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Antunes ASLM, Reis-de-Oliveira G, Martins-de-Souza D. Molecular overlaps of neurological manifestations of COVID-19 and schizophrenia from a proteomic perspective. Eur Arch Psychiatry Clin Neurosci 2025; 275:109-122. [PMID: 39028452 DOI: 10.1007/s00406-024-01842-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 06/06/2024] [Indexed: 07/20/2024]
Abstract
COVID-19, a complex multisystem disorder affecting the central nervous system, can also have psychiatric sequelae. In addition, clinical evidence indicates that a diagnosis of a schizophrenia spectrum disorder is a risk factor for mortality in patients with COVID-19. In this study, we aimed to explore brain-specific molecular aspects of COVID-19 by using a proteomic approach. We analyzed the brain proteome of fatal COVID-19 cases and compared it with differentially regulated proteins found in postmortem schizophrenia brains. The COVID-19 proteomic dataset revealed a strong enrichment of proteins expressed by glial and neuronal cells and processes related to diseases with a psychiatric and neurodegenerative component. Specifically, the COVID-19 brain proteome enriches processes that are hallmark features of schizophrenia. Furthermore, we identified shared and distinct molecular pathways affected in both conditions. We found that brain ageing processes are likely present in both COVID-19 and schizophrenia, albeit possibly driven by distinct processes. In addition, alterations in brain cell metabolism were observed, with schizophrenia primarily impacting amino acid metabolism and COVID-19 predominantly affecting carbohydrate metabolism. The enrichment of metabolic pathways associated with astrocytic components in both conditions suggests the involvement of this cell type in the pathogenesis. Both COVID-19 and schizophrenia influenced neurotransmitter systems, but with distinct impacts. Future studies exploring the underlying mechanisms linking brain ageing and metabolic dysregulation may provide valuable insights into the complex pathophysiology of these conditions and the increased vulnerability of schizophrenia patients to severe outcomes.
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Affiliation(s)
- André S L M Antunes
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.
| | | | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, University of Campinas, Campinas, Brazil.
- D'or Institute for Research and Education, São Paulo, Brazil.
- Experimental Medicine Research Cluster (EMRC), Estate University of Campinas, Campinas, Brazil.
- INCT in Modelling Human Complex Diseases with 3D Platforms (Model3D), INCT in Modelling Human Complex Diseases with 3D Platforms (Model3D), São Paulo, Brazil.
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Pradhan G, Juvale K. Structure activity relationship for anticancer activities of spirooxindole derivatives: A comprehensive review. Bioorg Chem 2025; 154:107975. [PMID: 39591685 DOI: 10.1016/j.bioorg.2024.107975] [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: 08/04/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024]
Abstract
Cancer remains one of the leading causes of mortality worldwide, necessitating the continuous search for novel therapeutic agents. Spirooxindole derivatives have recently emerged as a class of compounds with significant potential for cancer treatment owing to their diverse pharmacological activities and unique structural features. The structural diversity of spirooxindole derivatives enables a wide range of modifications, facilitating optimization of their pharmacokinetic and pharmacodynamic properties. Moreover, their ability to interact with multiple molecular targets involved in cancer progression, including kinases, receptors, and enzymes, makes them attractive candidates for multi-targeted therapy. In preclinical studies, numerous spirooxindole derivatives have demonstrated promising antiproliferative activity against various cancer cell lines, including breast, lung, colon, and prostate cancers. Mechanistic investigations have revealed their ability to induce cell cycle arrest and apoptosis and inhibit angiogenesis and metastasis, underscoring their potential as effective anticancer agents. However, challenges such as off-target effects, drug resistance, and limited bioavailability need to be addressed to maximize the therapeutic potential of these compounds. Continued research efforts to elucidate their molecular mechanisms, optimize their pharmacological properties, and conduct rigorous clinical evaluations are warranted to harness their full therapeutic benefits for cancer treatment. This review provides a comprehensive overview of recent advancements in developing spirooxindole derivatives as anticancer agents with structure-activity relationships.
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Affiliation(s)
- Gandhar Pradhan
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Kapil Juvale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India.
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Bhatnagar A, Raj G, Das S, Kannihali A, Rajakumara E, Murray G, Ray S. Integrated bioinformatics and interaction analysis to advance chronotherapies for mental disorders. Front Pharmacol 2024; 15:1444342. [PMID: 39703389 PMCID: PMC11655208 DOI: 10.3389/fphar.2024.1444342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/12/2024] [Indexed: 12/21/2024] Open
Abstract
Introduction Robust connections have been identified between the pathophysiology of mental disorders and the functioning of the circadian system. The overarching objective of this study was to investigate the potential for circadian rhythms to be leveraged for therapeutics in mental disorders. Methods We considered two approaches to chronotherapy-optimal timing of existing medications ("clocking the drugs") and redressing circadian abnormalities with small molecules ("drugging the clock"). We assessed whether circadian rhythm-modulating compounds can interact with the prominent drug targets of mental disorders utilizing computational tools like molecular docking and molecular dynamics simulation analysis. Results Firstly, an analysis of transcript-level rhythmic patterns in recognized drug targets for mental disorders found that 24-hour rhythmic patterns were measurable in 54.4% of targets in mice and 35.2% in humans. We also identified several drug receptors exhibiting 24-hour rhythmicity involved in critical physiological pathways for neural signaling and communication, such as neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, and dopaminergic and cholinergic synapses. These findings advocate that further research into the timing of drug administration in mental disorders is urgently required. We observed that many pharmacological modulators of mammalian circadian rhythms, including KL001, SR8278, SR9009, Nobiletin, and MLN4924, exhibit stable binding with psychotropic drug targets. Discussion These findings suggest that circadian clock-modulating pharmacologically active small molecules could be investigated further for repurposing in the treatment of mood disorders. In summary, the present analyses indicate the potential of chronotherapeutic approaches to mental disorder pharmacotherapy and specify the need for future circadian rhythm-oriented clinical research.
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Affiliation(s)
- Apoorva Bhatnagar
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
- Centre for Mental Health, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Gupta Raj
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
| | - Sandip Das
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
| | - Arpita Kannihali
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
| | - Eerappa Rajakumara
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
| | - Greg Murray
- Centre for Mental Health, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Sandipan Ray
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India
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Su C, Zhang L, Pan Y, Jiao J, Luo P, Chang X, Zhang H, Si X, Chen W, Huang Y. Enhancing aggression in Henan gamecocks via augmentation of serotonergic-dopaminergic signaling and attenuation of neuroimmune response. Poult Sci 2024; 103:104055. [PMID: 39190992 PMCID: PMC11395772 DOI: 10.1016/j.psj.2024.104055] [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: 05/08/2024] [Revised: 06/18/2024] [Accepted: 06/27/2024] [Indexed: 08/29/2024] Open
Abstract
Animal aggression is one of the most conserved behaviors. Excessive and inappropriate aggression was a serious social concern across species. After long-term selection under strict stress conditions, Henan gamecock serves as a good model for studying aggressive behavior. In this research, we constructed a Henan game chicken backcross population containing 25% Rhode Island Red (RIR), and conducted brain transcriptomics and serum metabolomics analyses on Henan gamecock (HGR) through its comparison with its female encounters (HGH) and the male backcross birds (BGR). The study revealed that seven differential metabolites in serum and 172 differentially expressed genes in the brain were commonly shared in both HGR vs. HGH and HGR vs. BGR comparisons. They exhibited the same patterns of modulation in Henan gamecocks, following either HGH < HGR > BGR or HGH > HGR < BGR style. Therein, some neurological genes involving in serotonergic and dopaminergic signaling were upregulated, while the levels of many genes related with neuro-immune function were decreased in Henan gamecock. In addition, many unknown genes specifically or highly expressed in the brain of the Henan gamecock were identified. These genes are potentially key candidates for enhancing the bird's aggression. Multi-omics joint analysis revealed that tyrosine metabolism and neuroactive ligand-receptor interaction were commonly affected. Overall, our results propose that the aggressiveness of Henan gamecocks can be heightened by the activation of the serotonergic-dopaminergic metabolic process in the brain, which concurrently impairs the neuroimmune system. Further research is needed to identify the function of these unknown genes on the bird's aggressive behavior.
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Affiliation(s)
- Chuanchen Su
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Lin Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Yuxian Pan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Jingya Jiao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Pengna Luo
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Xinghai Chang
- Henan Changxing Agriculture and Animal Husbandry co., LTD, Kaifeng, Henan 475000, China
| | - Huaiyong Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Xuemeng Si
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Wen Chen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China
| | - Yanqun Huang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou Henan 450046, China.
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Ghaffari-Bohlouli P, Jafari H, Okoro OV, Alimoradi H, Nie L, Jiang G, Kakkar A, Shavandi A. Gas Therapy: Generating, Delivery, and Biomedical Applications. SMALL METHODS 2024; 8:e2301349. [PMID: 38193272 DOI: 10.1002/smtd.202301349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/11/2023] [Indexed: 01/10/2024]
Abstract
Oxygen (O2), nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), and hydrogen (H2) with direct effects, and carbon dioxide (CO2) with complementary effects on the condition of various diseases are known as therapeutic gases. The targeted delivery and in situ generation of these therapeutic gases with controllable release at the site of disease has attracted attention to avoid the risk of gas poisoning and improve their performance in treating various diseases such as cancer therapy, cardiovascular therapy, bone tissue engineering, and wound healing. Stimuli-responsive gas-generating sources and delivery systems based on biomaterials that enable on-demand and controllable release are promising approaches for precise gas therapy. This work highlights current advances in the design and development of new approaches and systems to generate and deliver therapeutic gases at the site of disease with on-demand release behavior. The performance of the delivered gases in various biomedical applications is then discussed.
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Affiliation(s)
- Pejman Ghaffari-Bohlouli
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec, H3A 0B8, Canada
| | - Hafez Jafari
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
| | - Oseweuba Valentine Okoro
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
| | - Houman Alimoradi
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
| | - Lei Nie
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
- College of Life Sciences, Xinyang Normal University, Xinyang, 464000, China
| | - Guohua Jiang
- School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Ashok Kakkar
- Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec, H3A 0B8, Canada
| | - Amin Shavandi
- 3BIO-BioMatter, École polytechnique de Bruxelles, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt, 50-CP 165/61, Brussels, 1050, Belgium
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Chandel P, Thapa K, Kanojia N, Rani L, Singh TG, Rohilla P. Exploring Therapeutic Potential of Phytoconstituents as a Gut Microbiota Modulator in the Management of Neurological and Psychological Disorders. Neuroscience 2024; 551:69-78. [PMID: 38754721 DOI: 10.1016/j.neuroscience.2024.05.002] [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: 02/16/2024] [Accepted: 05/02/2024] [Indexed: 05/18/2024]
Abstract
The functioning of the brain and its impact on behavior, emotions, and cognition can be affected by both neurological and psychiatric disorders that impose a significant burden on global health. Phytochemicals are helpful in the treatment of several neurological and psychological disorders, including anxiety, depression, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD), because they have symptomatic benefits with few adverse reactions. Changes in gut microbiota have been associated with many neurological and psychiatric conditions. This review focuses on the potential efficacy of phytochemicals such as flavonoids, terpenoids, and polyphenols in regulating gut flora and providing symptomatic relief for a range of neurological and psychological conditions. Evidence-based research has shown the medicinal potentials of these phytochemicals, but additional study is required to determine whether altering gut microbiota might slow the advancement of neurological and psychological problems.
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Affiliation(s)
- Prarit Chandel
- Chitkara University, School of Pharmacy, Himachal Pradesh, India
| | - Komal Thapa
- Chitkara University, School of Pharmacy, Himachal Pradesh, India.
| | - Neha Kanojia
- Chitkara University, School of Pharmacy, Himachal Pradesh, India
| | - Lata Rani
- Chitkara University, School of Pharmacy, Himachal Pradesh, India
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Bernardus Saayman JL, Harvey BH, Wegener G, Brink CB. Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression. Eur J Pharmacol 2024; 969:176434. [PMID: 38458412 DOI: 10.1016/j.ejphar.2024.176434] [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: 11/23/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND Major depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. AIM To investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. METHODS ACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. RESULTS Sub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. CONCLUSION This study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.
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Affiliation(s)
- Juandré Lambertus Bernardus Saayman
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen™), Faculty of Health Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa
| | - Brian Herbert Harvey
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen™), Faculty of Health Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa; South African Medical Research Council Unit on Risk and Resilience on Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Rondebosch, 7700, South Africa; The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia
| | - Gregers Wegener
- Translational Neuropsychiatry Unit (TNU), Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark
| | - Christiaan Beyers Brink
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen™), Faculty of Health Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
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Yeh CY, Cai HY, Kuo HH, Lin YY, He ZJ, Cheng HC, Yang CJ, Huang CYF, Chang YC. ALDOA coordinates PDE3A through the β-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations. Biochem Biophys Res Commun 2024; 696:149489. [PMID: 38244313 DOI: 10.1016/j.bbrc.2024.149489] [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: 10/30/2023] [Revised: 12/21/2023] [Accepted: 01/05/2024] [Indexed: 01/22/2024]
Abstract
Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through β-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.
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Affiliation(s)
- Chia-Ying Yeh
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Huei Yu Cai
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Han-His Kuo
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - You-Yu Lin
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Zhao-Jing He
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiao-Chen Cheng
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Jen Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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Palà E, García-Rodríguez P, Bustamante A, Penalba A, Lamana-Vallverdú M, Guamán-Pilco DR, Delgado P, Riba I, Jimenez-Balado J, Planas A, Simó-Servat O, Escudero-Martinez I, Montaner J. Common and specific proteins and pathways in heart and cerebral ischemia. J Stroke Cerebrovasc Dis 2024; 33:107467. [PMID: 37944280 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107467] [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: 07/13/2023] [Revised: 10/16/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVE To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies. METHODS Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler. RESULTS Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3. CONCLUSIONS The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets.
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Affiliation(s)
- Elena Palà
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Paula García-Rodríguez
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | | | - Anna Penalba
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Marcel Lamana-Vallverdú
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Daisy R Guamán-Pilco
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Pilar Delgado
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain.
| | - Iolanda Riba
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain; Santa Maria University Hospital, Neurology service, Lleida, Spain.
| | - Joan Jimenez-Balado
- Hospital del Mar Research Institute, Neurovascular Research Lab, Barcelona, Spain.
| | - Alejandra Planas
- Diabetes Research and Metabolism Unit. Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain.
| | - Olga Simó-Servat
- Diabetes Research and Metabolism Unit. Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain; CIBERDEM, ISCIII, Madrid, Spain.
| | | | - Joan Montaner
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR)-Universitat Autónoma de Barcelona, Barcelona, Spain; Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville & Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain.
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Yan Y, Zhao Y, Lu Y, Acharya AP, Wang W, Zhan CG, Ye J, Du F, Zhu X, Xu Y. Characterization of 2 Novel Phosphodiesterase 2 Inhibitors Hcyb1 and PF-05180999 on Depression- and Anxiety-Like Behavior. Int J Neuropsychopharmacol 2023; 26:415-425. [PMID: 37208298 PMCID: PMC10289143 DOI: 10.1093/ijnp/pyad020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/17/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Phosphodiesterase 2A (PDE2A) represents a novel target for new therapies addressing psychiatric disorders. To date, the development of PDE2A inhibitors suitable for human clinical evaluation has been hampered by the poor brain accessibility and metabolic stability of the available compounds. METHODS Corticosterone (CORT)-induced neuronal cell lesion and restraint stress mouse model were used to measure the neuroprotective effect in cells and antidepressant-like behavior in mice. RESULTS The cell-based assay showed that both Hcyb1 and PF were potent in protecting cells against stress hormone CORT insults by stimulating cAMP and cGMP signaling in hippocampal cells (HT-22). Administration of both compounds before treatment of CORT to cells increased cAMP/cGMP, VASP phosphorylation at Ser239 and Ser157, cAMP response element binding protein phosphorylation at Ser133, and brain derived neurotrophic factor BDNF expression. Further in vivo study showed that both Hcyb1 and PF displayed -antidepressant- and anxiolytic-like effects against restraint stress as indicated by reduced immobility time in the forced swimming and tail suspension tasks as well as increased open arm entries and time spent in open arms and holes visit in elevated plus maze and hole-board tests, respectively. The biochemical study confirmed that these antidepressant- and anxiolytic-like effects of Hcyb1 and PF were related to cAMP and cGMP signaling in the hippocampus. CONCLUSIONS The results extend the previous studies and validate that PDE2A is a tractable target for drug development in the treatment of emotional disorders such as depression and anxiety.
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Affiliation(s)
- Yuqing Yan
- Department of Anesthesiology, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
| | - Yuhan Zhao
- Department of Anesthesiology, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
| | - Yue Lu
- Department of Anesthesiology, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
| | - Abhinav P Acharya
- Chemical Engineering School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona, USA
| | - Wei Wang
- Department of Pharmacology and Toxicology, Arizona Center for Drug Discovery, College of Pharmacy, University of Arizona, Tucson, Arizona, USA
| | - Chang-Guo Zhan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
| | - Jianghong Ye
- Department of Anesthesiology, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
| | - Fu Du
- FD NeuroTechnologies Consulting and Services, Inc., Columbia, Maryland, USA
| | - Xiongwei Zhu
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ying Xu
- Department of Anesthesiology, Rutgers, the State University of New Jersey, Newark, New Jersey, USA
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
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11
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Phosphodiesterase inhibitor and selective serotonin reuptake inhibitor combination therapy versus monotherapy for the treatment of major depressive disorder: a systematic review and meta-analysis. Int Clin Psychopharmacol 2023:00004850-990000000-00045. [PMID: 36752703 DOI: 10.1097/yic.0000000000000457] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Selective serotonin reuptakeinhibitors (SSRIs) are the gold standard treatment for major depressive disorder (MDD). However, the use of phosphodiesterase (PDE) inhibitors in the treatment of MDD remains unclear. Our study aims to compare the effect of PDE inhibitor combination therapy to SSRI monotherapy for the treatment of MDD. METHODS We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science databases, for studies that assess the impact of PDE inhibitor therapy on MDD patients. The primary outcome of our study was treatment response rate at the end of study time. Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. A P-value <0.05 was considered statistically significant. RESULTS A total of four randomized control trials (RCTs), including 270 patients with MDD, were included in the analysis. Follow-up periods ranged from 6 to 12 weeks. The PDE inhibitor group was associated with a significantly higher treatment response rate (OR, 4.77; 95% CI, 2.05-11.12; P = 0.0003). CONCLUSION Our meta-analysis demonstrated that MDD patients receiving PDE inhibitor combination therapy had a higher treatment response rate than MDD patients receiving SSRI monotherapy. Further large-scale RCTs with long-term follow-ups are necessary to validate our findings.
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12
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Lakhssassi K, Sarto MP, Marín B, Lahoz B, Folch J, Alabart JL, Serrano M, Calvo JH. Exploring differentially expressed genes in hypothalamic, pars tuberalis and pineal gland transcriptomes in different sexual behavior phenotypes in rams using RNA-Seq. J Anim Sci 2023; 101:skac365. [PMID: 36331073 PMCID: PMC9833037 DOI: 10.1093/jas/skac365] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022] Open
Abstract
Reproductive seasonality is a limiting factor in sheep production. Sexual behavior is a key element in reproductive efficiency, and this function is regulated by the hypothalamus-pituitary-gonadal (HPG) axis. To understand the mechanisms of sexual behavior, transcriptomic sequencing technology was used to identify differentially expressed genes (DEGs) in the hypothalamus (HT), pars tuberalis (PT) and pineal gland (PG) in Rasa Aragonesa rams with different sexual behavior. Bioinformatics analysis of the 16,401 identified genes by RNA-Seq revealed 103 and 12 DEGs in the HT and the PG, respectively, at a false discovery rate (FDR) of 5% with an absolute value of expression ≥ 1 (log2FC). However, no DEGs were found in the PT. Functional annotation and pathway enrichment analysis showed that DEGs of HT were enriched mainly in neuroactive ligand-receptor interactions and signaling pathways, including notable candidate genes such as MTNR1A, CHRNA2, FSHB, LHB, GNRHR, AVP, PRL, PDYN, CGA, GABRD, and TSHB, which play a crucial role in sexual behavior. The GnRH and cAMP signaling pathways were also highlighted. In addition, gene set enrichment analysis (GSEA) identified potential pathways, dominated mainly by biological process category, that could be responsible for the differences in sexual behavior observed in rams. The intracellular protein transport and pattern specification process were enriched within the PT and the transcription factor binding and protein ubiquitination pathways for the PG. Thus, these pathways together may play an important role in the regulation of the sexual behavior in Rasa Aragonesa rams through the hypothalamic-pituitary-gonadal axis. The validation of 5 DEGs using reverse transcription quantitative polymerase chain reaction (RT-qPCR) showed expression patterns like the found with RNA-Seq. Overall, these results contribute to understanding the genomic basis of sexual behavior in rams. Our study demonstrates that multiple networks and pathways orchestrate sexual behavior in sheep.
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Affiliation(s)
- Kenza Lakhssassi
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
- INRA Instituts, 6356 Rabat, Morocco
| | - María Pilar Sarto
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
| | - Belén Marín
- Centre for Encephalopathies and Emerging Transmissible Diseases, Faculty of Veterinary Medicine, University of Zaragoza, 50018 Zaragoza, Spain
| | - Belén Lahoz
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
| | - José Folch
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
| | - José Luis Alabart
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
| | - Malena Serrano
- Department of Animal Breeding and Genetics, INIA-CSIC, 28040 Madrid, Spain
| | - Jorge Hugo Calvo
- Agrifood Research and Technology Centre of Aragon-IA2, 50059 Zaragoza, Spain
- ARAID, 50018 Zaragoza, Spain
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13
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Li ZH, Yang GH, Wang F. Molecular mechanisms of Baihedihuang decoction as a treatment for breast cancer related anxiety: A network pharmacology and molecular docking study. World J Clin Cases 2022; 10:12104-12115. [PMID: 36483797 PMCID: PMC9724542 DOI: 10.12998/wjcc.v10.i33.12104] [Citation(s) in RCA: 3] [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: 07/15/2022] [Revised: 09/04/2022] [Accepted: 10/12/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The therapeutic effects of a combination of Chinese medicines called Baihedihuang decoction (BD) have been clinically verified, although its molecular targets in breast cancer related anxiety remain unknown.
AIM To explore the molecular mechanisms of BD for breast cancer related anxiety treatment.
METHODS We used the Traditional Chinese Medicine Systems Pharmacology database to screen the active ingredients and potential targets of BD, and constructed the "drug-ingredient-target" network map with the help of Cytoscape 3.8 software. Also, we used the Online Mendelian Inheritance in Man, DrugBank, and Gencards databases to collect the disease targets of breast cancer related anxiety, and used the STRING platform to perform protein interaction analysis and construct the protein-protein interaction network. Metascape platform was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of key targets. Molecular docking technology was used to verify the drug component/target disease network.
RESULTS We screened 16 active ingredients of BD for breast cancer related anxiety, with 113 target proteins. There are 931 disease targets of breast cancer related anxiety, and finally, 43 key targets and 305 Kyoto Encyclopedia of Genes and Genomes pathways were generated. The main active ingredients of BD for breast cancer related anxiety are verbascoside, β-sitosterol, stigmasterol, catalpol, etc. CDK2, TP53, HTR2A, ESR1, etc. are its key targets, and the main involved signaling pathways may include neuroactive ligand-receptor interaction pathway, 5-hydroxytryptaminergic synapse, P53 signaling pathway, cGMP-PKG signaling pathway, the cAMP signaling pathway, etc. Finally, molecular docking was performed with Vina software to validate the key active ingredients in BD with the selected key action targets. The molecular docking results showed that verbascoside, β-sitosterol, stigmasterol and CDK2 could stably bind and interact through amino acid residues SER249, ARG260, PRO228, ALA282, SER276, LYS273, ASN272, etc.
CONCLUSION The therapeutic effect of BD for breast cancer related anxiety is multi-level, multi-target, and multi-pathway. The findings of this study provide ideas and basis for further research.
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Affiliation(s)
- Zhong-Hui Li
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Guo-Hua Yang
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Fang Wang
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
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14
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Pharmacological modulation of phosphodiesterase-7 as a novel strategy for neurodegenerative disorders. Inflammopharmacology 2022; 30:2051-2061. [PMID: 36272040 DOI: 10.1007/s10787-022-01072-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/06/2022] [Indexed: 11/05/2022]
Abstract
Neurodegenerative illness develops as a result of genetic defects that cause changes at numerous levels, including genomic products and biological processes. It entails the degradation of cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). PDE7 modulates intracellular cAMP signalling, which is involved in numerous essential physiological and pathological processes. For the therapy of neurodegenerative illnesses, the normalization of cyclic nucleotide signalling through PDE inhibition remains intriguing. In this article, we shall examine the role of PDEs in neurodegenerative diseases. Alzheimer's disease, Multiple sclerosis, Huntington's disease, Parkinson's disease, Stroke, and Epilepsy are related to alterations in PDE7 expression in the brain. Earlier, animal models of neurological illnesses including Alzheimer's disease, Parkinson's disease, and multiple sclerosis have had significant results to PDE7 inhibitors, i.e., VP3.15; VP1.14. In addition, modulation of CAMP/CREB/GSK/PKA signalling pathways involving PDE7 in neurodegenerative diseases has been addressed. To understand the etiology, treatment options of these disorders mediated by PDE7 and its subtypes can be the focus of future research.
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15
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Chen Y, Dong Y, Yan J, Wang L, Yu S, Jiao K, Paquet-Durand F. Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors. Int J Mol Sci 2022; 23:12170. [PMID: 36293024 PMCID: PMC9603353 DOI: 10.3390/ijms232012170] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/28/2022] [Accepted: 10/08/2022] [Indexed: 08/31/2023] Open
Abstract
The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood. The aim of this study was to systematically map the transcriptional changes that occur in the degenerating mouse retina at the single cell level. To this end, we employed single-cell RNA-sequencing (scRNA-seq) and retinal degeneration-1 (rd1) mice to profile the impact of the disease mutation on the diverse retinal cell types during early post-natal development. The transcriptome data allowed to annotate 43,979 individual cells grouped into 20 distinct clusters. We further characterized cluster-specific metabolic and biological changes in individual cell types. Our results highlight Ca2+-signaling as relevant to hereditary photoreceptor degeneration. Although metabolic reprogramming in retina, known as the 'Warburg effect', has been documented, further metabolic changes were noticed in rd1 mice. Such metabolic changes in rd1 mutation was likely regulated through mitogen-activated protein kinase (MAPK) pathway. By combining single-cell transcriptomes and immunofluorescence staining, our study revealed cell type-specific changes in gene expression, as well as interplay between Ca2+-induced cell death and metabolic pathways.
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Affiliation(s)
- Yiyi Chen
- Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
- Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany
| | - Yujie Dong
- Yunnan Eye Institute & Key Laboratory of Yunnan Province, 650021 Kunming, China
| | - Jie Yan
- Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
- Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany
| | - Lan Wang
- Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
- Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany
| | - Shirley Yu
- Graduate Training Centre of Neuroscience, University of Tübingen, 72076 Tübingen, Germany
| | - Kangwei Jiao
- Yunnan Eye Institute & Key Laboratory of Yunnan Province, 650021 Kunming, China
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16
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Differential expression of serum extracellular vesicle microRNAs and analysis of target-gene pathways in major depressive disorder. Biomark Neuropsychiatry 2022. [DOI: 10.1016/j.bionps.2022.100049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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17
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Medeiros KAAL, Almeida-Souza TH, Silva RS, Santos HF, Santos EV, Gois AM, Leal PC, Santos JR. Involvement of nitric oxide in the neurobiology of fear-like behavior. Nitric Oxide 2022; 124:24-31. [PMID: 35533947 DOI: 10.1016/j.niox.2022.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/06/2022] [Accepted: 04/26/2022] [Indexed: 12/20/2022]
Abstract
Fear is an emotional reaction that arises in dangerous situations, inducing the adaptation to an existing condition. This behavior was conserved in all vertebrates throughout evolution and is observed in mammals, birds, fish, amphibians, and reptiles. The neurocircuitry of fear involves areas of the limbic system, cortical regions, midbrain, and brainstem. These areas communicate with each other so that there is an expression of fear and memory formation to deal with the same situation at another time. The effect of nitric oxide (NO) on fear modulation has been explored. NO is a gaseous compound that easily diffuses through the cell membrane and is produced through the oxidation reaction of l-Arginine to l-citrulline catalyzed by nitric oxide synthase (NOS). Activating the intracellular NO receptor (soluble guanylyl cyclase enzyme - sGC) triggers an enzymatic cascade that can culminate in plastic events in the neuron. NOS inhibitors induce anxiolytic-like responses in fear modulation, whereas NO donors promote fear- and anxiety-like behaviors. This review describes the neurobiology of fear in mammals and non-mammals, how NO is produced in the central nervous system, and how NO acts in fear-like behavior.
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Affiliation(s)
- Katty A A L Medeiros
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil
| | - Thiago H Almeida-Souza
- Laboratory of Neurophysiology, Department of Physiology, Federal University of Sergipe, São Cristovão, SE, Brazil
| | - Rodolfo S Silva
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil
| | - Heitor F Santos
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil
| | - Eliziane V Santos
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil
| | - Auderlan M Gois
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil
| | - Pollyana C Leal
- Graduate Program of Dentistry, Federal University of Sergipe, Aracaju, SE, Brazil
| | - José R Santos
- Laboratory of Behavioral and Evolutionary Neurobiology, Department of Biosciences, Federal University of Sergipe, Itabaiana, SE, Brazil.
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18
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Zhu X, Li T, Hu E, Duan L, Zhang C, Wang Y, Tang T, Yang Z, Fan R. Proteomics Study Reveals the Anti-Depressive Mechanisms and the Compatibility Advantage of Chaihu-Shugan-San in a Rat Model of Chronic Unpredictable Mild Stress. Front Pharmacol 2022; 12:791097. [PMID: 35111057 PMCID: PMC8802092 DOI: 10.3389/fphar.2021.791097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/13/2021] [Indexed: 12/27/2022] Open
Abstract
Background: Chaihu-Shugan-San is a classical prescription to treat depression. According to the traditional Chinese medicine (TCM) principle, the 2 decomposed recipes in Chaihu-Shugan-San exert synergistic effects, including Shu Gan (stagnated Gan-Qi dispersion) and Rou Gan (Gan nourishment to alleviate pain). However, the specific mechanism of Chaihu-Shugan-San on depression and its compatibility rule remain to be explored. Objective: We aimed to explore the anti-depression mechanisms and analyze the advantage of TCM compatibility of Chaihu-Shugan-San. Methods: The chronic unpredictable mild stress (CUMS) rat model was established. Antidepressant effects were evaluated by sucrose preference test (SPT), and forced swimming test (FST). Tandem Mass Tag (TMT)-based quantitative proteomics of the hippocampus was used to obtain differentially expressed proteins (DEPs). Bioinformatics analysis including Gene Ontology (GO), pathway enrichment, and protein-protein interaction (PPI) networks was utilized to study the DEPs connections. At last, the achieved key targets were verified by western blotting. Results: Chaihu-Shugan-San increased weight gain and food intake, as well as exhibited better therapeutic effects including enhanced sucrose preference and extended immobility time when compared with its decomposed recipes. Proteomics showed Chaihu-Shugan-San, Shu Gan, and Rou Gan regulated 110, 12, and 407 DEPs, respectively. Compared with Shu Gan or Rou Gan alone, the expression of 22 proteins was additionally changed by Chaihu-Shugan-San treatment, whereas the expression of 323 proteins whose expression was changed by Shu Gan or Rou Gan alone were not changed by Chaihu-Shugan-San treatment. Bioinformatics analysis demonstrated that Chaihu-Shugan-San affected neurotransmitter’s release and transmission cycle (e.g., γ-aminobutyric acid (GABA), glutamate, serotonin, norepinephrine, dopamine, and acetylcholine). GABA release pathway is also targeted by the 22 DEPs. Unexpectedly, only 2 pathways were enriched by the 323 DEPs: Metabolism and Cellular responses to external stimuli. Lastly, the expression of Gad2, Vamp2, and Pde2a was verified by western blotting. Conclusions: Chaihu-Shugan-San treats depression via multiple targets and pathways, which may include regulations of 110 DEPs and some neurotransmitter’s transmission cycle. Compared with Shu Gan and Rou Gan, the 22 Chaihu-Shugan-San advanced proteins and the affected GABA pathway may be the advantages of Chaihu-Shugan-San compatibility. This research offers data and theory support for the clinical application of Chaihu-Shugan-San.
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Affiliation(s)
- Xiaofei Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Teng Li
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - En Hu
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lihua Duan
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunhu Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yang Wang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Tao Tang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaoyu Yang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Rong Fan
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central, South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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19
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Wagner K, Unger L, Salman MM, Kitchen P, Bill RM, Yool AJ. Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease. Int J Mol Sci 2022; 23:1388. [PMID: 35163313 PMCID: PMC8836214 DOI: 10.3390/ijms23031388] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders.
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Affiliation(s)
- Kim Wagner
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
| | - Lucas Unger
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Mootaz M. Salman
- Department of Physiology Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK;
- Oxford Parkinson’s Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Philip Kitchen
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Roslyn M. Bill
- College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (L.U.); (P.K.)
| | - Andrea J. Yool
- School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia;
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20
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Abdallah MS, Ramadan AN, Omara‐Reda H, Mansour NO, Elsokary MA, Elsawah HK, Zaki SA, Abo Mansour HE, Mosalam EM. Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder. CNS Neurosci Ther 2021; 27:1540-1548. [PMID: 34545997 PMCID: PMC8611782 DOI: 10.1111/cns.13731] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/02/2021] [Accepted: 09/10/2021] [Indexed: 12/28/2022] Open
Abstract
AIMS Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study. METHODS 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment. RESULTS Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers. CONCLUSION CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819.
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Affiliation(s)
- Mahmoud S. Abdallah
- Department of Clinical PharmacyFaculty of PharmacyUniversity of Sadat CitySadat CityEgypt
| | - Ahmed N. Ramadan
- Department of NeuropsychiatryFaculty of MedicineMenoufia UniversityShebin El‐KomEgypt
| | - Hend Omara‐Reda
- Department of NeuropsychiatryFaculty of MedicineMenoufia UniversityShebin El‐KomEgypt
| | - Noha O. Mansour
- Clinical Pharmacy and Pharmacy Practice DepartmentFaculty of PharmacyMansoura UniversityMansouraEgypt
| | - Mohamed A. Elsokary
- Department of BiostatisticsHigh Institute of Public HealthAlexandria UniversityAlexandriaEgypt
| | - Hozaifa K. Elsawah
- Department of BiostatisticsHigh Institute of Public HealthAlexandria UniversityAlexandriaEgypt
| | - Shimaa Abdelsattar Zaki
- Department of Clinical Biochemistry and Molecular DiagnosticsNational Liver InstituteMenoufia UniversityShebin El‐KomEgypt
| | - Hend E. Abo Mansour
- Department of BiochemistryFaculty of PharmacyMenoufia UniversityShebin El‐KomEgypt
| | - Esraa M. Mosalam
- Department of BiochemistryFaculty of PharmacyMenoufia UniversityShebin El‐KomEgypt
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21
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Jansen van Vuren E, Steyn SF, Brink CB, Möller M, Viljoen FP, Harvey BH. The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment. Biomed Pharmacother 2021; 135:111200. [PMID: 33421734 PMCID: PMC7834135 DOI: 10.1016/j.biopha.2020.111200] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/15/2020] [Accepted: 12/26/2020] [Indexed: 12/12/2022] Open
Abstract
The recent outbreak of the corona virus disease (COVID-19) has had major global impact. The relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is of great concern, with an evident link between corona virus infections and various central and peripheral nervous system manifestations. Unmitigated neuro-inflammation has been noted to underlie not only the severe respiratory complications of the disease but is also present in a range of neuro-psychiatric illnesses. Several neurological and psychiatric disorders are characterized by immune-inflammatory states, while treatments for these disorders have distinct anti-inflammatory properties and effects. With inflammation being a common contributing factor in SARS-CoV-2, as well as psychiatric disorders, treatment of either condition may affect disease progression of the other or alter response to pharmacological treatment. In this review, we elucidate how viral infections could affect pre-existing psychiatric conditions and how pharmacological treatments of these conditions may affect overall progress and outcome in the treatment of SARS-CoV-2. We address whether any treatment-induced benefits and potential adverse effects may ultimately affect the overall treatment approach, considering the underlying dysregulated neuro-inflammatory processes and potential drug interactions. Finally, we suggest adjunctive treatment options for SARS-CoV-2-associated neuro-psychiatric symptoms.
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Affiliation(s)
- Esmé Jansen van Vuren
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
| | - Stephan F Steyn
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
| | - Christiaan B Brink
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
| | - Marisa Möller
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
| | - Francois P Viljoen
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
| | - Brian H Harvey
- Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa; South African MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
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Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response. Transl Psychiatry 2021; 11:127. [PMID: 33589590 PMCID: PMC7884410 DOI: 10.1038/s41398-021-01248-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/15/2020] [Accepted: 01/07/2021] [Indexed: 01/31/2023] Open
Abstract
Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10-6) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10-6), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10-6, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10-4). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.
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Regan JT, Mirczuk SM, Scudder CJ, Stacey E, Khan S, Worwood M, Powles T, Dennis-Beron JS, Ginley-Hidinger M, McGonnell IM, Volk HA, Strickland R, Tivers MS, Lawson C, Lipscomb VJ, Fowkes RC. Sensitivity of the Natriuretic Peptide/cGMP System to Hyperammonaemia in Rat C6 Glioma Cells and GPNT Brain Endothelial Cells. Cells 2021; 10:cells10020398. [PMID: 33672024 PMCID: PMC7919485 DOI: 10.3390/cells10020398] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/05/2021] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
C-type natriuretic peptide (CNP) is the major natriuretic peptide of the central nervous system and acts via its selective guanylyl cyclase-B (GC-B) receptor to regulate cGMP production in neurons, astrocytes and endothelial cells. CNP is implicated in the regulation of neurogenesis, axonal bifurcation, as well as learning and memory. Several neurological disorders result in toxic concentrations of ammonia (hyperammonaemia), which can adversely affect astrocyte function. However, the relationship between CNP and hyperammonaemia is poorly understood. Here, we examine the molecular and pharmacological control of CNP in rat C6 glioma cells and rat GPNT brain endothelial cells, under conditions of hyperammonaemia. Concentration-dependent inhibition of C6 glioma cell proliferation by hyperammonaemia was unaffected by CNP co-treatment. Furthermore, hyperammonaemia pre-treatment (for 1 h and 24 h) caused a significant inhibition in subsequent CNP-stimulated cGMP accumulation in both C6 and GPNT cells, whereas nitric-oxide-dependent cGMP accumulation was not affected. CNP-stimulated cGMP efflux from C6 glioma cells was significantly reduced under conditions of hyperammonaemia, potentially via a mechanism involving changed in phosphodiesterase expression. Hyperammonaemia-stimulated ROS production was unaffected by CNP but enhanced by a nitric oxide donor in C6 cells. Extracellular vesicle production from C6 cells was enhanced by hyperammonaemia, and these vesicles caused impaired CNP-stimulated cGMP signalling in GPNT cells. Collectively, these data demonstrate functional interaction between CNP signalling and hyperammonaemia in C6 glioma and GPNT cells, but the exact mechanisms remain to be established.
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Affiliation(s)
- Jacob T. Regan
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Samantha M. Mirczuk
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (I.M.M.); (C.L.)
| | - Christopher J. Scudder
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (I.M.M.); (C.L.)
| | - Emily Stacey
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Sabah Khan
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Michael Worwood
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Torinn Powles
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - J. Sebastian Dennis-Beron
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Matthew Ginley-Hidinger
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
| | - Imelda M. McGonnell
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (I.M.M.); (C.L.)
| | - Holger A. Volk
- Stiftung Tierärztliche Hochschule Hannover, Klinik für Kleintiere, Bünteweg, 930559 Hannover, Germany;
| | - Rhiannon Strickland
- Clinical Sciences & Services, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK; (R.S.); (V.J.L.)
| | - Michael S. Tivers
- Paragon Veterinary Referrals, Paragon Business Village Paragon Way, Red Hall Cres, Wakefield WF1 2DF, UK;
| | - Charlotte Lawson
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (I.M.M.); (C.L.)
| | - Victoria J. Lipscomb
- Clinical Sciences & Services, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK; (R.S.); (V.J.L.)
| | - Robert C. Fowkes
- Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (J.T.R.); (S.M.M.); (C.J.S.); (E.S.); (S.K.); (M.W.); (T.P.); (J.S.D.-B.); (M.G.-H.)
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; (I.M.M.); (C.L.)
- Correspondence: ; Tel.: +44-207-468-1215
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Chung JY, Jeong JH, Song J. Resveratrol Modulates the Gut-Brain Axis: Focus on Glucagon-Like Peptide-1, 5-HT, and Gut Microbiota. Front Aging Neurosci 2020; 12:588044. [PMID: 33328965 PMCID: PMC7732484 DOI: 10.3389/fnagi.2020.588044] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022] Open
Abstract
Resveratrol is a natural polyphenol that has anti-aging and anti-inflammatory properties against stress condition. It is reported that resveratrol has beneficial functions in various metabolic and central nervous system (CNS) diseases, such as obesity, diabetes, depression, and dementia. Recently, many researchers have emphasized the connection between the brain and gut, called the gut-brain axis, for treating both CNS neuropathologies and gastrointestinal diseases. Based on previous findings, resveratrol is involved in glucagon-like peptide 1 (GLP-1) secreted by intestine L cells, the patterns of microbiome in the intestine, the 5-hydroxytryptamine (5-HT) level, and CNS inflammation. Here, we review recent evidences concerning the relevance and regulatory function of resveratrol in the gut-brain axis from various perspectives. Here, we highlight the necessity for further study on resveratrol's specific mechanism in the gut-brain axis. We present the potential of resveratrol as a natural therapeutic substance for treating both neuropathology and gastrointestinal dysfunction.
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Affiliation(s)
- Ji Yeon Chung
- Department of Neurology, Chosun University Medical School, Gwangju, South Korea
| | - Jae-Ho Jeong
- Department of Microbiology, Chonnam National University Medical School, Gwangju, South Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Gwangju, South Korea
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Sharma VK, Singh TG, Singh S. Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer's Disease. Curr Drug Targets 2020; 21:1371-1384. [PMID: 32718286 DOI: 10.2174/1389450121666200727104728] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/16/2022]
Abstract
Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer's disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.
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Affiliation(s)
- Vivek K Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India,Govt. College of Pharmacy, Rohru, District Shimla, Himachal Pradesh-171207, India
| | - Thakur G Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Jankowska A, Wesołowska A, Pawłowski M, Chłoń-Rzepa G. Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer’s Disease. Curr Med Chem 2020; 27:5351-5373. [DOI: 10.2174/0929867326666190620095623] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 04/30/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive
impairments such as memory loss, decline in language skills, and disorientation that affects
over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological
symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently
available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile
plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia.
A large body of evidence indicates that impaired signaling pathways of cyclic-3′,5′-
Adenosine Monophosphate (cAMP) and cyclic-3′,5′-guanosine Monophosphate (cGMP) may contribute
to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors,
commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation
of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood,
and emotion processing. The purpose of this review was to update the most recent reports on the
development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic
and disease-modifying therapy of AD. This review collected the chemical structures of representative
multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies,
and current opinions regarding the potential utility of these compounds for the comprehensive
therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds
were calculated and discussed.
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Affiliation(s)
- Agnieszka Jankowska
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Anna Wesołowska
- Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Maciej Pawłowski
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Grażyna Chłoń-Rzepa
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
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Dadomo H, Ponzi D, Nicolini Y, Vignali A, Ablondi F, Ceresini G, Maggio M, Palanza P, Govoni P, Volpi R, Parmigiani S. Behavioral and hormonal effects of prolonged Sildenafil treatment in a mouse model of chronic social stress. Behav Brain Res 2020; 392:112707. [PMID: 32461132 DOI: 10.1016/j.bbr.2020.112707] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/07/2020] [Accepted: 05/13/2020] [Indexed: 10/24/2022]
Abstract
Chronic social defeat can inhibit the reproductive system of subordinate males and causes behavioral deficits. Sildenafil treatment increases mice testosterone levels through its effects on Leydig cells of mice and it has been found to work as an antidepressant drug both in humans and in animal models. Since previous findings showed that sildenafil can counteract the inhibitory effects of chronic social defeat on agonistic, reproductive and anxiety-like behaviors of subordinate male mice, we investigated whether these behavioral outcomes can be explained by Sildenafil stimulation of testosterone. CD1 mice underwent an intruder-resident paradigm. After the fifth day of test, subordinate mice were injected with either a 10 mg/kg Sildenafil or a saline solution for 4 weeks. The results of the present study showed that Sildenafil treatment increased counterattacking behaviors and sexual motivation of subordinate males in addition to limiting the increase in body weight often observed in subordinate mice following chronic psychosocial stress. Moreover, sildenafil treated mice showed a pattern of behaviors reflecting lower anxiety. In agreement with previous studies, Sildenafil also increased testosterone levels. These data demonstrate that sildenafil can counteract the effects of chronic stress, possibly through its stimulatory effects on Leydig cells. These data demonstrate that sildenafil might counteract the effects of chronic psychosocial stress through centrally and peripherally mediated mechanisms.
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Affiliation(s)
- H Dadomo
- Department of Medicine and Surgery, University of Parma, Italy.
| | - D Ponzi
- Department of Medicine and Surgery, University of Parma, Italy
| | - Y Nicolini
- Department of Medicine and Surgery, University of Parma, Italy
| | - A Vignali
- Department of Medicine and Surgery, University of Parma, Italy
| | - F Ablondi
- Department of Medicine and Surgery, University of Parma, Italy
| | - G Ceresini
- Department of Medicine and Surgery, University of Parma, Italy
| | - M Maggio
- Department of Medicine and Surgery, University of Parma, Italy
| | - P Palanza
- Department of Medicine and Surgery, University of Parma, Italy
| | - P Govoni
- Department of Medicine and Surgery, University of Parma, Italy
| | - R Volpi
- Department of Medicine and Surgery, University of Parma, Italy
| | - S Parmigiani
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Italy
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Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome. Life Sci 2020; 256:117960. [PMID: 32534033 DOI: 10.1016/j.lfs.2020.117960] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/30/2020] [Accepted: 06/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.
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Duarte-Silva E, Filho AJMC, Barichello T, Quevedo J, Macedo D, Peixoto C. Phosphodiesterase-5 inhibitors: Shedding new light on the darkness of depression? J Affect Disord 2020; 264:138-149. [PMID: 32056743 DOI: 10.1016/j.jad.2019.11.114] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Phosphodiesterase-5 inhibitors (PDE5Is) are used to treat erectile dysfunction (ED). Recently, the antidepressant-like effect of PDE5Is was demonstrated in animal models of depression. In clinical settings, PDE5Is were studied only for ED associated depression. Hence, there are no studies evaluating the effects of PDE5Is for the treatment of major depressive disorder (MDD) without ED. In this review article, we aimed to discuss the use of PDE5Is in the context of MDD, highlighting the roles of PDE genes in the development of MDD, the potential mechanisms by which PDE5Is can be beneficial for MDD and the potentials and limitations of PDE5Is repurposing to treat MDD. METHODS We used PubMed (MEDLINE) database to collect the studies cited in this review. Papers written in English language regardless the year of publication were selected. RESULTS A few preclinical studies support the antidepressant-like activity of PDE5Is. Clinical studies in men with ED and depression suggest that PDE5Is improve depressive symptoms. No clinical studies were conducted in subjects suffering from depression without ED. Antidepressant effect of PDE5Is may be explained by multiple mechanisms including inhibition of brain inflammation and modulation of neuroplasticity. LIMITATIONS The low number of preclinical and absence of clinical studies to support the antidepressant effect of PDE5Is. CONCLUSIONS No clinical trial was conducted to date evaluating PDE5Is in depressed patients without ED. PDE5Is' anti-inflammatory and neuroplasticity mechanisms may justify the potential antidepressant effect of these drugs. Despite this, clinical trials evaluating their efficacy in depressed patients need to be conducted.
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Affiliation(s)
- Eduardo Duarte-Silva
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ-PE), Recife, PE, Brazil; Graduate Program in Biosciences and Biotechnology for Health (PPGBBS), Aggeu Magalhães Institute (IAM), Recife, PE, Brazil.
| | - Adriano José Maia Chaves Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Tatiana Barichello
- Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, United States; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina-UNESC, Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
| | - João Quevedo
- Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, United States; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina-UNESC, Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
| | - Danielle Macedo
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, Brazil
| | - Christina Peixoto
- Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ-PE), Recife, PE, Brazil; National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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Jankowska A, Świerczek A, Wyska E, Gawalska A, Bucki A, Pawłowski M, Chłoń-Rzepa G. Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research. Curr Drug Targets 2020; 20:122-143. [PMID: 30091414 DOI: 10.2174/1389450119666180808105056] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 07/27/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022]
Abstract
Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.
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Affiliation(s)
- Agnieszka Jankowska
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Artur Świerczek
- Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Elżbieta Wyska
- Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Alicja Gawalska
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Adam Bucki
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Maciej Pawłowski
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Grażyna Chłoń-Rzepa
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
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Choi JB, Cho KJ, Kim JC, Pae CU, Koh JS. An open-label, single-arm pilot study to evaluate the efficacy of daily low dose tadalafil on depression in patients with erectile dysfunction. Transl Androl Urol 2019; 8:501-506. [PMID: 31807426 DOI: 10.21037/tau.2019.08.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background Many studies have reported not only that depression and antidepressant medications can cause erectile dysfunction (ED), but also that having ED may increase the risk of depression. We investigated the effect of a daily low dose of a phosphodiesterase (PDE) type 5 inhibitor (tadalafil, 5 mg) on depression and levels of brain-derived neurotrophic factor (BDNF) in patients with ED. Methods Ten male patients with at least a 3-month history of ED [International Index of Erectile Function (IIEF)-5 score ≤21] and depression [the Korean version of the Patient Health Questionnaire (PHQ)-9 score ≥5] were analyzed in this study. The subjects were prescribed a low dose of a PDE5 inhibitor (tadalafil 5 mg) once daily for 8 weeks. The survey questionnaires were performed using the PHQ-15 and the PHQ-9 before and after administration of 8 weeks of tadalafil. Blood samples used for measuring serum BDNF levels were taken and measured at baseline and after 8 weeks of treatment. Results The mean changes in the PHQ-9 and PHQ-15 scores were 3.60±3.27 and 2.00±2.98, respectively. Analyses of the mean changes in the PHQ-9 scores revealed that the depressive symptoms of the subjects were significantly improved after administration of eight weeks of tadalafil (P<0.05). And, there was also a statistically significant increase in the PHQ-15 scores (P<0.05). Serum levels of BDNF were higher after tadalafil treatment compared to before treatment; however, this difference was not statistically significant. Conclusions The results of this prospective, clinical study suggest that daily low dose tadalafil may have a potential role in the treatment of depression in patients with ED.
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Affiliation(s)
- Jin Bong Choi
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kang Jun Cho
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Joon Chul Kim
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chi-Un Pae
- Department of Psychiatry, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jun Sung Koh
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Prata DP, Costa-Neves B, Cosme G, Vassos E. Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review. J Psychiatr Res 2019; 114:178-207. [PMID: 31096178 DOI: 10.1016/j.jpsychires.2019.04.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 01/02/2023]
Abstract
OBJECTIVES To systematically review findings of GWAS in schizophrenia (SZ) and in bipolar disorder (BD); and to interpret findings, with a focus on identifying independent replications. METHOD PubMed search, selection and review of all independent GWAS in SZ or BD, published since March 2011, i.e. studies using non-overlapping samples within each article, between articles, and with those of the previous review (Li et al., 2012). RESULTS From the 22 GWAS included in this review, the genetic associations surviving standard GWAS-significance were for genetic markers in the regions of ACSL3/KCNE4, ADCY2, AMBRA1, ANK3, BRP44, DTL, FBLN1, HHAT, INTS7, LOC392301, LOC645434/NMBR, LOC729457, LRRFIP1, LSM1, MDM1, MHC, MIR2113/POU3F2, NDST3, NKAPL, ODZ4, PGBD1, RENBP, TRANK1, TSPAN18, TWIST2, UGT1A1/HJURP, WHSC1L1/FGFR1 and ZKSCAN4. All genes implicated across both reviews are discussed in terms of their function and implication in neuropsychiatry. CONCLUSION Taking all GWAS to date into account, AMBRA1, ANK3, ARNTL, CDH13, EFHD1 (albeit with different alleles), MHC, PLXNA2 and UGT1A1 have been implicated in either disorder in at least two reportedly non-overlapping samples. Additionally, evidence for a SZ/BD common genetic basis is most strongly supported by the implication of ANK3, NDST3, and PLXNA2.
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Affiliation(s)
- Diana P Prata
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, Portugal; Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, UK; Instituto Universitário de Lisboa (ISCTE-IUL), Centro de Investigação e Intervenção Social, Lisboa, Portugal.
| | - Bernardo Costa-Neves
- Lisbon Medical School, University of Lisbon, Av. Professor Egas Moniz, 1649-028, Lisbon, Portugal; Centro Hospitalar Psiquiátrico de Lisboa, Av. do Brasil, 53 1749-002, Lisbon, Portugal
| | - Gonçalo Cosme
- Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências, Universidade de Lisboa, Portugal
| | - Evangelos Vassos
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, SE5 8AF, UK
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Trakadis YJ, Sardaar S, Chen A, Fulginiti V, Krishnan A. Machine learning in schizophrenia genomics, a case-control study using 5,090 exomes. Am J Med Genet B Neuropsychiatr Genet 2019; 180:103-112. [PMID: 29704323 DOI: 10.1002/ajmg.b.32638] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 02/28/2018] [Accepted: 03/30/2018] [Indexed: 12/21/2022]
Abstract
Our hypothesis is that machine learning (ML) analysis of whole exome sequencing (WES) data can be used to identify individuals at high risk for schizophrenia (SCZ). This study applies ML to WES data from 2,545 individuals with SCZ and 2,545 unaffected individuals, accessed via the database of genotypes and phenotypes (dbGaP). Single nucleotide variants and small insertions and deletions were annotated by ANNOVAR using the reference genome hg19/GRCh37. Rare (predicted functional) variants with a minor allele frequency ≤1% and genotype quality ≥90 including missense, frameshift, stop gain, stop loss, intronic, and exonic splicing variants were selected. A file containing all cases and controls, the names of genes with variants meeting our criteria, and the number of variants per gene for each individual, was used for ML analysis. The supervised machine-learning algorithm used the patterns of variants observed in the different genes to determine which subset of genes can best predict that an individual is affected. Seventy percent of the data was used to train the algorithm and the remaining 30% of data (n = 1,526) was used to evaluate its efficiency. The supervised ML algorithm, gradient boosted trees with regularization (eXtreme Gradient Boosting implementation) was the best performing algorithm yielding promising results (accuracy: 85.7%, specificity: 86.6%, sensitivity: 84.9%, area under the receiver-operator characteristic curve: 0.95). The top 50 features (genes) of the algorithm were analyzed using bioinformatics resources for new insights about the pathophysiology of SCZ. This manuscript presents a novel predictor which could potentially enable studies exploring disease-modifying intervention in the early stages of the disease.
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Affiliation(s)
- Yannis J Trakadis
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
| | - Sameer Sardaar
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
| | - Anthony Chen
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
| | - Vanessa Fulginiti
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
| | - Ankur Krishnan
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
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Aulsebrook ML, Starck M, Grace MR, Graham B, Thordarson P, Pal R, Tuck KL. Interaction of Nucleotides with a Trinuclear Terbium(III)-Dizinc(II) Complex: Efficient Sensitization of Terbium Luminescence by Guanosine Monophosphate and Application to Real-Time Monitoring of Phosphodiesterase Activity. Inorg Chem 2018; 58:495-505. [PMID: 30561998 DOI: 10.1021/acs.inorgchem.8b02731] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
An in-depth study of the interaction of a trinuclear terbium(III)-dizinc(II) complex with an array of nucleotides differing in the type of nucleobase and number of phosphate groups, as well as cyclic versus acyclic variants, is presented. The study examined the nature of the interaction and the efficiency at which guanine was able to sensitize terbium(III) luminescence. Competitive binding and titration studies were performed to help establish the nature/mode of the interactions. These established that (1) interaction occurs by the coordination of phosphate groups to zinc(II) (in addition to uridine in the case of uridine monophosphate), (2) acyclic nucleotides bind more strongly than cyclic counterparts because of their higher negative charge, (3) guanine-containing nucleotides are able to sensitize terbium(III) luminescence with the efficiency of sensitization following the order guanosine monophosphate (GMP) > guanosine diphosphate > guanosine triphosphate because of the mode of binding, and (4) nucleoside monophosphates bind to a single zinc(II) ion, whereas di- and triphosphates appear to bind in a bridging mode between two host molecules. Furthermore, it has been shown that guanine is a sensitizer of terbium(III) luminescence. On the basis of the ability of GMP to effectively sensitize terbium(III)-based luminescence while cyclic GMP (cGMP) does not, the complex has been utilized to monitor the catalytic conversion of cGMP to GMP by a phosphodiesterase enzyme in real time using time-gated luminescence on a benchtop fluorimeter. The complex has the potential to find broad application in monitoring the activity of enzymes that process nucleotides (co)substrates, including high-throughput drug-screening programs.
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Affiliation(s)
| | - Matthieu Starck
- Department of Chemistry , Durham University , Durham DH1 3LE , U.K
| | - Michael R Grace
- School of Chemistry , Monash University , Clayton , Victoria 3800 , Australia
| | - Bim Graham
- Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria 3052 , Australia
| | - Pall Thordarson
- School of Chemistry, the Australian Centre for Nanomedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology , University of New South Wales , Sydney , New South Wales 2052 , Australia
| | - Robert Pal
- Department of Chemistry , Durham University , Durham DH1 3LE , U.K
| | - Kellie L Tuck
- School of Chemistry , Monash University , Clayton , Victoria 3800 , Australia
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Duarte-Silva E, Araújo SMDR, Oliveira WH, Lós DBD, França MERD, Bonfanti AP, Peron G, Thomaz LDL, Verinaud L, Nunes AKDS, Peixoto CA. Sildenafil ameliorates EAE by decreasing apoptosis in the spinal cord of C57BL/6 mice. J Neuroimmunol 2018; 321:125-137. [DOI: 10.1016/j.jneuroim.2018.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/16/2018] [Accepted: 06/04/2018] [Indexed: 12/27/2022]
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Liu L, Zheng J, Huang XF, Zhu X, Ding SM, Ke HM, O'Donnell JM, Zhang HT, Song GQ, Xu Y. The neuroprotective and antidepressant-like effects of Hcyb1, a novel selective PDE2 inhibitor. CNS Neurosci Ther 2018; 24:652-660. [PMID: 29704309 DOI: 10.1111/cns.12863] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
Abstract
AIMS Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression. METHODS Hcyb1 was synthesized and its selectivity upon PDE2 was tested. Moreover, HT-22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP/cGMP signaling by neurochemical, enzyme-linked immunosorbent, and immunoblot assays in vitro. The antidepressant-like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. RESULTS Hcyb1 had a highly selective inhibition of PDE2A (IC50 = 0.57 ± 0.03 μmol/L) and over 250-fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10-10 and 10-9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10-9 ~10-7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10-minute treatment. Furthermore, Hcyb1 at the concentrations of 10-9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT-22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. CONCLUSION These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.
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Affiliation(s)
- Li Liu
- School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China
| | - Jing Zheng
- School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China
| | - Xian-Feng Huang
- School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China
| | - Xia Zhu
- Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Shu-Ming Ding
- School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China
| | - Heng-Ming Ke
- Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA
| | - James M O'Donnell
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Han-Ting Zhang
- Department of Behavioral Medicine & Psychiatry and Physiology, Pharmacology & Neuroscience, Rockefeller Neurosciences Institute, West Virginia University Health Science Center, Morgantown, WV, USA
| | - Guo-Qiang Song
- School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China
| | - Ying Xu
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA
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Tang H, Zhang Y. Identification and bioinformatics analysis of overlapping differentially expressed genes in depression, papillary thyroid cancer and uterine fibroids. Exp Ther Med 2018; 15:4810-4816. [PMID: 29805500 PMCID: PMC5952074 DOI: 10.3892/etm.2018.6023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 10/26/2017] [Indexed: 01/04/2023] Open
Abstract
It is hypothesized that there may be common characteristics between the genetic regulatory networks of different diseases. To identify these potential similarities, analysis of overlapping differentially expressed genes (DEGs) in several diseases, which are believed to be associated in traditional Chinese medicine (TCM) was performed in the present study. The gene expression profiles associated with depression, papillary thyroid carcinoma (PTC) and uterine fibroids (UF) were preliminarily analyzed using Gene Expression Omnibus 2R tools. Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis and protein-protein interaction network analysis of the overlapping DEGs in depression, PTC and UF was performed. The results indicated that multiple genes, including activating transcription factor 3 and WSC domain containing 2 and the phosphoinositide 3 kinase/protein kinase b signaling pathway and its downstream effectors may be common factors associated with depression, PTC and/or UF. The neuroendocrine functions of the hypothalamic-pituitary-ovarian axis and hypothalamic-pituitary-thyroid axis were also identified as being mutually associated with depression, PTC and/or UF. However, due to the limitations of DNA microassays, it is recommended that future studies take epigenetics into consideration. Further transcriptomic, methylomic and metabolomic analyses of depression, PTC and UF are also required to identify and elucidate the key associated biomarkers. In conclusion, the results of the current study shed light on the potential genetic interconnections between depression, PTC and UF, which may be beneficial for understanding their underlying coregulatory mechanisms and contributing to the development of homeotherapy based on bioinformatics prediction.
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Affiliation(s)
- Hanxiao Tang
- Department of Pharmacy, Affiliated Tongde Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310012, P.R. China
| | - Yongsheng Zhang
- The Diagnostic Institute of Chinese Medicine, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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The Role of Phosphodiesterase-2 in Psychiatric and Neurodegenerative Disorders. ADVANCES IN NEUROBIOLOGY 2018; 17:307-347. [PMID: 28956338 DOI: 10.1007/978-3-319-58811-7_12] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cyclic nucleotide PDEs are a super-family of enzymes responsible for regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Through their catalysis, PDEs are able to exert tight regulation over these important intracellular signaling cascades. Previously, PDEs have been implicated in learning and memory, as well as in mood disorders, such as anxiety and depression. PDE2 is of special interest due to its high level of expression in the forebrain, specifically in the isocortex, entorhinal cortex, striatum, hippocampus, amygdala, and medial habenula. Many of these brain regions are considered participants of the limbic system, which is known as the emotional regulatory center of the brain, and is important for modulating emotion and long-term memory. Therefore, PDE2s coincidental expression in these areas suggests an important role for PDE2 in these behaviors, and researchers are continuing to uncover the complex connections. It was shown that PDE2 inhibitors have pro-cognitive effects in tests of memory, including the object recognition test. PDE2 inhibitors are also protective against cognitive deficits in various models of cognitive impairment. Additionally, PDE2 inhibitors are protective against many different forms of stress-induced anxiety-like and depression-like behaviors. Currently, there is a great need for novel therapeutics for the treatment of mood and cognitive disorders, especially anxiety and depression, and other neurodegenerative diseases, such as Alzheimer's disease, and PDE2 is emerging as a viable target for future drug development for many of these diseases.
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Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a. Psychopharmacology (Berl) 2017; 234:1803-1813. [PMID: 28337525 DOI: 10.1007/s00213-017-4587-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 03/01/2017] [Indexed: 01/21/2023]
Abstract
RATIONALE Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. OBJECTIVES We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. METHODS Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. RESULTS Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. CONCLUSIONS PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.
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Hesse R, Lausser L, Gummert P, Schmid F, Wahler A, Schnack C, Kroker KS, Otto M, Tumani H, Kestler HA, Rosenbrock H, von Arnim CAF. Reduced cGMP levels in CSF of AD patients correlate with severity of dementia and current depression. Alzheimers Res Ther 2017; 9:17. [PMID: 28274265 PMCID: PMC5343324 DOI: 10.1186/s13195-017-0245-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/13/2017] [Indexed: 01/21/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets. Biomarkers that are able to monitor potential treatment effects and that reflect the underlying pathology are of crucial interest. METHODS In this study, we measured cGMP and cAMP in cerebrospinal fluid (CSF) in a cohort of 133 subjects including 68 AD patients and 65 control subjects. To address the association with disease progression we correlated cognitive status with cyclic nucleotide levels. Because a high burden of NPSs is associated with decrease in cognitive function, we performed an exhaustive evaluation of AD-relevant marker combinations in a depressive subgroup. RESULTS We show that cGMP, but not cAMP, levels in the CSF of AD patients are significantly reduced compared with the control group. Reduced cGMP levels in AD patients correlate with memory impairment based on Mini-Mental State Examination score (r = 0.17, p = 0.048) and tau as a marker of neurodegeneration (r = -0.28, p = 0.001). Moreover, we were able to show that AD patients suffering from current depression show reduced cGMP levels (p = 0.07) and exhibit a higher degree of cognitive impairment than non-depressed AD patients. CONCLUSION These results provide further evidence for an involvement of cGMP in AD pathogenesis and accompanying co-morbidities, and may contribute to elucidating synaptic plasticity alterations during disease progression.
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Affiliation(s)
- Raphael Hesse
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Ludwig Lausser
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Pauline Gummert
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Florian Schmid
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Anke Wahler
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Cathrin Schnack
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Katja S. Kroker
- Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | - Markus Otto
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Hayrettin Tumani
- Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Hans A. Kestler
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Holger Rosenbrock
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
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Chen X, Long F, Cai B, Chen X, Chen G. A novel relationship for schizophrenia, bipolar and major depressive disorder Part 7: A hint from chromosome 7 high density association screen. Behav Brain Res 2015; 293:241-51. [PMID: 26192912 DOI: 10.1016/j.bbr.2015.06.043] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 06/25/2015] [Accepted: 06/25/2015] [Indexed: 11/18/2022]
Abstract
Convergent evidence from genetics, symptology and psychopharmacology imply that there are intrinsic connection between schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). Also, any two or even three of these disorders could co-existe in some families. A total of 47,144 single nucleotide polymorphism (SNPs) on chromosome 7 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD, and 1000 controls. Associated SNP loci were comprehensively revealed and outstanding susceptibility genes were identified including CNTNAP2. a neurexin family gene. Unexpectedly, flanking genes for up to 94.74 % of of the associated SNPs were replicated (P≤9.9 E-8) in an enlarged cohort of 986 SCZ patients. Considering other convergent evidence, our results further implicate that BPD and MDD are subtypes of SCZ.
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Affiliation(s)
- Xing Chen
- Department of Medical Genetics, Institute of Basic Medicine, Shandong Academy of Medical Sciences, 18877 Jingshi Road, Jinan 250062, Shandong, People's Republic of China
| | - Feng Long
- Department of Medical Genetics, Institute of Basic Medicine, Shandong Academy of Medical Sciences, 18877 Jingshi Road, Jinan 250062, Shandong, People's Republic of China
| | - Bin Cai
- CapitalBio corporation, 18 Life Science Parkway, Changping District, Beijing 102206, People's Republic of China
| | - Xiaohong Chen
- CapitalBio corporation, 18 Life Science Parkway, Changping District, Beijing 102206, People's Republic of China
| | - Gang Chen
- Department of Medical Genetics, Institute of Basic Medicine, Shandong Academy of Medical Sciences, 18877 Jingshi Road, Jinan 250062, Shandong, People's Republic of China.
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Barmashenko G, Buttgereit J, Herring N, Bader M, Ozcelik C, Manahan-Vaughan D, Braunewell KH. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats. Front Mol Neurosci 2014; 7:95. [PMID: 25520616 PMCID: PMC4249455 DOI: 10.3389/fnmol.2014.00095] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/12/2014] [Indexed: 12/15/2022] Open
Abstract
The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning.
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Affiliation(s)
- Gleb Barmashenko
- Guest Group, In vitro-Electrophysiology Laboratory, Department of Neurophysiology, Medical Faculty, Ruhr University Bochum Bochum, Germany ; Department of Neurophysiology, Medical Faculty, Ruhr University Bochum Bochum, Germany
| | - Jens Buttgereit
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Charité Medical Faculty Berlin, Germany ; Max Delbrück Center for Molecular Medicine Berlin, Germany
| | - Neil Herring
- Max Delbrück Center for Molecular Medicine Berlin, Germany ; Department of Physiology, Anatomy and Genetics, Burdon Sanderson Cardiac Science Centre - BHF Centre of Research Excellence, University of Oxford Oxford, UK
| | - Michael Bader
- Max Delbrück Center for Molecular Medicine Berlin, Germany
| | - Cemil Ozcelik
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Charité Medical Faculty Berlin, Germany ; Max Delbrück Center for Molecular Medicine Berlin, Germany
| | | | - Karl H Braunewell
- Guest Group, In vitro-Electrophysiology Laboratory, Department of Neurophysiology, Medical Faculty, Ruhr University Bochum Bochum, Germany
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Wang C, Zhang J, Lu Y, Lin P, Pan T, Zhao X, Liu A, Wang Q, Zhou W, Zhang HT. Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice. Metab Brain Dis 2014; 29:673-82. [PMID: 24705918 DOI: 10.1007/s11011-014-9533-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 03/18/2014] [Indexed: 12/25/2022]
Abstract
Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.
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Affiliation(s)
- Chuang Wang
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China,
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A molecular pathway analysis of the glutamatergic-monoaminergic interplay serves to investigate the number of depressive records during citalopram treatment. J Neural Transm (Vienna) 2014; 122:465-75. [PMID: 24986638 DOI: 10.1007/s00702-014-1267-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 06/24/2014] [Indexed: 12/28/2022]
Abstract
The efficacy of current antidepressant (AD) drugs for the treatment of major depressive disorder (MDD) lays behind expectations. The correct genetic differentiation between severe and less severe cases before treatment may pave the way to the most correct clinical choices in clinical practice. Genetics may pave the way such identification, which in turns may provide perspectives for the synthesis of new ADs by correcting the molecular unbalances that differentiate severe and less severe depressive patients. We investigated 1,903 MDD patients from the STAR*D study. Outcome was the number of severe depressive records, defined as a Quick Inventory of Depressive Symptomatology (QIDS)-Clinician rated (C) total score >15, corrected for the number of observations for each patient during the first 14 weeks of citalopram treatment. Predictors were the genetic variations harbored by genes involved in the glutamatergic-monoaminergic interplay as defined in a previous work published by our group. Clinical and socio-demographic stratification factor analyses were taken in cases and controls. Covariated linear regression was the statistical model for the analysis. SNPs were analyzed in groups (molecular pathway analysis) testing the hypothesis that the distribution of significant (p < 0.05) associations between SNPs and the outcome segregates within each pathway/gene subset. The best associated results are relative to two signle SNPs, (rs7744492 in AKAP12 p = 0.0004 and rs17046113 in CAMK2D p = 0.0006) and a molecular pathway (cAMP biosynthetic process p = 0.005). After correction for multitesting, none of them resulted to be significantly associated. These results are consistent with previous findings in literature and further stress that the molecular mechanisms targeted by current ADs may not be the key biological variables that differentiate severe from mild depression.
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45
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Otero C, Peñaloza JP, Rodas PI, Fernández-Ramires R, Velasquez L, Jung JE. Temporal and spatial regulation of cAMP signaling in disease: role of cyclic nucleotide phosphodiesterases. Fundam Clin Pharmacol 2014; 28:593-607. [PMID: 24750474 DOI: 10.1111/fcp.12080] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 03/28/2014] [Accepted: 04/17/2014] [Indexed: 01/19/2023]
Abstract
Since its discovery, cAMP has been proposed as one of the most versatile second messengers. The remarkable feature of cAMP to tightly control highly diverse physiological processes, including metabolism, homeostasis, secretion, muscle contraction, cell proliferation and migration, immune response, and gene transcription, is reflected by millions of different articles worldwide. Compartmentalization of cAMP in space and time, maintained by mainly phosphodiesterases, contributes to the maintenance of equilibrium inside the cell where one signal can trigger many different events. Novel cAMP sensors seem to carry out certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Measuring space and time events with biosensors will increase our current knowledge on the pathophysiology of diseases, such as chronic obstructive pulmonary disease, asthma, cognitive impairment, cancer, and renal and heart failure. Further insights into the cAMP dynamics will help to optimize the pharmacological treatment for these diseases.
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Affiliation(s)
- Carolina Otero
- Center for Integrative Medicine and Innovative Science, Universidad Andres Bello, Santiago, Chile; Centro para el Desarrollo de la Nanociencia y Nanotecnologia, Santiago, Chile
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46
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Schwan G, Barbar Asskar G, Höfgen N, Kubicova L, Funke U, Egerland U, Zahn M, Nieber K, Scheunemann M, Sträter N, Brust P, Briel D. Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism. ChemMedChem 2014; 9:1476-87. [PMID: 24729456 DOI: 10.1002/cmdc.201300522] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 02/25/2014] [Indexed: 11/10/2022]
Abstract
Based on the potent phosphodiesterase 10 A (PDE10A) inhibitor PQ-10, we synthesized 32 derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands were evaluated, as well as their inhibitory potency toward PDE10A and other PDEs, and their metabolic stability was determined in vitro. According to our findings, halo-alkyl substituents at position 2 of the quinazoline moiety and/or halo-alkyloxy substituents at positions 6 or 7 affect not only the compounds' affinity, but also their selectivity toward PDE10A. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group at position 6 of the quinazoline ring, the selectivity for PDE10A over PDE3A increased. The same result was obtained by 6,7-difluoride substitution on the quinoxaline moiety. Finally, fluorinated compounds (R)-7-(fluoromethoxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline (16 a), 19 a-d, (R)-tert-butyl-3-(6-fluoroquinoxalin-2-yloxy)pyrrolidine-1-carboxylate (29), and 35 (IC50 PDE10A 11-65 nM) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability over that of the lead structure PQ-10.
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Affiliation(s)
- Gregor Schwan
- Institut für Pharmazie, Universität Leipzig, Brüderstr. 34, 04103 Leipzig (Germany), Fax: (+49) 341 9736889
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47
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Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Mol Psychiatry 2014; 19:228-34. [PMID: 23319000 DOI: 10.1038/mp.2012.183] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 11/16/2012] [Accepted: 11/26/2012] [Indexed: 12/16/2022]
Abstract
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
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48
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Nada SE, Tulsulkar J, Shah ZA. Heme oxygenase 1-mediated neurogenesis is enhanced by Ginkgo biloba (EGb 761®) after permanent ischemic stroke in mice. Mol Neurobiol 2013; 49:945-56. [PMID: 24154866 DOI: 10.1007/s12035-013-8572-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 10/10/2013] [Indexed: 01/20/2023]
Abstract
Stroke is the fourth leading cause of death and a major cause of disability in stroke survivors. Studies have underlined the importance of repair mechanisms in the recovery phase of stroke. Neurogenesis in response to brain injury is one of the regeneration processes that, if enhanced, may offer better stroke treatment alternatives. Previously, we have demonstrated antioxidant, neuritogenic, and angiogenic properties of Ginkgo biloba/EGb 761® (EGb 761) in different mouse models of stroke. In the present study, we were interested to study whether EGb 761 could protect mice from permanent middle cerebral artery occlusion (pMCAO) and enhance neurogenesis. EGb 761 pre- and posttreated mice had lower infarct volume and improved motor skills with enhanced proliferation of neuronal stem/progenitor cells (NSPCs) at 24 h and 7 days posttreatment. Netrin-1 and its receptors (DCC and UNC5B) that mediate axonal attraction and repulsion were observed to be overexpressed in NSPCs only, implying that netrin-1 and its receptors might have partly played a role in enhanced neurogenesis. Interestingly, in heme oxygenase 1 knockout mice (HO1(-/-)), neurogenesis was significantly lower than in vehicle-treated mice at day 8. Furthermore, EGb 761 posttreated mice also demonstrated heme oxygenase 1 (HO1)-activated pathway of phosphorylated glycogen synthase kinase 3 α/β (p-GSK-3 α/β), collapsin response mediator protein 2 (CRMP-2), semaphorin3A (SEMA3A), and Wnt, suggesting probable signaling pathways involved in proliferation, differentiation, and migration of NSPCs. Together, these results propose that EGb 761 not only has antioxidant, neuritogenic, and angiogenic properties, but can also augment the repair and regeneration mechanisms following stroke.
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Affiliation(s)
- Shadia E Nada
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Avenue, Toledo, OH, 43614, USA
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49
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Podda MV, Grassi C. New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels. Pflugers Arch 2013; 466:1241-57. [PMID: 24142069 DOI: 10.1007/s00424-013-1373-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 09/27/2013] [Accepted: 09/28/2013] [Indexed: 01/07/2023]
Abstract
Cyclic nucleotides play fundamental roles in the central nervous system (CNS) under both physiological and pathological conditions. The impact of cAMP and cGMP signaling on neuronal and glial cell functions has been thoroughly characterized. Most of their effects have been related to cyclic nucleotide-dependent protein kinase activity. However, cyclic nucleotide-gated (CNG) channels, first described as key mediators of sensory transduction in retinal and olfactory receptors, have been receiving increasing attention as possible targets of cyclic nucleotides in the CNS. In the last 15 years, consistent evidence has emerged for their expression in neurons and astrocytes of the rodent brain. Far less is known, however, about the functional role of CNG channels in these cells, although several of their features, such as Ca(2+) permeability and prolonged activation in the presence of cyclic nucleotides, make them ideal candidates for mediators of physiological functions in the CNS. Here, we review literature suggesting the involvement of CNG channels in a number of CNS cellular functions (e.g., regulation of membrane potential, neuronal excitability, and neurotransmitter release) as well as in more complex phenomena, like brain plasticity, adult neurogenesis, and pain sensitivity. The emerging picture is that functional and dysfunctional cyclic nucleotide signaling in the CNS has to be reconsidered including CNG channels among possible targets. However, concerted efforts and multidisciplinary approaches are still needed to get more in-depth knowledge in this field.
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Affiliation(s)
- Maria Vittoria Podda
- Institute of Human Physiology, Medical School, Università Cattolica, Largo Francesco Vito 1, 00168, Rome, Italy
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50
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Podda MV, Piacentini R, Barbati SA, Mastrodonato A, Puzzo D, D’Ascenzo M, Leone L, Grassi C. Role of cyclic nucleotide-gated channels in the modulation of mouse hippocampal neurogenesis. PLoS One 2013; 8:e73246. [PMID: 23991183 PMCID: PMC3750014 DOI: 10.1371/journal.pone.0073246] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 07/18/2013] [Indexed: 12/25/2022] Open
Abstract
Neural stem cells generate neurons in the hippocampal dentate gyrus in mammals, including humans, throughout adulthood. Adult hippocampal neurogenesis has been the focus of many studies due to its relevance in processes such as learning and memory and its documented impairment in some neurodegenerative diseases. However, we are still far from having a complete picture of the mechanism regulating this process. Our study focused on the possible role of cyclic nucleotide-gated (CNG) channels. These voltage-independent channels activated by cyclic nucleotides, first described in retinal and olfactory receptors, have been receiving increasing attention for their involvement in several brain functions. Here we show that the rod-type, CNGA1, and olfactory-type, CNGA2, subunits are expressed in hippocampal neural stem cells in culture and in situ in the hippocampal neurogenic niche of adult mice. Pharmacological blockade of CNG channels did not affect cultured neural stem cell proliferation but reduced their differentiation towards the neuronal phenotype. The membrane permeant cGMP analogue, 8-Br-cGMP, enhanced neural stem cell differentiation to neurons and this effect was prevented by CNG channel blockade. In addition, patch-clamp recording from neuron-like differentiating neural stem cells revealed cGMP-activated currents attributable to ion flow through CNG channels. The current work provides novel insights into the role of CNG channels in promoting hippocampal neurogenesis, which may prove to be relevant for stem cell-based treatment of cognitive impairment and brain damage.
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Affiliation(s)
- Maria Vittoria Podda
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
| | - Roberto Piacentini
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
| | | | - Alessia Mastrodonato
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
| | - Daniela Puzzo
- Section of Physiology, Department of Bio-Medical Sciences, University of Catania, Catania, Italy
| | - Marcello D’Ascenzo
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
| | - Lucia Leone
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
| | - Claudio Grassi
- Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy
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