | - Mohammed Al Bratty
- Department of Pharmaceutical Chemistry, College of Pharmacy, 123285Jazan University, Jazan, Saudi Arabia
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Maneshian M, Nasirinezhad F, Mohammadi F, Behzadi M, Asadi-Shekaari M, Shabani M. Minocycline Mitigation of Tremor Syndrome and Defect of Cognitive and Balance Induced by Harmaline. Basic Clin Neurosci 2021; 12:255-268. [PMID: 34925722 PMCID: PMC8672663 DOI: 10.32598/bcn.12.2.1980.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/05/2020] [Accepted: 11/13/2020] [Indexed: 11/24/2022] Open
Abstract
Introduction: Minocycline has anti-inflammatory, anti-apoptotic, and anti-oxidant effects. Preclinical data suggest that minocycline could be beneficial for treating common neurological disorders, including Parkinson disease and multiple sclerosis. Methods: In this study, the effects of minocycline on harmaline-induced motor and cognitive impairments were studied in male Wistar rats. The rats were divided into four groups of ten animals each. Harmaline was used for the induction of Essential Tremor (ET). Minocycline (90 mg/kg, IP) was administered 30 minutes before the saline or harmaline. Tremor intensity, spontaneous locomotor activity, passive avoidance memory, anxiety-related behaviors, and motor function were assessed in the rats. Results: The results showed that minocycline could recover tremor intensity and step width but failed to recuperate the motor balance. The memory impairments observed in harmaline-treated rats were somewhat reversed by administration of minocycline. The cerebellum and inferior olive nucleus were studied for neuronal degeneration using histochemistry and transmission electron microscopy techniques. Harmaline caused ultrastructural changes and neuronal cell loss in inferior olive and cerebellar Purkinje cells. Minocycline exhibited neuroprotective changes on cerebellar Purkinje cells and inferior olivary neurons. Conclusion: These results open new therapeutic perspectives for motor and memory impairments in ET. However, further studies are needed to clarify the exact mechanisms.
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Affiliation(s)
- Marzieh Maneshian
- Department of Physiology, Physiological Research Center, Iran University of Medical Sciences, Tehran, Iran.,Intracellular Recording Lab, Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Farinaz Nasirinezhad
- Department of Physiology, Physiological Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammadi
- Intracellular Recording Lab, Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Mina Behzadi
- Intracellular Recording Lab, Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Asadi-Shekaari
- Intracellular Recording Lab, Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Shabani
- Intracellular Recording Lab, Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
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