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Ekwudo MN, Gubert C, Hannan AJ. The microbiota-gut-brain axis in Huntington's disease: pathogenic mechanisms and therapeutic targets. FEBS J 2025; 292:1282-1315. [PMID: 38426291 PMCID: PMC11927060 DOI: 10.1111/febs.17102] [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: 10/13/2023] [Revised: 01/08/2024] [Accepted: 02/14/2024] [Indexed: 03/02/2024]
Abstract
Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'.
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Affiliation(s)
- Millicent N. Ekwudo
- Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
| | - Carolina Gubert
- Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
| | - Anthony J. Hannan
- Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
- Department of Anatomy and PhysiologyUniversity of MelbourneParkvilleAustralia
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Biancotti JC, Sescleifer AM, Sferra SR, Penikis AB, Halbert-Elliott KM, Bubb CR, Kunisaki SM. Maternal Minocycline as Fetal Therapy in a Rat Model of Myelomeningocele. J Surg Res 2024; 301:696-703. [PMID: 39168042 DOI: 10.1016/j.jss.2024.07.088] [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: 02/27/2024] [Revised: 07/11/2024] [Accepted: 07/19/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION This study aimed to investigate whether the maternal administration of minocycline, a tetracycline antibiotic known to have anti-inflammatory and neuroprotective properties in models of neural injury, reduces inflammation and neural cell death in a fetal rat model of myelomeningocele (MMC). METHODS E10 pregnant rats were gavaged with olive oil or olive oil + retinoic acid to induce fetal MMC. At E12, the dams were exposed to regular drinking water or water containing minocycline (range, 40-140 mg/kg/day). At E21, fetal lumbosacral spinal cords were isolated for immunohistochemistry and quantitative gene expression studies focused on microglia activity, inflammation, and apoptosis (P < 0.05). RESULTS There was a trend toward decreased activated Iba1+ microglial cells within the dorsal spinal cord of MMC pups following minocycline exposure when compared to water (H2O) alone (P = 0.052). Prenatal minocycline exposure was correlated with significantly reduced expression of the proinflammatory cytokine, IL-6 (minocycline: 1.75 versus H2O: 3.52, P = 0.04) and apoptosis gene, Bax (minocycline: 0.71 versus H2O: 1.04, P < 0.001) among MMC pups. CONCLUSIONS This study found evidence that the maternal administration of minocycline reduces selected markers of inflammation and apoptosis within the exposed dorsal spinal cords of fetal MMC rats. Further study of minocycline as a novel prenatal treatment strategy to mitigate spinal cord damage in MMC is warranted.
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Affiliation(s)
- Juan C Biancotti
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Anne M Sescleifer
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Shelby R Sferra
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Annalise B Penikis
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Kyra M Halbert-Elliott
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ciaran R Bubb
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Shaun M Kunisaki
- Division of General Pediatric Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland.
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Saha P, Saha R, Datta Chaudhuri R, Sarkar R, Sarkar M, Koley H, Chawla-Sarkar M. Unveiling the Antiviral Potential of Minocycline: Modulation of Nuclear Export of Viral Ribonuclear Proteins during Influenza Virus Infection. Viruses 2024; 16:1317. [PMID: 39205291 PMCID: PMC11359333 DOI: 10.3390/v16081317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Influenza A virus (IAV) poses a global threat worldwide causing pandemics, epidemics, and seasonal outbreaks. Annual modification of vaccines is costly due to continual shifts in circulating genotypes, leading to inadequate coverage in low- and middle-income countries like India. Additionally, IAVs are evolving resistance to approved antivirals, necessitating a search for alternative treatments. In this study, the antiviral role of the FDA-approved antibiotic minocycline against IAV strains was evaluated in vitro and in vivo by quantifying viral gene expression by qRT-PCR, viral protein levels by Western blotting, and viral titers. Our findings demonstrate that minocycline at a non-toxic dose effectively inhibits IAV replication, regardless of viral strain or cell line. Its antiviral mechanism operates independently of interferon signaling by targeting the MEK/ERK signaling pathway, which is crucial for the export of viral ribonucleoproteins (vRNPs). Minocycline prevents the assembly and release of infectious viral particles by causing the accumulation of vRNPs within the nucleus. Moreover, minocycline also inhibits IAV-induced late-stage apoptosis, further suppressing viral propagation. The antiviral activity of minocycline against IAVs could offer a promising solution amidst the challenges posed by influenza and the limitations of current treatments.
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Affiliation(s)
- Priyanka Saha
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Ritubrita Saha
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Ratul Datta Chaudhuri
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Rakesh Sarkar
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Mehuli Sarkar
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Hemanta Koley
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
| | - Mamta Chawla-Sarkar
- Division of Virology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
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Field SE, Curle AJ, Barker RA. Inflammation and Huntington's disease - a neglected therapeutic target? Expert Opin Investig Drugs 2024; 33:451-467. [PMID: 38758356 DOI: 10.1080/13543784.2024.2348738] [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: 12/19/2023] [Accepted: 04/24/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD. AREAS COVERED To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system. EXPERT OPINION We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.
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Affiliation(s)
- Sophie E Field
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Annabel J Curle
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Roger A Barker
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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Tang Y, Chatterjee J, Wagoner N, Bozeman S, Gutmann DH. Estrogen-induced glial IL-1β mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma. Ann Clin Transl Neurol 2024; 11:812-818. [PMID: 38229454 PMCID: PMC10963305 DOI: 10.1002/acn3.51995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/18/2024] Open
Abstract
Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1β (IL-1β), which is neurotoxic to RGCs in vitro. Importantly, both IL-1β neutralization and leuprolide-mediated estrogen suppression decrease IL-1β expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss.
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Affiliation(s)
- Yunshuo Tang
- Department of NeurologyWashington University School of MedicineSt. LouisMissouri63110USA
- Department of OphthalmologyWashington University School of MedicineSt. LouisMissouri63110USA
| | - Jit Chatterjee
- Department of NeurologyWashington University School of MedicineSt. LouisMissouri63110USA
| | - Ngan Wagoner
- Department of NeurologyWashington University School of MedicineSt. LouisMissouri63110USA
| | - Stephanie Bozeman
- Department of NeurologyWashington University School of MedicineSt. LouisMissouri63110USA
| | - David H. Gutmann
- Department of NeurologyWashington University School of MedicineSt. LouisMissouri63110USA
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Moqadami A, Khalaj-Kondori M, Hosseinpour Feizi MA, Baradaran B. Minocycline declines interleukin-1ß-induced apoptosis and matrix metalloproteinase expression in C28/I2 chondrocyte cells: an in vitro study on osteoarthritis. EXCLI JOURNAL 2024; 23:114-129. [PMID: 38487083 PMCID: PMC10938238 DOI: 10.17179/excli2023-6710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/15/2024] [Indexed: 03/17/2024]
Abstract
Osteoarthritis (OA) is a degenerative joint disease that occurs with aging. In its late phases, it is determined by the loss of chondrocytes and the breakdown of the extracellular matrix, resulting in pain and functional impairment. Interleukin-1 beta (IL-1β) is increased in the injured joints and contributes to the OA pathobiology by inducing chondrocyte apoptosis and up-regulation of matrix metalloproteinases (MMPs). Here, we aimed to understand whether minocycline could protect chondrocytes against the IL-1β-induced effects. The human C28/I2 chondrocyte cell line was treated with IL-1β or IL-1β plus minocycline. Cell viability/toxicity, cell cycle progression, and apoptosis were assessed with MMT assay and flow cytometry. Expression of apoptotic genes and MMPs were evaluated with qRT-PCR and western blotting. IL-1β showed a significant cytotoxic effect on the C28/I2 chondrocyte cells. The minocycline effective concentration (EC50) significantly protected the C28/I2 cells against the IL-1β-induced cytotoxic effect. Besides, minocycline effectively lowered IL-1β-induced sub-G1 cell population increase, indicating the minocycline anti-apoptotic effect. When assessed by real-time PCR and western blotting, the minocycline treatment group showed an elevated level of Bcl-2 and a significant decrease in the mRNA and protein expression of the apoptotic markers Bax and Caspase-3 and Matrix metalloproteinases (MMPs) such as MMP-3 and MMP-13. In conclusion, IL-1β promotes OA by inducing chondrocyte death and MMPs overexpression. Treatment with minocycline reduces these effects and decreases the production of apoptotic factors as well as the MMP-3 and MMP-13. Minocycline might be considered as an anti-IL-1β therapeutic supplement in the treatment of osteoarthritis. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Amin Moqadami
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Peruch M, Giacomello E, Radaelli D, Concato M, Addobbati R, Fluca AL, Aleksova A, D’Errico S. Subcellular Effectors of Cocaine Cardiotoxicity: All Roads Lead to Mitochondria-A Systematic Review of the Literature. Int J Mol Sci 2023; 24:14517. [PMID: 37833964 PMCID: PMC10573028 DOI: 10.3390/ijms241914517] [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: 08/23/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine levels and alteration in calcium homeostasis, thus inducing an increased oxygen demand. Moreover, there is evidence to suggest that mitochondria alterations play a crucial role in the development of cocaine cardiotoxicity. We performed a systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) scheme to evaluate the mitochondrial mechanisms determining cocaine cardiotoxicity. Among the initial 106 articles from the Pubmed database and the 17 articles identified through citation searching, 14 final relevant studies were extensively reviewed. Thirteen articles included animal models and reported the alteration of specific mitochondria-dependent mechanisms such as reduced energy production, imbalance of membrane potential, increased oxidative stress, and promotion of apoptosis. However, only one study evaluated human cocaine overdose samples and observed the role of cocaine in oxidative stress and the induction of apoptosis though mitochondria. Understanding the complex processes mediated by mitochondria through forensic analysis and experimental models is crucial for identifying potential therapeutic targets to mitigate or reverse cocaine cardiotoxicity in humans.
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Affiliation(s)
- Michela Peruch
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
| | - Emiliana Giacomello
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
| | - Davide Radaelli
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
| | - Monica Concato
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
| | - Riccardo Addobbati
- Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, 34137 Trieste, Italy;
| | - Alessandra Lucia Fluca
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34149 Trieste, Italy
| | - Aneta Aleksova
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
- Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34149 Trieste, Italy
| | - Stefano D’Errico
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.P.); (E.G.); (D.R.); (M.C.); (A.L.F.); (A.A.)
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Bilal W, Khawar MB, Afzal A, Naseer A, Hamid SE, Shahzaman S, Qamar F. Recent advances to Neuroprotection: repurposing drugs against neuroinflammatory disorders. Mol Biol Rep 2023:10.1007/s11033-023-08490-6. [PMID: 37231215 DOI: 10.1007/s11033-023-08490-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023]
Abstract
Cell death is a natural mechanism for biological clearance for the maintenance of homeostasis in a dynamic microenvironment of the central nervous system. Stress and various factors can lead to imbalance between cellular genesis and cell death leading to dysfunctionality and a number of neuropathological disorders. Drug repurposing can help bypass development time and cost. A complete understanding of drug actions and neuroinflammatory pathways can lead to effective control of neurodegenerative disorders. This review covers recent advances in various neuroinflammatory pathways understanding, biomarkers, and drug repurposing for neuroprotection.
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Affiliation(s)
- Wishah Bilal
- Institute of Zoology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Babar Khawar
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal, Pakistan.
| | - Ali Afzal
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences & Technology, University of Central Punjab, Lahore, Pakistan
| | - Arshia Naseer
- Institute of Zoology, University of the Punjab, Lahore, Pakistan
| | - Syeda Eisha Hamid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences & Technology, University of Central Punjab, Lahore, Pakistan
| | - Sara Shahzaman
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences & Technology, University of Central Punjab, Lahore, Pakistan
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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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Jia Q, Li S, Li XJ, Yin P. Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics. Front Immunol 2022; 13:1088124. [PMID: 36618375 PMCID: PMC9815700 DOI: 10.3389/fimmu.2022.1088124] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Huntington's disease (HD) is a progressive neurodegenerative disease characterized by preferential loss of neurons in the striatum in patients, which leads to motor and cognitive impairments and death that often occurs 10-15 years after the onset of symptoms. The expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (HTT) has been defined as the cause of HD, but the mechanism underlying neuronal death remains unclear. Multiple mechanisms, including inflammation, may jointly contribute to HD pathogenesis. Altered inflammation response is evident even before the onset of classical symptoms of HD. In this review, we summarize the current evidence on immune and inflammatory changes, from HD animal models to clinical phenomenon of patients with HD. The understanding of the impact of inflammation on HD would help develop novel strategies to treat HD.
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Affiliation(s)
| | | | | | - Peng Yin
- *Correspondence: Xiao-Jiang Li, ; Peng Yin,
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van der Bent ML, Evers MM, Vallès A. Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1. Biologics 2022; 16:141-160. [PMID: 36213816 PMCID: PMC9532260 DOI: 10.2147/btt.s270657] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/14/2022] [Indexed: 11/12/2022]
Abstract
Huntington's disease is a devastating heritable neurodegenerative disorder that is caused by the presence of a trinucleotide CAG repeat expansion in the Huntingtin gene, leading to a polyglutamine tract in the protein. Various mechanisms lead to the production of N-terminal Huntingtin protein fragments, which are reportedly more toxic than the full-length protein. In this review, we summarize the current knowledge on the production and toxicity of N-terminal Huntingtin protein fragments. Further, we expand on various therapeutic strategies targeting N-terminal Huntingtin on the protein, RNA and DNA level. Finally, we compare the therapeutic approaches that are clinically most advanced, including those that do not target N-terminal Huntingtin, discussing differences in mode of action and translational applicability.
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Affiliation(s)
| | - Melvin M Evers
- uniQure biopharma B.V., Department of Research and Development, Amsterdam, the Netherlands
| | - Astrid Vallès
- uniQure biopharma B.V., Department of Research and Development, Amsterdam, the Netherlands
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12
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Hutchison DM, Hosking AM, Hong EM, Grando SA. Mitochondrial Autoantibodies and the Role of Apoptosis in Pemphigus Vulgaris. Antibodies (Basel) 2022; 11:55. [PMID: 36134951 PMCID: PMC9495650 DOI: 10.3390/antib11030055] [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: 08/03/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
Pemphigus vulgaris (PV) is an IgG autoantibody-mediated, potentially fatal mucocutaneous disease manifested by progressive non-healing erosions and blisters. Beyond acting to inhibit adhesion molecules, PVIgGs elicit a unique process of programmed cell death and detachment of epidermal keratinocytes termed apoptolysis. Mitochondrial damage by antimitochondrial antibodies (AMA) has proven to be a critical link in this process. AMA act synergistically with other autoantibodies in the pathogenesis of PV. Importantly, absorption of AMA inhibits the ability of PVIgGs to induce blisters. Pharmacologic agents that protect mitochondrial function offer a new targeted approach to treating this severe immunoblistering disease.
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Affiliation(s)
- Dana M. Hutchison
- Department of Dermatology, University of California Irvine, Irvine, CA 92697, USA
- Beckman Laser Institute, University of California Irvine, Irvine, CA 92612, USA
- Department of Internal Medicine, Riverside Community Hospital, Riverside, CA 92501, USA
| | - Anna-Marie Hosking
- Department of Dermatology, University of California Irvine, Irvine, CA 92697, USA
| | - Ellen M. Hong
- Beckman Laser Institute, University of California Irvine, Irvine, CA 92612, USA
- Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
| | - Sergei A. Grando
- Department of Dermatology, University of California Irvine, Irvine, CA 92697, USA
- Department of Biochemistry, University of California Irvine, Irvine, CA 92697, USA
- Institute for Immunology, University of California Irvine, Irvine, CA 92697, USA
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Najdawi ZR, Abu-Asab MS. An Ultrastructural Perspective on Cell Death. JORDAN MEDICAL JOURNAL 2022; 56:10.35516/jmj.v56i1.232. [PMID: 36168597 PMCID: PMC9511926 DOI: 10.35516/jmj.v56i1.232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
In the field of cell death, there is still a wide gap between the molecular models and their ultrastructural phenotypes. Because only very few published works included electron microscopy (EM) images, many ultrastructural features have not yet been incorporated into the descriptions of death modes. Some of the EM features that appear in dying cells have not been incorporated in describing death modes. It includes the accumulation of lipid droplets and glycogen, the appearance of extranuclear chromatin in the cytoplasm, and the various ways mitochondria become damaged. We argue that electron microscopy should be routinely included in these studies because it exposes some new features that molecular studies do not. It has successfully recognized new modes of cell death, such as entosis, methuosis, and paraptosis. Elucidating the precise sequence of events in death modes could be the cornerstone for offering the proper therapy of many diseases by slowing down or stopping the progression of degeneration. This review presents our own experience applying ultrastructural interpretations to death modes and explaining their biochemical implications. We complement the molecular and biochemical data and point out missing features that should be considered and studied.
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Khatoon R, Kaushik P, Parvez S. Mitochondria-Related Apoptosis Regulation by Minocycline: A Study on a Transgenic Drosophila Model of Alzheimer's Disease. ACS OMEGA 2022; 7:19106-19112. [PMID: 35721948 PMCID: PMC9202010 DOI: 10.1021/acsomega.1c05653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 02/21/2022] [Indexed: 06/15/2023]
Abstract
Alzheimer's disease (AD) is a very complicated and multifactorial neurological disorder having limited therapeutic interventions illustrated by the impairment in memory and cognitive function. Several lines of confirmation are stoutly connected with mitochondrial function perturbation as a significant causative factor in AD, while the molecular mechanisms involved in AD pathogenesis are still poorly understood. Minocycline, a well-known antibiotic, has confirmed efficacy against mitochondrial defects and oxidative stress as a neuroprotective effect. In view of this property, we examined the remedial effect of minocycline on AD. To attain insight into the molecular machinery responsible for AD pathogenesis, we preferred the UAS/GAL4 scheme for the development of AD in flies that overexpress the Aβ42 protein in the brain of Drosophila. The warning signs like the declined lifespan, locomotion deficit and memory loss, impaired mitochondrial membrane potential, and increased caspase 3 expression with mitogen-associated protein kinases linked with AD pathogenesis were examined in the existence of minocycline. Minocycline halted the Aβ42-induced symptoms including behavioral changes and altered the mitochondrial membrane potential along with apoptotic factors' protein expression (JNK/p-JNK and caspase 3). Thus, the current study could be functional to find out the role of minocycline in human Aβ42-overexpressed transgenic AD flies.
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Affiliation(s)
| | | | - Suhel Parvez
- . Tel.: +91 11 26059688x5573. Fax: +91 11 26059663
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15
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Antidepressant-like Effects of Renin Inhibitor Aliskiren in an Inflammatory Mouse Model of Depression. Brain Sci 2022; 12:brainsci12050655. [PMID: 35625041 PMCID: PMC9139539 DOI: 10.3390/brainsci12050655] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/09/2022] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Depression is considered a neuropsychic disease that has global prevalence and is associated with disability. The pathophysiology of depression is not well understood; however, emerging evidence has indicated that neuroinflammation could contribute to developing depression symptoms. One of the factors that have a role in the development of neuroinflammation is the renin–angiotensin system. Therefore, the goal of the current study is to determine the antidepressant-like effects of Aliskiren, a renin inhibitor, against lipopolysaccharide (LPS)-induced depressive-like behavior in mice, glial cell activation, and the upregulation of proinflammatory cytokines in the prefrontal cortex. For behavioral studies, the open field test (OFT), tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT) were used. Inflammatory markers were assessed using real-time polymerase chain reaction (RT-PCR). LPS administration (0.5 mg/kg, intraperitoneal injection (i.p.)) sufficiently reduced the number of crossings in OFT, whereas Aliskiren pretreatment (10 mg/kg, i.p.) attenuated the LPS effect for two hours after LPS injection. The treatments did not show effects on locomotor activity in OFT 24 h after LPS administration. LPS increased the immobility time in TST and FST or reduced sucrose consumption in SPT after 24 h. Aliskiren reversed the effects induced by LPS in TST, FST, and SPT. CD11 b mRNA, a microglial marker, GFAP mRNA, an astroglial marker, and proinflammatory cytokines genes (TNF-α, IL-1β, and IL-6) were upregulated in the prefrontal cortex in LPS exposed animals. However, Aliskiren reduced LPS-induced inflammatory genes in the prefrontal cortex. Hence, the outcomes conclude that Aliskiren prevents depressive illness associated with neuroinflammation in humans.
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Czerwińska-Główka D, Skonieczna M, Barylski A, Golba S, Przystaś W, Zabłocka-Godlewska E, Student S, Cwalina B, Krukiewicz K. Bifunctional conducting polymer matrices with antibacterial and neuroprotective effects. Bioelectrochemistry 2022; 144:108030. [PMID: 34896782 DOI: 10.1016/j.bioelechem.2021.108030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/24/2021] [Accepted: 11/29/2021] [Indexed: 11/02/2022]
Abstract
Current trends in the field of neural tissue engineering include the design of advanced biomaterials combining excellent electrochemical performance with versatile biological characteristics. The purpose of this work was to develop an antibacterial and neuroprotective coating based on a conducting polymer - poly(3,4-ethylenedioxypyrrole) (PEDOP), loaded with an antibiotic agent - tetracycline (Tc). Employing an electrochemical technique to immobilize Tc within a growing polymer matrix allowed to fabricate robust PEDOP/Tc coatings with a high charge storage capacity (63.65 ± 6.05 mC/cm2), drug release efficiency (629.4 µg/cm2 ± 62.7 µg/cm2), and low charge transfer resistance (2.4 ± 0.1 kΩ), able to deliver a stable electrical signal. PEDOP/Tc were found to exhibit strong antimicrobial effects against Gram-negative bacteria Escherichia coli, expressed through negligible adhesion, reduction in viability, and a characteristic elongation of bacterial cells. Cytocompatibility and neuroprotective effects were evaluated using a rat neuroblastoma B35 cell line, and were analyzed using MTT, cell cycle, and Annexin-V apoptosis assays. The presence of Tc was found to enhance neural cell viability and neurite outgrowth. The results confirmed that PEDOP/Tc can serve as an efficient neural electrode coating able to enhance charge transfer, as well as to exhibit bifunctional biological characteristics, different for eukaryotic and prokaryotic cells.
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Affiliation(s)
- Dominika Czerwińska-Główka
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M.Strzody 9, 44-100 Gliwice, Poland
| | - Magdalena Skonieczna
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland; Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Adrian Barylski
- Institute of Materials Engineering, University of Silesia, 75 Pulku Piechoty, 41-500 Chorzow, Poland
| | - Sylwia Golba
- Institute of Materials Engineering, University of Silesia, 75 Pulku Piechoty, 41-500 Chorzow, Poland
| | - Wioletta Przystaś
- Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland; Department of Air Protection, Faculty of Energy and Environmental Engineering, Silesian University of Technology, S. Konarskiego 22B, 44-100 Gliwice, Poland
| | - Ewa Zabłocka-Godlewska
- Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland; Department of Air Protection, Faculty of Energy and Environmental Engineering, Silesian University of Technology, S. Konarskiego 22B, 44-100 Gliwice, Poland
| | - Sebastian Student
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland; Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
| | - Beata Cwalina
- Biotechnology Centre, Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland; Department of Environmental Biotechnology, Faculty of Energy and Environmental Engineering, Silesian University of Technology, S.Konarskiego 18, 44-100 Gliwice, Poland
| | - Katarzyna Krukiewicz
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M.Strzody 9, 44-100 Gliwice, Poland.
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17
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Zhang R, Yong VW, Xue M. Revisiting Minocycline in Intracerebral Hemorrhage: Mechanisms and Clinical Translation. Front Immunol 2022; 13:844163. [PMID: 35401553 PMCID: PMC8993500 DOI: 10.3389/fimmu.2022.844163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/24/2022] [Indexed: 01/31/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is an important subtype of stroke with an unsatisfactory prognosis of high mortality and disability. Although many pre-clinical studies and clinical trials have been performed in the past decades, effective therapy that meaningfully improve prognosis and outcomes of ICH patients is still lacking. An active area of research is towards alleviating secondary brain injury after ICH through neuroprotective pharmaceuticals and in which minocycline is a promising candidate. Here, we will first discuss new insights into the protective mechanisms of minocycline for ICH including reducing iron-related toxicity, maintenance of blood-brain barrier, and alleviating different types of cell death from preclinical data, then consider its shortcomings. Finally, we will review clinical trial perspectives for minocycline in ICH. We hope that this summary and discussion about updated information on minocycline as a viable treatment for ICH can facilitate further investigations.
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Affiliation(s)
- Ruiyi Zhang
- The Departments of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - V. Wee Yong
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - Mengzhou Xue
- The Departments of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Liu E, Karpf L, Bohl D. Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons. Front Mol Neurosci 2022; 14:767041. [PMID: 34970118 PMCID: PMC8712677 DOI: 10.3389/fnmol.2021.767041] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/16/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.
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Affiliation(s)
- Elise Liu
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Léa Karpf
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Delphine Bohl
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
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19
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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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20
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Sawant N, Morton H, Kshirsagar S, Reddy AP, Reddy PH. Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics. Mol Neurobiol 2021; 58:6350-6377. [PMID: 34519969 DOI: 10.1007/s12035-021-02556-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/05/2021] [Indexed: 12/12/2022]
Abstract
Huntington's disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.
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Affiliation(s)
- Neha Sawant
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Hallie Morton
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Sudhir Kshirsagar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Arubala P Reddy
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Neurology, Department of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Department of Internal Medicine, Cell Biology & Biochemistry, Public Health and School of Health Professions, Texas Tech University Health Sciences Center, Neuroscience & Pharmacology3601 4th Street, NeurologyLubbock, TX, 79430, USA.
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21
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Razavi SM, Khayatan D, Arab ZN, Momtaz S, Zare K, Jafari RM, Dehpour AR, Abdolghaffari AH. Licofelone, a potent COX/5-LOX inhibitor and a novel option for treatment of neurological disorders. Prostaglandins Other Lipid Mediat 2021; 157:106587. [PMID: 34517113 DOI: 10.1016/j.prostaglandins.2021.106587] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/17/2021] [Accepted: 09/04/2021] [Indexed: 12/13/2022]
Abstract
Neurological disorders result in disability and morbidity. Neuroinflammation is a key factor involved in progression or resolution of a series of neurological disorders like Huntington disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Spinal Cord Injury (SCI), and Seizure. Thereby, anti-inflammatory drugs have been developed to improve the neurodegenerative impairments. Licofelone is an approved osteoarthritis drug that inhibits both the COX (cyclooxygenase) and 5-LOX (lipoxygenase) pathways. Licofelone has pain-relieving and anti-inflammatory effects and it was shown to have neuroprotective properties in the central nervous system, which is implicated in its regulatory effect on the COX/5-LOX pathway, inflammatory cytokines, and immune responses. In this study, we briefly review the various features of neurological disorders and the function of COX/LOX in their flare up and current pharmacological products for their management. Moreover, this review attempts to summarize potential therapeutics that target the immune responses within the central nervous system. A better understanding of the interactions between Licofelone and the nervous systems will be crucial to demonstrate the possible efficacy of Licofelone in neurological disorders.
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Affiliation(s)
- Seyed Mehrad Razavi
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Danial Khayatan
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Najafi Arab
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Kimia Zare
- School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Razieh Mohammad Jafari
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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22
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Mello BSF, Chaves Filho AJM, Custódio CS, Rodrigues PDA, Carletti JV, Vasconcelos SMM, Sousa FCFD, Sanders LLO, Macedo DS. Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression. J Affect Disord 2021; 292:733-745. [PMID: 34161892 DOI: 10.1016/j.jad.2021.05.083] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/06/2021] [Accepted: 05/30/2021] [Indexed: 12/27/2022]
Abstract
Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-1β levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNFα levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK3β), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.
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Affiliation(s)
- Bruna Stefânia Ferreira Mello
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Adriano José Maia Chaves Filho
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Charllyany Sabino Custódio
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Patrícia de Araújo Rodrigues
- Laboratory of Neuroscience and Behavior, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Jaqueline V Carletti
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Silvânia Maria Mendes Vasconcelos
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Francisca Cléa Florenço de Sousa
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Lia Lira Olivier Sanders
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Danielle S Macedo
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, SP, Brazil.
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Jia X, Zhang A, Li Z, Peng X, Tian X, Gao F. Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine-tolerant rats. J Neurochem 2021; 158:373-390. [PMID: 33950542 DOI: 10.1111/jnc.15383] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/29/2021] [Accepted: 05/01/2021] [Indexed: 12/14/2022]
Abstract
The adverse side effects of opioids, especially antinociceptive tolerance, limit their clinical application. A recent study reported that platelet-derived growth factor receptor β (PDGFRβ) blockage selectively inhibited morphine tolerance. Autophagy has been reported to contribute to the cellular and behavioral responses to morphine. However, little is known about the relationship between PDGFRβ and autophagy in the mechanisms of morphine tolerance. In this study, rats were intrathecally administered with morphine twice daily for 7 days to induce antinociceptive tolerance, which was evaluated using a tail-flick latency test. By administration autophagy inhibitor 3-Methyladenine, PDGFRβ inhibitor imatinib, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 hydrochloride and minocycline hydrochloride, western blot, immunofluorescence, and transmission electron microscopy techniques were used to elucidate the roles of PDGFRβ, autophagy, and related signaling pathways in morphine tolerance. This study demonstrated for the first time that spinal PDGFRβ in microglia promotes autophagy in gamma-aminobutyric acid (GABA) interneurons through activating p38 MAPK pathway during the development of morphine tolerance, which suggest a potential strategy for preventing the development of morphine tolerance clinically, thereby improving the use of opioids in pain management.
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Affiliation(s)
- Xiaoqian Jia
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Anqi Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Li
- Department of Anesthesiology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Xiaoling Peng
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuebi Tian
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Gao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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24
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Chaves Filho AJM, Mottin M, Soares MVR, Jucá PM, Andrade CH, Macedo DS. Tetracyclines, a promise for neuropsychiatric disorders: from adjunctive therapy to the discovery of new targets for rational drug design in psychiatry. Behav Pharmacol 2021; 32:123-141. [PMID: 33595954 DOI: 10.1097/fbp.0000000000000585] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, represent the leading cause of disability worldwide. Nevertheless, the current pharmacotherapy has several limitations, and a large portion of patients do not respond appropriately to it or remain with disabling symptoms overtime. Traditionally, pharmacological interventions for psychiatric disorders modulate dysfunctional neurotransmitter systems. In the last decades, compelling evidence has advocated for chronic inflammatory mechanisms underlying these disorders. Therefore, the repurposing of anti-inflammatory agents has emerged as an attractive therapeutic tool for mental disorders. Minocycline (MINO) and doxycycline (DOXY) are semisynthetic second-generation tetracyclines with neuroprotective and anti-inflammatory properties. More recently, the most promising results obtained in clinical trials using tetracyclines for major psychiatric disorders were for schizophrenia. In a reverse translational approach, tetracyclines inhibit microglial reactivity and toxic inflammation by mechanisms related to the inhibition of nuclear factor kappa B signaling, cyclooxygenase 2, and matrix metalloproteinases. However, the molecular mechanism underlying the effects of these tetracyclines is not fully understood. Therefore, the present review sought to summarize the latest findings of MINO and DOXY use for major psychiatric disorders and present the possible targets to their molecular and behavioral effects. In conclusion, tetracyclines hold great promise as (ready-to-use) agents for being used as adjunctive therapy for human neuropsychiatric disorders. Hence, the understanding of their molecular mechanisms may contribute to the discovery of new targets for the rational drug design of novel psychoactive agents.
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Affiliation(s)
- Adriano José Maia Chaves Filho
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Melina Mottin
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Michele Verde-Ramo Soares
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
| | - Paloma Marinho Jucá
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
| | - Carolina Horta Andrade
- Laboratory for Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO
| | - Danielle S Macedo
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE
- National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, SP, Brazil
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25
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Tu Y, Li X, Zhu X, Liu X, Guo C, Jia D, Tang TS. Determining the Fate of Neurons in SCA3: ATX3, a Rising Decision Maker in Response to DNA Stresses and Beyond. Front Cell Dev Biol 2021; 8:619911. [PMID: 33425926 PMCID: PMC7793700 DOI: 10.3389/fcell.2020.619911] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022] Open
Abstract
DNA damage response (DDR) and apoptosis are reported to be involved in the pathogenesis of many neurodegenerative diseases including polyglutamine (polyQ) disorders, such as Spinocerebellar ataxia type 3 (SCA3) and Huntington's disease (HD). Consistently, an increasing body of studies provide compelling evidence for the crucial roles of ATX3, whose polyQ expansion is defined as the cause of SCA3, in the maintenance of genome integrity and regulation of apoptosis. The polyQ expansion in ATX3 seems to affect its physiological functions in these distinct pathways. These advances have expanded our understanding of the relationship between ATX3's cellular functions and the underlying molecular mechanism of SCA3. Interestingly, dysregulated DDR pathways also contribute to the pathogenesis of other neurodegenerative disorder such as HD, which presents a common molecular mechanism yet distinct in detail among different diseases. In this review, we provide a comprehensive overview of the current studies about the physiological roles of ATX3 in DDR and related apoptosis, highlighting the crosslinks between these impaired pathways and the pathogenesis of SCA3. Moreover, whether these mechanisms are shared in other neurodegenerative diseases are analyzed. Finally, the preclinical studies targeting DDR and related apoptosis for treatment of polyQ disorders including SCA3 and HD are also summarized and discussed.
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Affiliation(s)
- Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Xiaoling Li
- Hebei Key Laboratory of Applied Chemistry, School of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, China
| | - Xuefei Zhu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
| | - Xiaokang Liu
- Hebei Key Laboratory of Applied Chemistry, School of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, China
| | - Caixia Guo
- Beijing Institute of Genomics (China National Center for Bioinformation), University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Tie-Shan Tang
- State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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26
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Abstract
Spinal cord injury results in significant loss of motor, sensory, and autonomic functions. Although a wide range of therapeutic agents have been shown to attenuate secondary injury or promote regeneration/repair in animal models of spinal cord injury, clinical translation of these strategies has been limited, in part due to difficulty in safely and effectively achieving therapeutic concentrations in the injured spinal cord tissue. Hydrogel-based drug delivery systems offer unique opportunities to locally deliver drugs to the injured spinal cord with sufficient dose and duration, while avoiding deleterious side effects associated with systemic drug administration. Such local drug delivery systems can be readily fabricated from biocompatible and biodegradable materials. In this review, hydrogel-based strategies for local drug delivery to the injured spinal cord are extensively reviewed, and recommendations are made for implementation.
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Affiliation(s)
- Robert B Shultz
- School of Biomedical Engineering, Science and Health Systems, Drexel University; Department of Neurosurgery; Department of Bioengineering, University of Pennsylvania; New Jersey Center for Biomaterials, Rutgers - The State University of New Jersey, Piscataway, NJ; Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
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27
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Romero-Miguel D, Lamanna-Rama N, Casquero-Veiga M, Gómez-Rangel V, Desco M, Soto-Montenegro ML. Minocycline in neurodegenerative and psychiatric diseases: An update. Eur J Neurol 2020; 28:1056-1081. [PMID: 33180965 DOI: 10.1111/ene.14642] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/30/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND PURPOSE Minocycline is a broad-spectrum antibiotic, effective as a chronic treatment for recurrent bacterial infections. Beyond its antibiotic action, minocycline also has important anti-inflammatory, antioxidant and antiapoptotic properties. Its efficacy has therefore been evaluated in many neurodegenerative and psychiatric diseases that have an inflammatory basis. Our aim was to review preclinical and clinical studies performed in neurological and psychiatric diseases whose treatment involved the use of minocycline and thereby to discern the possible beneficial effect of minocycline in these disorders. METHODS Completed and ongoing preclinical studies and clinical trials of minocycline for both neurodegenerative diseases and psychiatric disorders, published from January 1995 to January 2020, were identified through searching relevant databases (https://www.ncbi.nlm.nih.gov/pubmed/, https://clinicaltrials.gov/). A total of 74 preclinical studies and 44 clinical trials and open-label studies were selected. RESULTS The results of the nearly 20 years of research identified are diverse. While minocycline mostly proved to be effective in animal models, clinical results showed divergent outcomes, with positive results in some studies counterbalanced by a number of cases with no significant improvements. Specific data for each disease are further individually described in this review. CONCLUSIONS Despite minocycline demonstrating antioxidant and anti-inflammatory effects, discrepancies between preclinical and clinical data indicate that we should be cautious in analyzing the outcomes. Improving and standardizing protocols and refining animal models could help us to determine if minocycline really is a useful drug in the treatment of these pathologies.
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Affiliation(s)
| | | | - Marta Casquero-Veiga
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,CIBER de Salud Mental (CIBERSAM), Madrid
| | | | - Manuel Desco
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,CIBER de Salud Mental (CIBERSAM), Madrid.,Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Spain.,Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - María Luisa Soto-Montenegro
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,CIBER de Salud Mental (CIBERSAM), Madrid
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28
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Abstract
Tetracyclines have been used to treat many bacterial infections. The use of these antibiotics for the treatment of viral diseases dates to the 1960s to 1970s. Over the decades, the effect of tetracyclines on the pathogenesis of viral infections has been demonstrated both clinically and experimentally. Tetracyclines can act on viral infections either through their antibacterial properties or through direct antiviral action. This review focuses on clinical and experimental data that support the use of tetracycline in treating viral infections and highlights an important approach to slowing disease progression during viral infections. Tetracycline treatment might represent a strategy for eliminating the infection or inhibiting the progression of COVID-19.
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29
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Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions. Biomedicines 2020; 8:biomedicines8100389. [PMID: 33003373 PMCID: PMC7601301 DOI: 10.3390/biomedicines8100389] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 09/25/2020] [Accepted: 09/26/2020] [Indexed: 12/15/2022] Open
Abstract
Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.
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30
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Rok J, Rzepka Z, Beberok A, Pawlik J, Wrześniok D. Cellular and Molecular Aspects of Anti-Melanoma Effect of Minocycline-A Study of Cytotoxicity and Apoptosis on Human Melanotic Melanoma Cells. Int J Mol Sci 2020; 21:E6917. [PMID: 32967177 PMCID: PMC7555712 DOI: 10.3390/ijms21186917] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/09/2020] [Accepted: 09/18/2020] [Indexed: 01/01/2023] Open
Abstract
Minocycline is a tetracycline compound with pleiotropic pharmacological properties. In addition to its antibacterial action, it shows many non-antimicrobial effects, including an anti-cancer activity. The anti-cancer action was confirmed in studies on ovarian carcinoma cells, hepatocellular carcinoma cells, glioma cells, or acute myeloid leukemia cells. Malignant melanoma remains a serious medical problem despite the extensive knowledge of the disease. The low effectiveness of the standard treatment, as well as the resistance to therapy, result in high mortality rates. This work aimed to investigate the potential and mechanisms of anti-melanoma action of minocycline. Human skin melanotic melanoma cell line COLO 829 was used in the study. The obtained results showed that minocycline decreased cell viability and inhibited the growth of melanoma cells, proportional to the drug concentration as well as to the time of incubation. The EC50 values were calculated to be 78.6 µM, 31.7 µM, and 13.9 µM for 24 h, 48 h, and 72 h, respectively. It was observed that treated cells had a disturbed cell cycle and significantly changed morphology. Moreover, minocycline caused a decrease in mitochondrial membrane potential and an increase in cells with a low level of reduced thiols. Finally, it was found that the anti-melanoma effect of minocycline was related to the induction of apoptosis. The drug activated caspases 8, 9, and 3/7 as well as increased the number of annexin V-positive cells. The presented results show that minocycline possesses anti-melanoma potential.
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Affiliation(s)
- Jakub Rok
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland; (Z.R.); (A.B.); (J.P.); (D.W.)
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31
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Torregrossa F, Sallì M, Grasso G. Emerging Therapeutic Strategies for Traumatic Spinal Cord Injury. World Neurosurg 2020; 140:591-601. [PMID: 32797989 DOI: 10.1016/j.wneu.2020.03.199] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 03/26/2020] [Indexed: 01/18/2023]
Abstract
Spinal cord injury (SCI) is a debilitating neurologic condition with tremendous socioeconomic impact on affected individuals and the health care system. The treatment of SCI principally includes surgical treatment and marginal pharmacologic and rehabilitation therapies targeting secondary events with minor clinical improvements. This unsuccessful result mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiologic changes that occur in the injured spinal cord. Once the nervous system is injured, cascades of cellular and molecular events are triggered at varying times. Although the cascade of tissue reactions and cell injury develops over a period of days or weeks, the most extensive cell death in SCI occurs within hours of trauma. This situation suggests that early intervention is likely to be the most promising approach to rescue the cord from further and irreversible cell damage. Over the past decades, a wealth of research has been conducted in preclinical and clinical studies with the hope to find new therapeutic strategies. Researchers have identified several targets for the development of potential therapeutic interventions (e.g., neuroprotection, replacement of cells lost, removal of inhibitory molecules, regeneration, and rehabilitation strategies to induce neuroplasticity). Most of these treatments have passed preclinical and initial clinical evaluations but have failed to be strongly conclusive in the clinical setting. This narrative review provides an update of the many therapeutic interventions after SCI, with an emphasis on the underlying pathophysiologic mechanisms.
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Affiliation(s)
- Fabio Torregrossa
- Neurosurgical Unit, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, Palermo, Italy
| | - Marcello Sallì
- Department of Neurosensory and Motor Surgery, University of Palermo, Palermo, Italy
| | - Giovanni Grasso
- Neurosurgical Unit, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, Palermo, Italy.
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32
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Rana A, Singh S, Deshmukh R, Kumar A. Pharmacological potential of tocopherol and doxycycline against traumatic brain injury-induced cognitive/motor impairment in rats. Brain Inj 2020; 34:1039-1050. [PMID: 32493074 DOI: 10.1080/02699052.2020.1772508] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/29/2020] [Accepted: 05/06/2020] [Indexed: 01/20/2023]
Abstract
Primary Objective The primary objective of this study was to explore the pharmacological potential of tocopherol and doxycycline against traumatic brain injury-induced cognitive/motor impairment in rats. Research Design Weight drop model of traumatic brain injury. Methods and Procedures After TBI, the animals were treated with doxycycline (50 and 100 mg/kg; p.o), tocopherol (5 and 10 mg/kg; p.o) alone and in combination as doxycycline and tocopherol (50 and 10 mg/kg; p.o) from 1st day to 28th day. The behavioral parameters were performed on a weekly basis from 1st day to 28th day. On 29th day, animals were sacrificed and striatum and cortex were homogenized for the estimation of biochemical (LPO, nitrite, and GSH), neuroinflammatory (IL-6, IL-1β, and TNF-α), and neurotransmitters (dopamine, norepinephrine, serotonin, GABA, and glutamate) analysis. Main Outcomes and Results Induction of TBI had significantly reduced locomotor activity, recognition memory, increased neuroinflammatory markers, and imbalance neurotransmitter levels. The treatment with doxycycline and tocopherol alone and in combination significantly attenuated locomotor activity, memory recognition, reduced neuroinflammation, preserved oxidative balance, and restored the level of neurotransmitters. Conclusions The neuroprotective effect of doxycycline and tocopherol might be due to its anti-inflammatory and free radical scavenging mechanisms. Abbreviations TBI: Traumatic brain injury; Doxy: Doxycycline; Toco: Tocopherol; LPO: Lipid peroxidation; MDA: Malondialdehyde; TNF-α: Tumor necrosis factor-alpha; IL-1b: Interleukin-1 beta; GSH: Glutathione; GABA: gamma-Aminobutyric acid.
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Affiliation(s)
- Arti Rana
- Department of Neuropharmacology, ISF College of Pharmacy , Moga, Punjab, India
| | - Shamsher Singh
- Department of Neuropharmacology, ISF College of Pharmacy , Moga, Punjab, India
| | - Rahul Deshmukh
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University (MRSPTU) , Bathinda, Punjab, India
| | - Anoop Kumar
- Department of Neuropharmacology, ISF College of Pharmacy , Moga, Punjab, India
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli , Lucknow, UP, India
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33
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Remodeling microglia to a protective phenotype in Parkinson's disease? Neurosci Lett 2020; 735:135164. [PMID: 32561452 DOI: 10.1016/j.neulet.2020.135164] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022]
Abstract
Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the pathological mechanisms of PD to translate them into therapy has remained a high research priority. In this review, we highlight evidence describing the involvement of microglial dysfunction in PD. Thereafter, we provide current knowledge suggesting that the substantia nigra pars compacta and putamen, compared to other brain regions, show a reduced microglial density, as well as altered morphological and functional properties in homeostatic conditions, while presenting dystrophic features associated with aging. Further, we describe that this defective microglial programing emerges as early as the second postnatal week, persists until adulthood and impacts negatively on their transcriptional pattern and provision of local trophic support. We emphasize the role of α-synuclein oligomers as a major dysfunctional signal underlining microglial-mediated phenotypic switch and adaptive response contributing to neurodegeneration. Moreover, we explore available avenues should microglia be considered as target for neuroprotective or restorative strategies including preventing the aggregation of α-synuclein protofibrils formation. However, we provide a note of caution regarding the success of microglial-targeted PD strategies, using minocycline as an example. In conclusion, we discuss putative neuroprotective agents that were unsuccessful in previous trials but could be reconsidered by focusing on the stage of microglial-dependent pathogenic events during PD in suitable cohorts of patients.
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34
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Puty B, Nogueira ICDC, Nogueira LS, Vasconcelos CP, Araújo TMC, Bittencourt LO, Ferreira RDO, Oliveira EHCD, Leal WG, Lima RR. Genotoxic effect of non-lethal concentrations of minocycline in human glial cell culture. Biomed Pharmacother 2020; 128:110285. [PMID: 32485569 DOI: 10.1016/j.biopha.2020.110285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/12/2020] [Accepted: 05/16/2020] [Indexed: 01/01/2023] Open
Abstract
Minocycline has been proposed as a neuroprotective agent with pleiotropic effects on several experimental models of neurodegenerative diseases, including microglial inhibition. However, although most studies have focused on the central actions of minocycline in affecting microglial functions, other central nervous system (CNS) cell types may also be affected by this drug toxicity. Hence, considering that glial cells play a pivotal role on CNS physiology and are the main responsible for neuronal integrity, a comprehensive investigation on the effects of minocycline treatment on human glial cells is mandatory before translational studies to afford neuroprotection in humans. Therefore, we explored the cytotoxic and genotoxic effects of minocycline at different concentrations in glial cells using an in vitro model. To achieve this, U87 glial cell were exposed to 10-50 μg/mL for 24 h. After exposure, cell viability, general metabolic status and genotoxic assays were performed. No changes were observed in cell viability, however, the general metabolic status decreased over 20 μg/mL. In addition, although no chromossome aberrations were observed, evidences of genotoxicity, such as increase on micronucleus, buds and bridges, were observed from 10 μg/mL. These results suggest that minocycline may induce genotoxic effects even at concentrations considered previously safe and should be used with caution in translational studies.
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Affiliation(s)
- Bruna Puty
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil
| | - Iago César da Costa Nogueira
- Laboratory of Cell Culture and Cytogenetics, Environmental Section, Evandro Chagas Institute, Ananindeua, Brazil
| | - Lygia S Nogueira
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil
| | | | - Teka Mayara Corrêa Araújo
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil
| | - Railson de Oliveira Ferreira
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil
| | | | - Walace Gomes Leal
- Laboratory of Experimental Neuroprotection and Neuroregeneration, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil.
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35
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Hergesheimer R, Lanznaster D, Vourc’h P, Andres C, Bakkouche S, Beltran S, Blasco H, Corcia P, Couratier P. Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother 2020; 21:1103-1110. [DOI: 10.1080/14656566.2020.1746270] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- R Hergesheimer
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
| | - D Lanznaster
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
| | - P Vourc’h
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
- CHU De Tours, Service de Biochimie et Biologie Moléculaire, Tours, France
| | - Cr Andres
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
- CHU De Tours, Service de Biochimie et Biologie Moléculaire, Tours, France
| | - Se Bakkouche
- CHU de Tours, Service de Neurologie, Tours, France
| | - S Beltran
- CHU de Tours, Service de Neurologie, Tours, France
| | - H Blasco
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
- CHU De Tours, Service de Biochimie et Biologie Moléculaire, Tours, France
| | - P Corcia
- UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France
- CHU de Tours, Service de Neurologie, Tours, France
| | - P Couratier
- CHU Limoges, Service de Neurologie, Centre Expert ALS, Limoges, France
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36
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Radad K, Amir YE, Al-Emam A, Al-Shraim M, Bin-Jaliah I, Krewenka C, Moldzio R. Minocycline protects against acrylamide-induced neurotoxicity and testicular damage in Sprague-Dawley rats. J Toxicol Pathol 2020; 33:87-95. [PMID: 32425341 PMCID: PMC7218239 DOI: 10.1293/tox.2019-0066] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/09/2019] [Indexed: 11/20/2022] Open
Abstract
This study investigated the protective effects of minocycline against acrylamide (ACR)-induced neurotoxicity and testicular damage in Sprague-Dawley rats. Forty rats were divided into five groups (eight rats each). Group I received saline (0.5 mL/rat) daily for 10 days and served as the untreated control group. Group II received ACR (30 mg/kg body weight (b.w.)) daily for 10 days. Group III received ACR (30 mg/kg b.w.) daily for 10 days and subsequently minocycline (60 mg/kg b.w.) for five days. Group IV received ACR (30 mg/kg b.w.) daily for 10 days followed by saline for five days and served as the control group for the ACR-minocycline-treated group. Group V received minocycline (60 mg/kg b.w.) for five days. All treatments were administered orally. Rats in group I and V showed normal locomotor behavior and normal histology of the brain and testes. Administration of ACR (Group II and IV) resulted in weight loss and gait abnormalities. Furthermore, neuronal degeneration in the hippocampus and cerebellum and degeneration of the seminiferous tubular epithelium with formation of spermatid giant cells were observed. Ultrastructurally, ACR specifically damaged spermatogonia and spermatocytes. Acrylamide was also seen to cause a significant increase of malondialdehyde levels in the brain and testes. Treatment of ACR-administered rats with minocycline (Group III) significantly alleviated the loss of body weight and improved locomotor function. Minocycline also ameliorated neuronal degeneration and seminiferous tubular damage and decreased malondialdehyde concentrations. In conclusion, minocycline protects against neurotoxic effects of acrylamide and seminiferous tubular damage. Decreasing lipid peroxidation by minocycline might play a role in such protection.
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Affiliation(s)
- Khaled Radad
- Department of Pathology, College of Medicine, King Khalid University, P.O.Box: 641, Abha, 61421, Aseer, Saudi Arabia
- Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt
| | - Yassmin El Amir
- Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt
| | - Ahmed Al-Emam
- Department of Pathology, College of Medicine, King Khalid University, P.O.Box: 641, Abha, 61421, Aseer, Saudi Arabia
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mubarak Al-Shraim
- Department of Pathology, College of Medicine, King Khalid University, P.O.Box: 641, Abha, 61421, Aseer, Saudi Arabia
| | - Ismaeel Bin-Jaliah
- Department of Physiology, College of Medicine, King Khalid University, P.O.Box: 641, Abha, 61421, Aseer, Saudi Arabia
| | - Christopher Krewenka
- Institute of Medical Biochemistry, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinaerplatz 1, A-1210, Austria
| | - Rudolf Moldzio
- Institute of Medical Biochemistry, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinaerplatz 1, A-1210, Austria
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Hu J, Lemasters JJ. Suppression of iron mobilization from lysosomes to mitochondria attenuates liver injury after acetaminophen overdose in vivo in mice: Protection by minocycline. Toxicol Appl Pharmacol 2020; 392:114930. [PMID: 32109512 DOI: 10.1016/j.taap.2020.114930] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 02/19/2020] [Accepted: 02/24/2020] [Indexed: 12/20/2022]
Abstract
Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction. Previous studies showed that translocation of Fe2+ from lysosomes into mitochondria by the mitochondrial Ca2+ uniporter (MCU) promotes the mitochondrial permeability transition (MPT) after APAP. Here, our Aim was to assess protection by iron chelation and MCU inhibition against APAP hepatotoxicity in mice. C57BL/6 mice and hepatocytes were administered toxic doses of APAP with and without starch-desferal (an iron chelator), minocycline (MCU inhibitor), or N-acetylcysteine (NAC). In mice, starch-desferal and minocycline pretreatment decreased ALT and liver necrosis after APAP by >60%. At 24 h after APAP, loss of fluorescence of mitochondrial rhodamine 123 occurred in pericentral hepatocytes often accompanied by propidium iodide labeling, indicating mitochondrial depolarization and cell death. Starch-desferal and minocycline pretreatment decreased mitochondrial depolarization and cell death by more than half. In cultured hepatocytes, cell killing at 10 h after APAP decreased from 83% to 49%, 35% and 27%, respectively, by 1 h posttreatment with minocycline, NAC, and minocycline plus NAC. With 4 h posttreatment in vivo, minocycline and minocycline plus NAC decreased ALT and necrosis by ~20% and ~50%, respectively, but NAC alone was not effective. In conclusion, minocycline and starch-desferal decrease mitochondrial dysfunction and severe liver injury after APAP overdose, suggesting that the MPT is likely triggered by iron uptake into mitochondria through MCU. In vivo, minocycline and minocycline plus NAC posttreatment after APAP protect at later time points than NAC alone, indicating that minocycline has a longer window of efficacy than NAC.
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Affiliation(s)
- Jiangting Hu
- Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States of America
| | - John J Lemasters
- Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States of America.
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Minocycline induces apoptosis of photoreceptor cells by regulating ER stress. Exp Eye Res 2020; 190:107887. [DOI: 10.1016/j.exer.2019.107887] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/31/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
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Boguszewska-Czubara A, Budzynska B, Skalicka-Wozniak K, Kurzepa J. Perspectives and New Aspects of Metalloproteinases' Inhibitors in the Therapy of CNS Disorders: From Chemistry to Medicine. Curr Med Chem 2019; 26:3208-3224. [PMID: 29756562 DOI: 10.2174/0929867325666180514111500] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 03/31/2017] [Accepted: 04/05/2018] [Indexed: 11/22/2022]
Abstract
Matrix metalloproteinases (MMPs) play a key role in remodeling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation, and survival. Their importance in a variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain but only some pathological ones. Numerous neurodegenerative diseases are a consequence of or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development of these diseases. In the present review, we discuss the role of metalloproteinase inhibitors, from the wellknown natural endogenous tissue inhibitors of metalloproteinases (TIMPs) to the exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplastic diseases, the knowledge about the enzymatic system in mammalian brain tissue still remains poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of the physiological function of the adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries, and others.
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Affiliation(s)
| | - Barbara Budzynska
- Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin, Poland
| | - Krystyna Skalicka-Wozniak
- Department of Pharmacognosy with Medicinal Plants Unit, Medical University of Lublin, Lublin, Poland
| | - Jacek Kurzepa
- Department of Medical Chemistry, Medical University of Lublin, Lublin, Poland
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Janata A, Magnet IAM, Schreiber KL, Wilson CD, Stezoski JP, Janesko-Feldman K, Kochanek PM, Drabek T. Minocycline fails to improve neurologic and histologic outcome after ventricular fibrillation cardiac arrest in rats. World J Crit Care Med 2019; 8:106-119. [PMID: 31853446 PMCID: PMC6918046 DOI: 10.5492/wjccm.v8.i7.106] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/17/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Prolonged cardiac arrest (CA) produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities. Among other potential mechanisms, microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults. Minocycline is neuroprotective in some brain ischemia models, either by blunting the microglial response or by a direct effect on neurons. AIM To improve survival, attenuate neurologic deficits, neuroinflammation, and histological damage after ventricular fibrillation (VF) CA in rats. METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression, epinephrine, bicarbonate, and defibrillation. After return of spontaneous circulation (ROSC), rats were randomized to two groups: (1) Minocycline 90 mg/kg intraperitoneally (i.p.) at 15 min ROSC, followed by 22.5 mg/kg i.p. every 12 h for 72 h; and (2) Controls, receiving the same volume of vehicle (phosphate-buffered saline). The rats were kept normothermic during the postoperative course. Neurologic injury was assessed daily using Overall Performance Category (OPC; 1 = normal, 5 = dead) and Neurologic Deficit Score (NDS; 0% = normal, 100% = dead). Rats were sacrificed at 72 h. Neuronal degeneration (Fluoro-Jade C staining) and microglia proliferation (anti-Iba-1 staining) were quantified in four selectively vulnerable brain regions (hippocampus, striatum, cerebellum, cortex) by three independent reviewers masked to the group assignment. RESULTS In the minocycline group, 8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group (P = 0.46). The degree of neurologic deficit at 72 h [median, (interquartile range)] was not different between survivors in minocycline vs controls: OPC 1.5 (1-2.75) vs 2 (1.25-3), P = 0.442; NDS 12 (2-20) vs 17 (7-51), P = 0.328) or between all studied rats. The number of degenerating neurons (minocycline vs controls, mean ± SEM: Hippocampus 58 ± 8 vs 76 ± 8; striatum 121 ± 43 vs 153 ± 32; cerebellum 20 ± 7 vs 22 ± 8; cortex 0 ± 0 vs 0 ± 0) or proliferating microglia (hippocampus 157 ± 15 vs 193 cortex 0 ± 0 vs 0 ± 0; 16; striatum 150 ± 22 vs 161 ± 23; cerebellum 20 ± 7 vs 22 ± 8; cortex 26 ± 6 vs 31 ± 7) was not different between groups in any region (all P > 0.05). Numerically, there were approximately 20% less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group, with a consistent pattern of histological damage across the individual regions of interest. CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function, neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.
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Affiliation(s)
- Andreas Janata
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Emergency Department, KA Rudolfstiftung, Vienna 1030, Austria
| | - Ingrid AM Magnet
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Emergency Medicine, Vienna General Hospital, Medical University of Vienna, Vienna 1090, Austria
| | - Kristin L Schreiber
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Caleb D Wilson
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Wyoming Otolaryngology, Wyoming Medical Center, Casper, WY 82604, United States
| | - Jason P Stezoski
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Keri Janesko-Feldman
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
| | - Tomas Drabek
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
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Musolino ST, Schartner EP, Hutchinson MR, Salem A. Minocycline attenuates 3,4-methylenedioxymethamphetamine-induced hyperthermia in the rat brain. Eur J Pharmacol 2019; 858:172495. [PMID: 31238065 DOI: 10.1016/j.ejphar.2019.172495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/21/2019] [Accepted: 06/21/2019] [Indexed: 10/26/2022]
Abstract
Hyperthermia is most dangerous clinical symptom of acute MDMA administration, and a key factor related to potentially life-threatening MDMA-induced complications. MDMA induces a consistently faster onset of brain hyperthermia when compared to a delayed and moderate hyperthermia in the body, and the most harmful effects of MDMA are related to its modulation of neural functions. The primary focus of this study was to investigate the effects of minocycline, a centrally acting tetracycline derivative on MDMA-induced brain hyperthermia at high ambient temperature. However, we also simultaneously recorded body temperature, heart rate, and locomotor activity changes, allowing us to gain a better understanding of the mechanisms underlying the MDMA-induced hyperthermic response. We also investigated the effects of MDMA at normal ambient temperature to provide further evidence as to the importance of environmental factors on the intensity of MDMA's temperature effects. At normal ambient temperature, MDMA (10 mg/kg, i.p.) induced a significant brain and body hypothermia for the first 90 min following drug administration, and significantly increased heart rate and locomotor activity compared to saline controls. At high ambient temperature however, MDMA (10 mg/kg, i.p.) induced a robust and extended brain and body hyperthermia, as well as significantly increased heart rate and locomotor activity. A 3-day minocycline (50 mg/kg, i.p.) pre-treatment significantly attenuated MDMA-induced increases in brain temperature, body temperature, heart rate, and locomotor activity. Our findings indicate that minocycline is more effective in attenuating the exacerbated MDMA-induced hyperthermic response in the brain compared to the body at high ambient temperature.
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Affiliation(s)
- Stefan T Musolino
- ARC Centre of Excellence for Nanoscale BioPhotonics and Institute for Photonics and Advanced Sensing, Adelaide, SA, 5005, Australia; Discipline of Pharmacology, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.
| | - Erik P Schartner
- ARC Centre of Excellence for Nanoscale BioPhotonics and Institute for Photonics and Advanced Sensing, Adelaide, SA, 5005, Australia; School of Physical Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Mark R Hutchinson
- ARC Centre of Excellence for Nanoscale BioPhotonics and Institute for Photonics and Advanced Sensing, Adelaide, SA, 5005, Australia; Discipline of Pharmacology, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Abdallah Salem
- Discipline of Pharmacology, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia
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Bawage SS, Tiwari PM, Pillai S, Dennis VA, Singh SR. Antibiotic Minocycline Prevents Respiratory Syncytial Virus Infection. Viruses 2019; 11:v11080739. [PMID: 31405261 PMCID: PMC6723987 DOI: 10.3390/v11080739] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/05/2019] [Accepted: 08/07/2019] [Indexed: 01/15/2023] Open
Abstract
Treatment drugs, besides their specific activity, often have multiple effects on the body. The undesired effect of the drug may be repurposed as therapeutics, saving significant investigative time and effort. Minocycline has anti-cancer, anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Presently, minocycline is also known to show anti-viral activity against Influenza virus, Japanese encephalitis virus, Simian immunodeficiency virus, Human immunodeficiency virus and West Nile virus. Here, we investigate the effect of minocycline on Respiratory syncytial virus (RSV), a common respiratory virus that causes severe mortality and morbidity in infants, children, and older adult populations. Currently, there is no effective vaccine or treatment for RSV infection; hence, there is a critical need for alternative and effective drug choices. Our study shows that minocycline reduces the RSV-mediated cytopathic effect and prevents RSV infection. This is the first study demonstrating the anti-viral activity of minocycline against RSV.
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Affiliation(s)
- Swapnil S Bawage
- Center for NanoBiotechnology Research, Life Science Building, Harris way, Montgomery, AL 36104, USA
| | - Pooja M Tiwari
- Center for NanoBiotechnology Research, Life Science Building, Harris way, Montgomery, AL 36104, USA
| | - Shreekumar Pillai
- Center for NanoBiotechnology Research, Life Science Building, Harris way, Montgomery, AL 36104, USA
| | - Vida A Dennis
- Center for NanoBiotechnology Research, Life Science Building, Harris way, Montgomery, AL 36104, USA
| | - Shree R Singh
- Center for NanoBiotechnology Research, Life Science Building, Harris way, Montgomery, AL 36104, USA.
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Refolo V, Stefanova N. Neuroinflammation and Glial Phenotypic Changes in Alpha-Synucleinopathies. Front Cell Neurosci 2019; 13:263. [PMID: 31263402 PMCID: PMC6585624 DOI: 10.3389/fncel.2019.00263] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/28/2019] [Indexed: 01/10/2023] Open
Abstract
The role of neuroinflammation has been increasingly recognized in the field of neurodegenerative diseases. Many studies focusing on the glial cells involved in the inflammatory responses of the brain, namely microglia and astroglia, have over the years pointed out the dynamic and changing behavior of these cells, accompanied by different morphologies and activation forms. This is particularly evident in diseased conditions, where glia react to any shift from homeostasis, acquiring different phenotypes. Particularly for microglia, it has soon become clear that such phenotypes are multiple, as multiple are the functions related to them. Several approaches have over time revealed different facets of microglial phenotypic diversity, and advanced genetic analyses, in recent years, have added new insights into microglial heterogeneity, opening novel scenarios that researchers have just started to explore. Among neurodegenerative diseases, an important section is represented by alpha-synucleinopathies. Here alpha-synuclein accumulates abnormally in the brain and, depending on its pattern of distribution, leads to the development of different clinical conditions. Also for these proteinopathies, neuroinflammation and glial activation have been identified as constant and crucial factors during disease development. In the present review we will address the current literature about glial phenotypic changes with respect to alpha-synucleinopathies, as well as consider the pathophysiological and therapeutic implications of such a dynamic cellular behavior.
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Affiliation(s)
| | - Nadia Stefanova
- Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Ghosh B, Nong J, Wang Z, Urban MW, Heinsinger NM, Trovillion VA, Wright MC, Lepore AC, Zhong Y. A hydrogel engineered to deliver minocycline locally to the injured cervical spinal cord protects respiratory neural circuitry and preserves diaphragm function. Neurobiol Dis 2019; 127:591-604. [PMID: 31028873 DOI: 10.1016/j.nbd.2019.04.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 04/06/2019] [Accepted: 04/23/2019] [Indexed: 12/13/2022] Open
Abstract
We tested a biomaterial-based approach to preserve the critical phrenic motor circuitry that controls diaphragm function by locally delivering minocycline hydrochloride (MH) following cervical spinal cord injury (SCI). MH is a clinically-available antibiotic and anti-inflammatory drug that targets a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations that cannot be achieved by systemic administration, which limits its clinical efficacy. We have developed a hydrogel-based MH delivery system that can be injected into the intrathecal space for local delivery of high concentrations of MH, without damaging spinal cord tissue. Implantation of MH hydrogel after unilateral level-C4/5 contusion SCI robustly preserved diaphragm function, as assessed by in vivo recordings of compound muscle action potential (CMAP) and electromyography (EMG) amplitudes. MH hydrogel also decreased lesion size and degeneration of cervical motor neuron somata, demonstrating its central neuroprotective effects within the injured cervical spinal cord. Furthermore, MH hydrogel significantly preserved diaphragm innervation by the axons of phrenic motor neurons (PhMNs), as assessed by both detailed neuromuscular junction (NMJ) morphological analysis and retrograde PhMN labeling from the diaphragm using cholera toxin B (CTB). In conclusion, our findings demonstrate that local MH hydrogel delivery to the injured cervical spinal cord is effective in preserving respiratory function after SCI by protecting the important neural circuitry that controls diaphragm activation.
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Affiliation(s)
- Biswarup Ghosh
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10th St., Bluemle Life Sciences Building - Room 245, Philadelphia, PA 19107, United States of America
| | - Jia Nong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Bossone 7-716, Philadelphia, PA 19104, United States of America
| | - Zhicheng Wang
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Bossone 7-716, Philadelphia, PA 19104, United States of America
| | - Mark W Urban
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10th St., Bluemle Life Sciences Building - Room 245, Philadelphia, PA 19107, United States of America
| | - Nicolette M Heinsinger
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10th St., Bluemle Life Sciences Building - Room 245, Philadelphia, PA 19107, United States of America
| | - Victoria A Trovillion
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10th St., Bluemle Life Sciences Building - Room 245, Philadelphia, PA 19107, United States of America
| | - Megan C Wright
- Department of Biology, Arcadia University, 450 S Easton Rd, 220 Boyer Hall, Glenside, PA 19038, United States of America
| | - Angelo C Lepore
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, 233 S. 10th St., Bluemle Life Sciences Building - Room 245, Philadelphia, PA 19107, United States of America.
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Bossone 7-716, Philadelphia, PA 19104, United States of America.
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Cankaya S, Cankaya B, Kilic U, Kilic E, Yulug B. The therapeutic role of minocycline in Parkinson's disease. Drugs Context 2019; 8:212553. [PMID: 30873213 PMCID: PMC6408180 DOI: 10.7573/dic.212553] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 01/04/2023] Open
Abstract
Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease (PD), Huntington's disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.
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Affiliation(s)
- Seyda Cankaya
- Department of Neurology, Faculty of Medicine, Alaaddin Keykubat University, Alanya, Turkey
| | - Baris Cankaya
- Department of Anesthesiology and Reanimation, Marmara University Pendik Education and Research Hospital, Istanbul, Turkey
| | - Ulkan Kilic
- Department of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Ertugrul Kilic
- Department of Medical Physiology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Burak Yulug
- Department of Neurology, Faculty of Medicine, Alaaddin Keykubat University, Alanya, Turkey
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Denis HL, Lauruol F, Cicchetti F. Are immunotherapies for Huntington's disease a realistic option? Mol Psychiatry 2019; 24:364-377. [PMID: 29487401 DOI: 10.1038/s41380-018-0021-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 12/22/2017] [Accepted: 01/15/2018] [Indexed: 01/28/2023]
Abstract
There is compelling evidence that the pathophysiology of many neurodegenerative diseases includes dysregulation of the immune system, with some elements that precede disease onset. However, if these alterations are prominent, why have clinical trials targeting this system failed to translate into long-lasting meaningful benefits for patients? This review focuses on Huntington's disease, a genetic disorder marked by notable cerebral and peripheral inflammation. We summarize ongoing and completed clinical trials that have involved pharmacological approaches to inhibit various components of the immune system and their pre-clinical correlates. We then discuss new putative treatment strategies using more targeted immunotherapies such as vaccination and intrabodies and how these may offer new hope in the treatment of Huntington's disease as well as other neurodegenerative diseases.
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Affiliation(s)
- Hélèna L Denis
- Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada.,Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada
| | - Florian Lauruol
- Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada.,Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada
| | - Francesca Cicchetti
- Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada. .,Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
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Zhang G, Zha J, Liu J, Di J. Minocycline impedes mitochondrial-dependent cell death and stabilizes expression of hypoxia inducible factor-1α in spinal cord injury. Arch Med Sci 2019; 15:475-483. [PMID: 30899301 PMCID: PMC6425201 DOI: 10.5114/aoms.2018.73520] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 01/01/2018] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION One of the crucial mechanisms following spinal cord injury is mitochondria-associated cell death. Minocycline, an anti-inflammatory drug, is well known to impede mitochondrial cell death. However, there has been no study on the effect of minocycline linking Fas cell surface death receptor (FAS)-mediated cell death and hypoxia inducible factor (HIF-1α), the targets involved in mitochondrial cell death. MATERIAL AND METHODS Male Sprague Dawley rats (N = 15, divided into three groups) were subjected to traumatic spinal cord injury and were injected with minocycline (n = 5) (90 mg/kg and later a 45 mg/kg dose twice a day (every 12 h)). Injection with sterile PBS in injured animals served as the vehicle (n = 5) and another group comprised healthy animals (n = 5). TUNEL assay was used to quantify cell death. The release of Smac/Diablo, cytochrome-c (cyt-c), HIF-1α, FAS ligand (FASL) and tumour necrosis factor-α (TNF-α) was measured using ELISA. Expression of HIF-1α, FASL and other cell death associated factors was quantified at the mRNA and protein level and confirmed with immunohistochemistry. RESULTS There was a marked reduction in the HIF-1α and FASL expression levels in the minocycline-treated group compared to the vehicle. The reduction of HIF-1α and FASL was associated with other factors linked to cell death (Smac/Diablo, cyt-c, TNF-α, p53, caspase-8 and BH3 interacting domain death agonist (BID)) (p < 0.5; *p < 0.05 vs. vehicle group, **p < 0.01 vs. vehicle group). CONCLUSIONS The present study focuses on the investigation of minocycline in inhibiting mitochondria-associated cell death by modulating FASL and HIF-1α expression, which are seemingly interlinked mechanisms contributing to cell death.
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Affiliation(s)
- Guolei Zhang
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Junpu Zha
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Junchuan Liu
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Di
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Kurisu K, Kim JY, You J, Yenari MA. Therapeutic Hypothermia and Neuroprotection in Acute Neurological Disease. Curr Med Chem 2019; 26:5430-5455. [PMID: 31057103 PMCID: PMC6913523 DOI: 10.2174/0929867326666190506124836] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/24/2018] [Accepted: 04/11/2019] [Indexed: 01/07/2023]
Abstract
Therapeutic hypothermia has consistently been shown to be a robust neuroprotectant in many labs studying different models of neurological disease. Although this therapy has shown great promise, there are still challenges at the clinical level that limit the ability to apply this routinely to each pathological condition. In order to overcome issues involved in hypothermia therapy, understanding of this attractive therapy is needed. We review methodological concerns surrounding therapeutic hypothermia, introduce the current status of therapeutic cooling in various acute brain insults, and review the literature surrounding the many underlying molecular mechanisms of hypothermic neuroprotection. Because recent work has shown that body temperature can be safely lowered using pharmacological approaches, this method may be an especially attractive option for many clinical applications. Since hypothermia can affect multiple aspects of brain pathophysiology, therapeutic hypothermia could also be considered a neuroprotection model in basic research, which would be used to identify potential therapeutic targets. We discuss how research in this area carries the potential to improve outcome from various acute neurological disorders.
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Affiliation(s)
- Kota Kurisu
- Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
| | - Jong Youl Kim
- Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
- Departments of Anatomy, Yonsei University College of Medicine, Seoul, South Korea
| | - Jesung You
- Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
- Department of Emergency Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Midori A. Yenari
- Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
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Koulaeinejad N, Haddadi K, ehteshami S, shafizad M, Salehifar E, Emadian O, Ali Mohammadpour R, Ala S. Effects of Minocycline on Neurological Outcomes In Patients With Acute Traumatic Brain Injury: A Pilot Study. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2019; 18:1086-1096. [PMID: 31531090 PMCID: PMC6706715 DOI: 10.22037/ijpr.2019.1100677] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Traumatic brain injury (TBI) is a public health problem worldwide. Secondary damage of brain injury begins within a few minutes after the trauma and can last a long time. It can be reversible, unlike primary injury. Therefore, therapeutic intervention can be used. The aims of this study were to assess the effects of minocycline on neurological function and serum S100B protein and neuron-specific enolase (NSE) levels in patients with moderate to severe TBI. Patients with acute onset of TBI and surgical evacuation of hematoma were randomized to receive either minocycline 100 mg orally twice daily or placebo for 7 days. The primary outcomes included changes in level of S100B and NSE at different time points during the trial. Additionally, changes in Glasgow coma scale (GCS) score were evaluated. The Glasgow Outcome Scale-Extended (GOS-E) score at 6 months after injury was assessed in discharge patients. Thirty four patients were randomized into the placebo (n = 20) and treatment (n = 14) groups. There was a marginal statistically significant differences in the normalized value of S100B between groups (p < 0.1). The reduction in serum NSE level from baseline to day 5 was statistically significant (p = 0.01) in minocycline group while it was not significantly decrease in placebo group (p = 0.2). Also, GCS improvement over time within the minocycline group was significant (p = 0.04) while was not significant in placebo group (p = 0.11). The GOS-E scores were not significantly different between minocycline and placebo group. Based on this study, it seems that the use of minocycline may be effective in acute TBI.
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Affiliation(s)
- Neda Koulaeinejad
- Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Kaveh Haddadi
- Department of Neurosurgery, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - saeid ehteshami
- Department of Neurosurgery, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - misagh shafizad
- Department of Neurosurgery, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Ebrahim Salehifar
- Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Omid Emadian
- Department of Pathology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Reza Ali Mohammadpour
- Department of Biostatistics, Faculty of Health Sciences, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Shahram Ala
- Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
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Ramírez-Cheyne JA, Duque GA, Ayala-Zapata S, Saldarriaga-Gil W, Hagerman P, Hagerman R, Payán-Gómez C. Fragile X syndrome and connective tissue dysregulation. Clin Genet 2018; 95:262-267. [DOI: 10.1111/cge.13469] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 11/03/2018] [Indexed: 12/15/2022]
Affiliation(s)
| | | | | | | | - Paul Hagerman
- UC Davis MIND Institute, University of California; Davis California
| | - Randi Hagerman
- UC Davis MIND Institute, University of California; Davis California
| | - César Payán-Gómez
- Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario; Bogotá Colombia
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