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Huang C, Zheng X, Yan S, Zhang Z. Advances in Clinical Therapies for Huntington's Disease and the Promise of Multi-Targeted/Functional Drugs Based on Clinicaltrials.gov. Clin Pharmacol Ther 2024; 116:1452-1471. [PMID: 38863261 DOI: 10.1002/cpt.3341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 05/27/2024] [Indexed: 06/13/2024]
Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects. While gene therapies, such as antisense oligonucleotides, small interfering RNAs and gene editing, have emerged in the field of HD treatment, their safety and efficacy are still under debate. Therefore, pharmacological therapy remains the most promising breakthrough, especially multi-target/functional drugs, which have diverse pharmacological effects. This review summarizes the latest progress in HD drug development based on clinicaltrials.gov search results (Search strategy: key word "Huntington's disease" in HD clinical investigational drugs registered as of December 31, 2023), and highlights the key role of multi-target/functional drugs in HD treatment strategies.
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Affiliation(s)
- Chunhui Huang
- School of Medicine, Jinan University, Guangzhou, China
- Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of TCM and New Drugs Research and Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China
| | - Xiao Zheng
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Sen Yan
- School of Medicine, Jinan University, Guangzhou, China
- Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of TCM and New Drugs Research and Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China
| | - Zaijun Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of TCM and New Drugs Research and Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China
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Liu J, Mouradian MM. Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases. Int J Mol Sci 2024; 25:2364. [PMID: 38397040 PMCID: PMC10888553 DOI: 10.3390/ijms25042364] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer's disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson's disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington's disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.
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Affiliation(s)
| | - M. Maral Mouradian
- RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA;
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Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function. Antioxidants (Basel) 2023; 12:antiox12030652. [PMID: 36978900 PMCID: PMC10044936 DOI: 10.3390/antiox12030652] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/22/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Neurotoxicity is induced by different toxic substances, including environmental chemicals, drugs, and pathogenic toxins, resulting in oxidative damage and neurodegeneration in mammals. The nervous system is extremely vulnerable to oxidative stress because of its high oxygen demand. Mitochondria are the main source of ATP production in the brain neuron, and oxidative stress-caused mitochondrial dysfunction is implicated in neurodegenerative diseases. H2S was initially identified as a toxic gas; however, more recently, it has been recognized as a neuromodulator as well as a neuroprotectant. Specifically, it modulates mitochondrial activity, and H2S oxidation in mitochondria produces various reactive sulfur species, thus modifying proteins through sulfhydration. This review focused on highlighting the neuron modulation role of H2S in regulating neurodegenerative diseases through anti-oxidative, anti-inflammatory, anti-apoptotic and S-sulfhydration, and emphasized the importance of H2S as a therapeutic molecule for neurological diseases.
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Liang XS, Sun ZW, Thomas AM, Li S. Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis. Stem Cells Int 2023; 2023:1109967. [PMID: 37168444 PMCID: PMC10164866 DOI: 10.1155/2023/1109967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 05/13/2023] Open
Abstract
Objective Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.
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Affiliation(s)
- Xue-Song Liang
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Zheng-Wu Sun
- Department of Clinical Pharmacy, Dalian Municipal Central Hospital, Dalian, China
| | - Aline M. Thomas
- The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shen Li
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
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5
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Tucci P, Lattanzi R, Severini C, Saso L. Nrf2 Pathway in Huntington's Disease (HD): What Is Its Role? Int J Mol Sci 2022; 23:ijms232315272. [PMID: 36499596 PMCID: PMC9739588 DOI: 10.3390/ijms232315272] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/08/2022] Open
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that occurs worldwide. Despite some progress in understanding the onset of HD, drugs that block or delay symptoms are still not available. In recent years, many treatments have been proposed; among them, nuclear transcriptional factor-2 (Nrf2) enhancer compounds have been proposed as potential therapeutic agents to treat HD. Nrf2 triggers an endogenous antioxidant pathway activated in different neurodegenerative disorders. Probably, the stimulation of Nrf2 during either the early phase or before HD symptoms' onset, could slow or prevent striatum degeneration. In this review, we present the scientific literature supporting the role of Nrf2 in HD and the potential prophylactic and therapeutic role of this compound.
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Affiliation(s)
- Paolo Tucci
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Roberta Lattanzi
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Cinzia Severini
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council of Italy (CNR), Viale del Policlinico 155, 00161 Rome, Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Correspondence:
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Afolabi O, Alabi B, Omobowale T, Oluranti O, Iwalewa O. Cysteamine mitigates torsion/detorsion-induced reperfusion injury via inhibition of apoptosis, oxidative stress and inflammatory responses in experimental rat model. Andrologia 2021; 54:e14243. [PMID: 34498746 DOI: 10.1111/and.14243] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/07/2021] [Accepted: 08/24/2021] [Indexed: 12/25/2022] Open
Abstract
Oxidative stress, inflammation and apoptosis are major pathways in pathophysiology of testicular torsion/detorsion (TTDT) reperfusion injury. This study evaluated the antioxidant, anti-inflammatory and anti-apoptotic role of cysteamine in TTDT-induced injury. Male Wistar rats (n = 32) were grouped into four (n = 8): sham, ischaemia-reperfusion injury (IRI), cysteamine (100 mg/kg and 200 mg/kg) for in vivo study. Samples were taken for biomolecular and histological evaluation 48 hr after detorsion. Tissue SOD, GPx, GSH, GST activity, total thiol, H2 O2 and MDA were assessed. Serum levels of NO, MPO, TNF-alpha and IL-6 and sperm motility, count and viability were assessed. Caspase-3 and bax were evaluated by immunohistochemistry. Significant difference was set as p < .05. Significant increase in H2 O2, MDA and nitrite but reduction in SOD, GPx, GSH, GST and total thiol in the testicular tissue of IRI rats was reversed by cysteamine. Serum MPO and TNF-α were significantly elevated in RI, while treated-RI rats showed decrease (p < .05) in tissue level of the inflammation markers. Reduced sperm motility in RI was significantly reversed by cysteamine. Increased tissue expression of bax and caspase-3 was reversed by cysteamine. Cysteamine protected the testis against reperfusion injury through anti-inflammatory, antioxidant effects and inhibition of apoptosis in rats.
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Affiliation(s)
- Oladele Afolabi
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Babatunde Alabi
- Department of Pharmacology and Therapeutics, Bowen University, Iwo, Nigeria
| | | | | | - Olugbenga Iwalewa
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Science, University of Ibadan, Ibadan, Nigeria
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Zhang J, Jasutkar HG, Mouradian MM. Targeting transglutaminase 2 as a potential disease modifying therapeutic strategy for synucleinopathies. Neural Regen Res 2021; 16:1560-1561. [PMID: 33433482 PMCID: PMC8323704 DOI: 10.4103/1673-5374.303027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/13/2020] [Accepted: 12/08/2020] [Indexed: 11/22/2022] Open
Affiliation(s)
- Jie Zhang
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA
| | - Hilary Grosso Jasutkar
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA
| | - M Maral Mouradian
- Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA
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8
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Tabassum R, Jeong NY, Jung J. Therapeutic importance of hydrogen sulfide in age-associated neurodegenerative diseases. Neural Regen Res 2020; 15:653-662. [PMID: 31638087 PMCID: PMC6975154 DOI: 10.4103/1673-5374.266911] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 04/27/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases. One of the major causes of age-related diseases is oxidative stress. In recent years, the importance of H2S has become clear, although its antioxidant function has not yet been fully explored. The enzymes cystathionine β-synthase, cystathionine γ-lya-se, and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H2S. Previously, H2S was considered a neuromodulator, given its role in long-term hippocampal potentiation, but it is now also recognized as an antioxidant in age-related neurodegeneration. Due to aerobic metabolism, the central nervous system is vulnerable to oxidative stress in brain aging, resulting in age-associated degenerative diseases. H2S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, which protect against the effects of aging by regulating apoptosis-related genes, including p53, Bax, and Bcl-2. This review explores the implications and mechanisms of H2S as an antioxidant in age-associated neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Down syndrome.
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Affiliation(s)
- Rubaiya Tabassum
- Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea
- Department of Medicine, Graduate School, Dong-A University, Busan, Korea
| | - Na Young Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea
- Department of Medicine, Graduate School, Dong-A University, Busan, Korea
| | - Junyang Jung
- Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, Korea
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9
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Ma Q, Fang X, Zhang J, Zhu L, Rao X, Lu Q, Sun Z, Yu H, Zhang Q. Discrimination of cysteamine from mercapto amino acids through isoelectric point-mediated surface ligand exchange of β-cyclodextrin-modified gold nanoparticles. J Mater Chem B 2020; 8:4039-4045. [DOI: 10.1039/d0tb00462f] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A pI-mediated R6G-β-CD@AuNPs system was designed for the first time for the discrimination of CA from GSH/Cys/Hcy in human serum samples.
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Affiliation(s)
- Quanbao Ma
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Xun Fang
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Junting Zhang
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Lili Zhu
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Xiabing Rao
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Qi Lu
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Zhijun Sun
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Huan Yu
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
| | - Qunlin Zhang
- School of Pharmacy
- Anhui Medical University
- Hefei 230032
- China
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10
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Paul BD, Snyder SH. Therapeutic Applications of Cysteamine and Cystamine in Neurodegenerative and Neuropsychiatric Diseases. Front Neurol 2019; 10:1315. [PMID: 31920936 PMCID: PMC6920251 DOI: 10.3389/fneur.2019.01315] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/27/2019] [Indexed: 12/31/2022] Open
Abstract
Current medications for neurodegenerative and neuropsychiatric diseases such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and Schizophrenia mainly target disease symptoms. Thus, there is an urgent need to develop novel therapeutics that can delay, halt or reverse disease progression. AD, HD, PD, and schizophrenia are characterized by elevated oxidative and nitrosative stress, which play a central role in pathogenesis. Clinical trials utilizing antioxidants to counter disease progression have largely been unsuccessful. Most antioxidants are relatively non-specific and do not adequately target neuroprotective pathways. Accordingly, a search for agents that restore redox balance as well as halt or reverse neuronal loss is underway. The small molecules, cysteamine, the decarboxylated derivative of the amino acid cysteine, and cystamine, the oxidized form of cysteamine, respectively, mitigate oxidative stress and inflammation and upregulate neuroprotective pathways involving brain-derived neurotrophic factor (BDNF) and Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Cysteamine can traverse the blood brain barrier, a desirable characteristic of drugs targeting neurodegeneration. This review addresses recent developments in the use of these aminothiols to counter neurodegeneration and neuropsychiatric deficits.
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Affiliation(s)
- Bindu D Paul
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Solomon H Snyder
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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11
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Cicchetti F, David L, Siddu A, Denis H. Cysteamine as a novel disease-modifying compound for Parkinson's disease: Over a decade of research supporting a clinical trial. Neurobiol Dis 2019; 130:104530. [DOI: 10.1016/j.nbd.2019.104530] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/04/2019] [Accepted: 07/09/2019] [Indexed: 10/26/2022] Open
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12
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Jensen MP, Barker RA. Disease-Modification in Huntington's Disease: Moving Away from a Single-Target Approach. J Huntingtons Dis 2019; 8:9-22. [PMID: 30636742 DOI: 10.3233/jhd-180320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss disease-modifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early on - before it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processes-e.g., huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.
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Affiliation(s)
- Melanie P Jensen
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Roger A Barker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.,Cambridge Stem Cell Institute, Cambridge, UK
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13
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Taylor K, Das S, Pearson M, Kozubek J, Strivens M, Gardner S. Systematic drug repurposing to enable precision medicine: A case study in breast cancer. ACTA ACUST UNITED AC 2019. [DOI: 10.4103/digm.digm_28_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Cystamine and cysteamine as inhibitors of transglutaminase activity in vivo. Biosci Rep 2018; 38:BSR20180691. [PMID: 30054429 PMCID: PMC6123069 DOI: 10.1042/bsr20180691] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 11/07/2018] [Accepted: 07/24/2018] [Indexed: 12/22/2022] Open
Abstract
Cystamine is commonly used as a transglutaminase inhibitor. This disulphide undergoes reduction in vivo to the aminothiol compound, cysteamine. Thus, the mechanism by which cystamine inhibits transglutaminase activity in vivo could be due to either cystamine or cysteamine, which depends on the local redox environment. Cystamine inactivates transglutaminases by promoting the oxidation of two vicinal cysteine residues on the enzyme to an allosteric disulphide, whereas cysteamine acts as a competitive inhibitor for transamidation reactions catalyzed by this enzyme. The latter mechanism is likely to result in the formation of a unique biomarker, N-(γ-glutamyl)cysteamine that could serve to indicate how cyst(e)amine acts to inhibit transglutaminases inside cells and the body.
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15
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Enns GM, Cohen BH. Clinical Trials in Mitochondrial Disease. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2017. [DOI: 10.1177/2326409817733013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Gregory M. Enns
- Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA
| | - Bruce H. Cohen
- Department of Pediatrics, NeuroDevelopmental Science Center and Mitochondrial Research Center, Akron Children's Hospital, Akron, OH
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16
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Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med 2017; 7:cshperspect.a024240. [PMID: 27940602 DOI: 10.1101/cshperspect.a024240] [Citation(s) in RCA: 258] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Finally, we outline some of the therapeutic strategies that are currently being pursued to slow down the disease.
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Affiliation(s)
- Maria Jimenez-Sanchez
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom
| | - Floriana Licitra
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom
| | - Benjamin R Underwood
- Department of Old Age Psychiatry, Beechcroft, Fulbourn Hospital, Cambridge CB21 5EF, United Kingdom
| | - David C Rubinsztein
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom
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17
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Gallego-Villar L, Hannibal L, Häberle J, Thöny B, Ben-Omran T, Nasrallah GK, Dewik AN, Kruger WD, Blom HJ. Cysteamine revisited: repair of arginine to cysteine mutations. J Inherit Metab Dis 2017; 40:555-567. [PMID: 28643139 PMCID: PMC5740875 DOI: 10.1007/s10545-017-0060-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/22/2017] [Accepted: 05/30/2017] [Indexed: 12/22/2022]
Abstract
Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.
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Affiliation(s)
- L Gallego-Villar
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Centre Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Centre Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany
| | - J Häberle
- University Children's Hospital and Children's Research Center, Zurich, Switzerland
| | - B Thöny
- University Children's Hospital and Children's Research Center, Zurich, Switzerland
| | - T Ben-Omran
- Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar
| | - G K Nasrallah
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Al-N Dewik
- Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar
| | - W D Kruger
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - H J Blom
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Centre Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany.
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18
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Enns GM, Cowan TM. Glutathione as a Redox Biomarker in Mitochondrial Disease-Implications for Therapy. J Clin Med 2017; 6:jcm6050050. [PMID: 28467362 PMCID: PMC5447941 DOI: 10.3390/jcm6050050] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/24/2017] [Accepted: 04/27/2017] [Indexed: 01/01/2023] Open
Abstract
Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, and the intracellular redox state, as reflected by levels of oxidized (GSSG) and reduced (GSH) glutathione, as well as the GSH/GSSG ratio, is considered to be an important indication of cellular health. The ability to quantify mitochondrial dysfunction in an affected patient will not only help with routine care, but also improve rational clinical trial design aimed at developing new therapies. Indeed, because multiple disorders have been associated with either primary or secondary deficiency of the mitochondrial electron transport chain and redox imbalance, developing mitochondrial therapies that have the potential to improve the intracellular glutathione status has been a focus of several clinical trials over the past few years. This review will also discuss potential therapies to increase intracellular glutathione with a focus on EPI-743 (α-tocotrienol quinone), a compound that appears to have the ability to modulate the activity of oxidoreductases, in particular NAD(P)H:quinone oxidoreductase 1.
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Affiliation(s)
- Gregory M Enns
- Departments of Pediatrics and Pathology, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94005-5208, USA.
| | - Tina M Cowan
- Departments of Pediatrics and Pathology, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94005-5208, USA.
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19
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Verny C, Bachoud-Lévi AC, Durr A, Goizet C, Azulay JP, Simonin C, Tranchant C, Calvas F, Krystkowiak P, Charles P, Youssov K, Scherer C, Prundean A, Olivier A, Reynier P, Saudou F, Maison P, Allain P, von Studnitz E, Bonneau D. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease. Mov Disord 2017; 32:932-936. [DOI: 10.1002/mds.27010] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 02/22/2017] [Accepted: 02/28/2017] [Indexed: 11/08/2022] Open
Affiliation(s)
- Christophe Verny
- Centre Hospitalier Universitaire d'Angers, Département de Neurologie et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
| | - Anne-Catherine Bachoud-Lévi
- Assistance Publique-Hôpitaux de Paris; Centre National de Référence Maladie de Huntington, Centre Hospitalier Universitaire H. Mondor - A. Chenevier de Créteil et INSERM U955, Equipe 01 Neuropsychologie interventionnelle, Créteil et Ecole Normale Supérieure, Institut d'Etudes Cognitives, Paris et Université Paris-Est, Faculté de Médecine; Créteil France
| | - Alexandra Durr
- Assistance Publique-Hôpitaux de Paris; Département de Génétique, and Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière; Paris France
| | - Cyril Goizet
- Centre Hospitalier Universitaire de Bordeaux; Hôpital Pellegrin, Service de Génétique Médicale, Université de Bordeaux, INSERM U1211; Bordeaux France
| | - Jean-Philippe Azulay
- Assistance Publique-Hôpitaux de Marseille; Hôpital de la Timone, Département de neurologie et de pathologie du mouvement, Institut de neurosciences de la Timone; UMR 7289 AMU-CNRS Marseille France
| | - Clémence Simonin
- Institut de Recherche sur le Cancer de Lille, INSERM UMR837, Centre Hospitalier Universitaire de Lille, Département de Neurologie et des Mouvements Anormaux; Lille France
| | - Christine Tranchant
- Hôpitaux Universitaire de Strasbourg; Hôpital Hautepierre, Service de Neurologie, Unité des Pathologies du mouvement; Strasbourg France
| | - Fabienne Calvas
- Centre Hospitalier Universitaire Purpan, Centre d'Investigation Clinique; Toulouse France
| | - Pierre Krystkowiak
- Centre Hospitalier Universitaire d'Amiens; Département de Neurologie, Université de Picardie Jules Verne, EA4559, Laboratoire de Neurosciences Fonctionnelles et Pathologie; Amiens France
| | - Perrine Charles
- Assistance Publique-Hôpitaux de Paris; Département de Génétique, and Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière; Paris France
| | - Katia Youssov
- Assistance Publique-Hôpitaux de Paris; Centre National de Référence Maladie de Huntington, Centre Hospitalier Universitaire H. Mondor - A. Chenevier de Créteil et INSERM U955, Equipe 01 Neuropsychologie interventionnelle, Créteil et Ecole Normale Supérieure, Institut d'Etudes Cognitives, Paris et Université Paris-Est, Faculté de Médecine; Créteil France
| | - Clarisse Scherer
- Centre Hospitalier Universitaire d'Angers, Département de Neurologie et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
| | - Adriana Prundean
- Centre Hospitalier Universitaire d'Angers, Département de Neurologie et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
| | - Audrey Olivier
- Centre Hospitalier Universitaire d'Angers, Département de Neurologie et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
| | - Pascal Reynier
- Centre Hospitalier Universitaire d'Angers, Département de Biochimie et Génétique et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
| | - Frédéric Saudou
- Université Grenoble Alpes, Grenoble Institut des Neurosciences; GIN, Grenoble France
- INSERM U1216
- Centre Hospitalier Universitaire de Grenoble; Grenoble France
| | - Patrick Maison
- INSERM U955, Equipe 01 Neuropsychologie interventionnelle; Créteil France
| | - Philippe Allain
- Centre Hospitalier Universitaire d'Angers, Département de Neurologie et UPRES EA 4638, Laboratoire de Psychologie des Pays de la Loire; Angers France
| | | | - Dominique Bonneau
- Centre Hospitalier Universitaire d'Angers, Département de Biochimie et Génétique et UMR CNRS 6214 - INSERM U1083 et Institut Mitovasc; Angers France
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20
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Gaetano Gatta N, Romano R, Fioretti E, Gentile V. Transglutaminase inhibition: possible therapeutic mechanisms to protect cells from death in neurological disorders. AIMS MOLECULAR SCIENCE 2017. [DOI: 10.3934/molsci.2017.4.399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Abstract
INTRODUCTION An inherited, chronic progressive, neurodegenerative disorder is Huntington's disease, characterized by motor, cognitive, and psychiatric symptoms. Predictive genetic testing allows earlier diagnosis and identification of gene carriers for Huntington's disease. These individuals are ideal candidates for testing of therapeutic interventions for disease modification. Areas covered: According to queries in Pubmed, Embase and clinical register databases, research and clinical studies emerge on symptomatic and neuroprotective therapies in Huntington's disease. This review discusses novel agents for symptomatic therapy and disease modification. They are currently in phase I and II of drug development Expert opinion: There are promising, safe and well tolerated compounds for amelioration of motor and neuropsychiatric symptoms, but their efficacy still needs to be proven in clinical trials. Deterioration of mutant huntingtin expression, antiapoptotic or cell death inhibition as disease modifying concepts was efficacious in models of Huntington's disease. However, the risk for clinical trial failures is high not only due to ineffectiveness of the tested agent. Negative study outcomes may also result from design misconceptions, underestimation of the heterogeneity of Huntington's disease, too short study durations and too small study cohorts.
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Affiliation(s)
- Thomas Müller
- a Department of Neurology , St. Joseph Hospital Berlin-Weißensee , Berlin , Germany
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22
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Lee YJ, Jung SH, Kim SH, Kim MS, Lee S, Hwang J, Kim SY, Kim YM, Ha KS. Essential Role of Transglutaminase 2 in Vascular Endothelial Growth Factor-Induced Vascular Leakage in the Retina of Diabetic Mice. Diabetes 2016; 65:2414-28. [PMID: 27207524 DOI: 10.2337/db15-1594] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 04/21/2016] [Indexed: 11/13/2022]
Abstract
Diabetic retinopathy is predominantly caused by vascular endothelial growth factor (VEGF)-induced vascular leakage; however, the underlying mechanism is unclear. Here we designed an in vivo transglutaminase (TGase) activity assay in mouse retina and demonstrated that hyperglycemia induced vascular leakage by activating TGase2 in diabetic retina. VEGF elevated TGase2 activity through sequential elevation of intracellular Ca(2+) and reactive oxygen species (ROS) concentrations in endothelial cells. The TGase inhibitors cystamine and monodansylcadaverin or TGase2 small interfering RNA (siRNA) prevented VEGF-induced stress fiber formation and vascular endothelial (VE)-cadherin disruption, which play a critical role in modulating endothelial permeability. Intravitreal injection of two TGase inhibitors or TGase2 siRNA successfully inhibited hyperglycemia-induced TGase activation and microvascular leakage in the retinas of diabetic mice. C-peptide or ROS scavengers also inhibited TGase activation in diabetic mouse retinas. The role of TGase2 in VEGF-induced vascular leakage was further supported using diabetic TGase2(-/-) mice. Thus, our findings suggest that ROS-mediated activation of TGase2 plays a key role in VEGF-induced vascular leakage by stimulating stress fiber formation and VE-cadherin disruption.
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Affiliation(s)
- Yeon-Ju Lee
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Se-Hui Jung
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Su-Hyeon Kim
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Min-Soo Kim
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea Department of Anesthesiology, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Sungeun Lee
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - JongYun Hwang
- Department of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Soo-Youl Kim
- Cancer Cell and Molecular Biology Branch, National Cancer Center, Goyang, Gyeonggi-do, Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
| | - Kwon-Soo Ha
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea
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23
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Kim Y, Kim TW, Park YS, Jeong EM, Lee DS, Kim IG, Chung H, Hwang YI, Lee WJ, Yu HG, Kang JS. The Role of Interleukin-22 and Its Receptor in the Development and Pathogenesis of Experimental Autoimmune Uveitis. PLoS One 2016; 11:e0154904. [PMID: 27166675 PMCID: PMC4864334 DOI: 10.1371/journal.pone.0154904] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/20/2016] [Indexed: 01/21/2023] Open
Abstract
IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19. To examine the effect of IL-22, ARPE-19 was treated with recombinant IL-22. The proliferation of ARPE-19 and the production of monocyte chemoattractant protein (MCP)-1 from ARPE-19 were clearly elevated. IL-22 induced MCP-1 which facilitated the migration of inflammatory cells. Moreover, IL-22 increased the IL-22Rα expression in ARPE-19 through the activation of PI3K/Akt. Experimental animal models of uveitis induced by interphotoreceptor retinoid binding protein 1-20 (IRBP1-20) exhibited elevation of hyperplasia RPE and IL-22 production. When CD4+ T cells from the uveitis patients were stimulated with IRBP1-20, the production of IL-22 definitely increased. In addition, we examine the regulatory role of cysteamine, which has an anti-inflammatory role in the cornea, in uveitis through the down-regulation of IL-22Rα expression. Cysteamine effectively suppressed the IRBP1-20-induced IL-22Rα expression and prevented the development of IRBP1-20-induced uveitis in the experimental animal model. These finding suggest that IL-22 and its receptor have a crucial role in the development and pathogenesis of uveitis by facilitating inflammatory cell infiltration, and that cysteamine may be a useful therapeutic drug in treating uveitis by down-regulating IL-22Rα expression in RPE.
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Affiliation(s)
- Yejin Kim
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae Wan Kim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Rheumatology Institute and Research for Sensory Organs Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
- Department of Ophthalmology, Seoul Metropolitan Government Seoul National University, Boramae Medical Center, Seoul, Republic of Korea
| | - Yun Seong Park
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eui Man Jeong
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong-Sup Lee
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - In-Gyu Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hum Chung
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young-il Hwang
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Wang Jae Lee
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyeong Gon Yu
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Seung Kang
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
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24
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Mason SL, Barker RA. Novel targets for Huntington's disease: future prospects. Degener Neurol Neuromuscul Dis 2016; 6:25-36. [PMID: 30050366 PMCID: PMC6053088 DOI: 10.2147/dnnd.s83808] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Huntington's disease (HD) is an incurable, inherited, progressive, neurodegenerative disorder that is characterized by a triad of motor, cognitive, and psychiatric problems. Despite the noticeable increase in therapeutic trials in HD in the last 20 years, there have, to date, been very few significant advances. The main hope for new and emerging therapeutics for HD is to develop a neuroprotective compound capable of slowing down or even stopping the progression of the disease and ultimately prevent the subtle early signs from developing into manifest disease. Recently, there has been a noticeable shift away from symptomatic therapies in favor of more mechanistic-based interventions, a change driven by a better understanding of the pathogenesis of this disorder. In this review, we discuss the status of, and supporting evidence for, potential novel treatments of HD that are currently under development or have reached the level of early Phase I/II clinical trials.
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Affiliation(s)
| | - Roger A Barker
- John van Geest Centre for Brain Repair, .,Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
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25
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Gaetano Gatta N, Cammarota G, Gentile V. Possible roles of transglutaminases in molecular mechanisms responsible for human neurodegenerative diseases. AIMS BIOPHYSICS 2016. [DOI: 10.3934/biophy.2016.4.529] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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26
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Cisbani G, Drouin-Ouellet J, Gibrat C, Saint-Pierre M, Lagacé M, Badrinarayanan S, Lavallée-Bourget M, Charest J, Chabrat A, Boivin L, Lebel M, Bousquet M, Lévesque M, Cicchetti F. Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease. Neurobiol Dis 2015; 82:430-444. [DOI: 10.1016/j.nbd.2015.07.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 07/08/2015] [Accepted: 07/22/2015] [Indexed: 12/22/2022] Open
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27
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Zhang ZY, Yang MF, Wang T, Li DW, Liu YL, Zhang JH, Sun BL. Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. Cell Mol Neurobiol 2015; 35:543-53. [PMID: 25527033 PMCID: PMC11486287 DOI: 10.1007/s10571-014-0150-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 12/11/2014] [Indexed: 01/05/2023]
Abstract
Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The aim of this study was to assess whether cysteamine prevents post-SAH oxidative stress injury via its antioxidative and anti-apoptotic effects. It was observed that intraperitoneal administration of cysteamine (20 mg/kg/day) could significantly alleviate EBI (including neurobehavioral deficits, brain edema, blood-brain barrier permeability, and cortical neuron apoptosis) after SAH in rats. Meanwhile, cysteamine treatment reduced post-SAH elevated the reactive oxygen species level, the concentration of malondialdehyde, 3-nitrotyrosine, and 8-hydroxydeoxyguanosine and increased the glutathione peroxidase enzymatic activity, the concentration of glutathione and brain-derived neurotrophic factor in brain cortex at 48 h after SAH. These results indicated that administration of cysteamine may ameliorate EBI and provide neuroprotection after SAH in rat models.
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Affiliation(s)
- Zong-yong Zhang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016 Shandong China
| | - Ming-feng Yang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016 Shandong China
| | - Tao Wang
- Department of Neurology, Taian Central Hospital Affiliated to Taishan Medical University, Taian, 271016 Shandong China
| | - Da-wei Li
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016 Shandong China
| | - Yun-lin Liu
- Department of Neurology, Taian Central Hospital Affiliated to Taishan Medical University, Taian, 271016 Shandong China
| | - Jin-hui Zhang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016 Shandong China
| | - Bao-liang Sun
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016 Shandong China
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28
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Serretiello E, Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy, Iannaccone M, Titta F, G. Gatta N, Gentile V. Possible pathophysiological roles of transglutaminase-catalyzed reactions in the pathogenesis of human neurodegenerative diseases. AIMS BIOPHYSICS 2015. [DOI: 10.3934/biophy.2015.4.441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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29
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Cho SY, Lee JH, Ju MK, Jeong EM, Kim HJ, Lim J, Lee S, Cho NH, Park HH, Choi K, Jeon JH, Kim IG. Cystamine induces AIF-mediated apoptosis through glutathione depletion. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1853:619-31. [PMID: 25549939 DOI: 10.1016/j.bbamcr.2014.12.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 12/09/2014] [Accepted: 12/22/2014] [Indexed: 12/18/2022]
Abstract
Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death.
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Affiliation(s)
- Sung-Yup Cho
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Jin-Haeng Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Mi-kyeong Ju
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Eui Man Jeong
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Hyo-Jun Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Jisun Lim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Seungun Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Nam-Hyuk Cho
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Hyun Ho Park
- Graduate School of Biochemistry, Yeungnam University, Gyeongsan 712-749, Republic of Korea
| | - Kihang Choi
- Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea
| | - Ju-Hong Jeon
- Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - In-Gyu Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
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30
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Prundean A, Youssov K, Humbert S, Bonneau D, Verny C. A phase II, open-label evaluation of cysteamine tolerability in patients with Huntington's disease. Mov Disord 2014; 30:288-9. [PMID: 25475049 DOI: 10.1002/mds.26101] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 09/29/2014] [Accepted: 10/27/2014] [Indexed: 11/10/2022] Open
Affiliation(s)
- Adriana Prundean
- Centre de référence des maladies neurogénétiques, Centre Hospitalier Universitaire, Angers, France
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31
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Karimi-Maleh H, Biparva P, Hatami M. A novel modified carbon paste electrode based on NiO/CNTs nanocomposite and (9, 10-dihydro-9, 10-ethanoanthracene-11, 12-dicarboximido)-4-ethylbenzene-1, 2-diol as a mediator for simultaneous determination of cysteamine, nicotinamide adenine dinucleotide and folic acid. Biosens Bioelectron 2013; 48:270-5. [PMID: 23707873 DOI: 10.1016/j.bios.2013.04.029] [Citation(s) in RCA: 191] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 04/07/2013] [Accepted: 04/16/2013] [Indexed: 10/26/2022]
Abstract
A carbon paste electrode (CPE) modified with (9, 10-dihydro-9, 10-ethanoanthracene-11, 12-dicarboximido)-4-ethylbenzene-1, 2-diol (DEDE) and NiO/CNTs nanocomposite was used for the sensitive voltammetric determination of cysteamine (CA), nicotinamide adenine dinucleotide (NADH) and folic acid (FA) for the first time. The synthesized materials were characterized with different methods such as XRD, cyclic voltammetry, electrochemical impedance spectroscopy (EIS) and square wave voltammetry (SWV). The modified electrode exhibited a potent and persistent electron mediating behavior followed by well-separated oxidation peaks of CA, NADH and FA. The peak currents were linearly dependent on CA, NADH and FA concentrations using square wave voltammetry (SWV) method in the ranges of 0.01-250, 1.0-500, and 3.0-550 µmol L⁻¹, with detection limits of 0.007, 0.6, and 0.9 µmol L⁻¹, respectively. The modified electrode was used for the determination of CA, NADH and FA in biological and pharmaceutical samples.
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Affiliation(s)
- Hassan Karimi-Maleh
- Department of Chemistry, Graduate University of Advanced Technology, Kerman, Iran.
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D’Argenio G, Mazzone G, Ribecco MT, Lembo V, Vitaglione P, Guarino M, Morisco F, Napolitano M, Fogliano V, Caporaso N. Garlic extract attenuating rat liver fibrosis by inhibiting TGF-β1. Clin Nutr 2013; 32:252-8. [DOI: 10.1016/j.clnu.2012.07.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Revised: 06/22/2012] [Accepted: 07/09/2012] [Indexed: 02/06/2023]
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Besouw M, Masereeuw R, van den Heuvel L, Levtchenko E. Cysteamine: an old drug with new potential. Drug Discov Today 2013; 18:785-92. [PMID: 23416144 DOI: 10.1016/j.drudis.2013.02.003] [Citation(s) in RCA: 136] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 12/28/2012] [Accepted: 02/08/2013] [Indexed: 01/23/2023]
Abstract
Cysteamine is an amino thiol with the chemical formula HSCH2CH2NH2. Endogenously, cysteamine is derived from coenzyme A degradation, although its plasma concentrations are low. Most experience with cysteamine as a drug originates from the field of the orphan disease cystinosis, in which cysteamine is prescribed to decrease intralysosomal cystine accumulation. However, over the years, the drug has been used for several other applications both in vitro and in vivo. In this article, we review the different applications of cysteamine, ending with an overview of ongoing clinical trials for new indications, such as neurodegenerative disorders and nonalcoholic fatty liver disease (NAFLD). The recent development of an enteric-coated cysteamine formulation makes cysteamine more patient friendly and will extend its applicability for both old and new indications.
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Affiliation(s)
- Martine Besouw
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.
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Mrzljak L, Munoz-Sanjuan I. Therapeutic Strategies for Huntington's Disease. Curr Top Behav Neurosci 2013; 22:161-201. [PMID: 24277342 DOI: 10.1007/7854_2013_250] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease, caused by expansion of the CAG repeat in the huntingtin (HTT) gene and characterized pathologically by the loss of pyramidal neurons in several cortical areas, of striatal medium spiny neurons, and of hypothalamic neurons. Clinically, a distinguishing feature of the disease is uncontrolled involuntary movements (chorea, dyskensias) accompanied by progressive cognitive, motor, and psychiatric impairment. This review focuses on the current state of therapeutic development for the treatment of HD, including the preclinical and clinical development of small molecules and molecular therapies.
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Iannaccone M, Stefanile A, Vivo GD, Martin A, Serretiello E, Gentile V. Transglutaminase inhibition: A therapy to protect cells from death in neurodegeneration? World J Biol Chem 2012; 3:184-186. [PMID: 23193435 PMCID: PMC3508428 DOI: 10.4331/wjbc.v3.i11.184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Revised: 10/10/2012] [Accepted: 10/30/2012] [Indexed: 02/05/2023] Open
Abstract
Transglutaminases (TGs; E.C. 2.3.2.13) are ubiquitous enzymes which catalyze post-translational modifications of proteins. TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. In particular, TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases. In support of this hypothesis, Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death, suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders. In this commentary, we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases, with particular reference to neurodegenerative diseases, and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases. Moreover, therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of the symptoms of patients with neurological diseases, characterized by aberrant TG activity, are also discussed.
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Gil-Mohapel JM. Screening of therapeutic strategies for Huntington's disease in YAC128 transgenic mice. CNS Neurosci Ther 2012; 18:77-86. [PMID: 21501423 DOI: 10.1111/j.1755-5949.2011.00246.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by an unstable expansion of cytosine-adenine-guanine (CAG) repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairment with loss of voluntary movement coordination that is later replaced by bradykinesia and rigidity. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, and the appearance of neuronal intranuclear inclusions of mutant huntingtin. The mechanisms responsible for neurodegeneration are still not fully understood although excitotoxicity and a consequent increase in intracellular calcium concentration as well as the activation of caspases and calapins are known to play a key role. There is currently no satisfactory treatment or cure for this disease. The YAC128 transgenic mice express the full-length human HD gene with 128 CAG repeats and constitute a unique model for the study of HD as they replicate the slow and biphasic progression of behavioral deficits characteristic of the human condition and show striatal neuronal loss. As such, these transgenic mice have been an invaluable model not only for the elucidation of the neurodegenerative pathways in HD, but also for the screening and development of new therapeutic approaches. Here, I will review the unique characteristics of this transgenic HD model and will provide a summary of the therapies that have been tested in these mice, namely: potentiation of the protective roles of wild-type huntingtin and mutant huntingtin aggregation, transglutaminase inhibition, inhibition of glutamate- and dopamine-induced toxicity, apoptosis inhibition, use of essential fatty acids, and the novel approach of intrabody gene therapy. The insights obtained from these and future studies will help identify potential candidates for clinical trials and will ultimately contribute to the discovery of a successful treatment for this devastating neurodegenerative disorder.
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Affiliation(s)
- Joana M Gil-Mohapel
- Division of Medical Sciences, Island Medical Program, University of Victoria, British Columbia, Canada.
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Noponen V, Belt H, Lahtinen M, Valkonen A, Salo H, Ulrichová J, Galandáková A, Sievänen E. Bile acid-cysteamine conjugates: structural properties, gelation, and toxicity evaluation. Steroids 2012; 77:193-203. [PMID: 22133545 DOI: 10.1016/j.steroids.2011.11.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 11/09/2011] [Accepted: 11/12/2011] [Indexed: 10/15/2022]
Abstract
Design, synthesis, and characterization of six novel bile acid-cysteamine conjugates together with investigation of their structural studies, gelation properties, and preliminary toxicity evaluation, are reported. Solid state properties of selected compounds were studied by means of X-ray diffraction and (13)C CPMAS NMR spectroscopy. N-(2-thioethyl)-3α,7α,12α-trihydroxy-5β-cholan-24-amide was shown to exhibit (pseudo)polymorphism, and a single crystal structure of its non-stoichiometric hydrate is reported herein. Cholyl and dehydrocholyl derivatives bearing three functionalities in their steroidal backbone were shown to undergo self-assembly leading to gelation in certain organic solvents. Preliminary morphology studies of the formed gels by scanning electron microscopy (SEM) were performed. The standard model mouse fibroblast cell line together with the MTT and NR tests were utilized for evaluating the toxicity of the prepared compounds. Lithocholyl, ursodeoxycholyl, and dehydrocholyl derivatives turned out to be relatively non-toxic in the conditions studied.
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Affiliation(s)
- Virpi Noponen
- University of Jyväskylä, Department of Chemistry, P.O. Box 35, FI-40014 Jyväskylä, Finland.
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Transglutaminase 2: biology, relevance to neurodegenerative diseases and therapeutic implications. Pharmacol Ther 2011; 133:392-410. [PMID: 22212614 DOI: 10.1016/j.pharmthera.2011.12.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 12/06/2011] [Indexed: 12/24/2022]
Abstract
Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease-specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Αβ, tau, α-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2). Additionally, the expression and activity of TG2 is increased in affected brain regions in these disorders. These observations along with experimental evidence in cellular and mouse models suggest that TG2 can contribute to the abnormal aggregation of disease causing proteins and consequently to neuronal damage. This accumulating evidence has provided the impetus to develop inhibitors of TG2 as possible neuroprotective agents. However, TG2 has other enzymatic activities in addition to its cross-linking function and can modulate multiple cellular processes including apoptosis, autophagy, energy production, synaptic function, signal transduction and transcription regulation. These diverse properties must be taken into consideration in designing TG2 inhibitors. In this review, we discuss the biochemistry of TG2, its various physiologic functions and our current understanding about its role in degenerative diseases of the brain. We also describe the different approaches to designing TG2 inhibitors that could be developed as potential disease-modifying therapies.
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Zádori D, Klivényi P, Plangár I, Toldi J, Vécsei L. Endogenous neuroprotection in chronic neurodegenerative disorders: with particular regard to the kynurenines. J Cell Mol Med 2011; 15:701-17. [PMID: 21155972 PMCID: PMC3922661 DOI: 10.1111/j.1582-4934.2010.01237.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Parkinson's disease (PD) and Huntington's disease (HD) are progressive chronic neurodegenerative disorders that are accompanied by a considerable impairment of the motor functions. PD may develop for familial or sporadic reasons, whereas HD is based on a definite genetic mutation. Nevertheless, the pathological processes involve oxidative stress and glutamate excitotoxicity in both cases. A number of metabolic routes are affected in these disorders. The decrease in antioxidant capacity and alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, are features that deserve particular interest, because the changes in levels of neuroactive kynurenine pathway compounds appear to be strongly related to the oxidative stress and glutamate excitotoxicity involved in the disease pathogenesis. Increase of the antioxidant capacity and pharmacological manipulation of the kynurenine pathway are therefore promising therapeutic targets in these devastating disorders.
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Affiliation(s)
- Dénes Zádori
- Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary
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Gibrat C, Cicchetti F. Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:380-9. [PMID: 21111020 DOI: 10.1016/j.pnpbp.2010.11.023] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 11/10/2010] [Accepted: 11/17/2010] [Indexed: 01/08/2023]
Abstract
Neurodegenerative disorders are a subset of disabling pathologies characterized, in part, by a progressive and specific loss of certain brain cell populations. Current therapeutic approaches for the treatment of these disorders are mainly designed towards symptom management and do not manifestly block their typified neuronal loss. However, research conducted over the past decade has reflected the increasing interest and need to find disease-modifying molecules. Among the several neuroprotective agents emerging from experimental animal work, cystamine, as well as its reduced form cysteamine, have been identified as potential candidate drugs. Given the significant benefits observed in a Huntington's disease (HD) model, cysteamine has recently leaped to clinical trial. Here, we review the beneficial properties of these compounds as reported in animal studies, their mechanistic underpinnings, and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically for HD and Parkinson's disease (PD).
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Affiliation(s)
- C Gibrat
- Centre de Recherche du CHUL (CHUQ), Axe Neurosciences, 2705 Boulevard Laurier, Québec, QC, Canada, G1V 4G2
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Experimental Models of HD and Reflection on Therapeutic Strategies. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2011; 98:419-81. [DOI: 10.1016/b978-0-12-381328-2.00016-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, García-Arencibia M, O'Kane CJ, Murphy MP, Rubinsztein DC. Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet 2010; 19:3413-29. [PMID: 20566712 PMCID: PMC2916709 DOI: 10.1093/hmg/ddq253] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Accepted: 06/15/2010] [Indexed: 12/12/2022] Open
Abstract
Many neurodegenerative diseases exhibit protein accumulation and increased oxidative stress. Therapeutic strategies include clearing aggregate-prone proteins by enhancing autophagy or decreasing oxidative stress with antioxidants. Many autophagy-inducing stimuli increase reactive oxygen species (ROS), raising concerns that the benefits of autophagy up-regulation may be counterbalanced by ROS toxicity. Here we show that not all autophagy inducers significantly increase ROS. However, many antioxidants inhibit both basal and induced autophagy. By blocking autophagy, antioxidant drugs can increase the levels of aggregate-prone proteins associated with neurodegenerative disease. In fly and zebrafish models of Huntington's disease, antioxidants exacerbate the disease phenotype and abrogate the rescue seen with autophagy-inducing agents. Thus, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties.
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Affiliation(s)
- Benjamin R. Underwood
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | - Sara Imarisio
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
- Department of Genetics and
| | - Angeleen Fleming
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK and
| | - Claudia Rose
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | - Gauri Krishna
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
- Department of Genetics and
| | | | - Marie Quick
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK and
| | - Viktor I. Korolchuk
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | - Maurizio Renna
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | - Sovan Sarkar
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | - Moisés García-Arencibia
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
| | | | - Michael P. Murphy
- MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK
| | - David C. Rubinsztein
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK
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Bousquet M, Gibrat C, Ouellet M, Rouillard C, Calon F, Cicchetti F. Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases. J Neurochem 2010; 114:1651-8. [PMID: 20569301 DOI: 10.1111/j.1471-4159.2010.06874.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 μM) was 0.15 ± 0.02 μL/g/s and was increased up to 0.34 ± 0.07 μL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.
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Affiliation(s)
- Mélanie Bousquet
- Centre de Recherche du CHUL (CHUQ), Axe Neurosciences, Québec, Québec, Canada
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D'Argenio G, Amoruso DC, Mazzone G, Vitaglione P, Romano A, Ribecco MT, D'Armiento MR, Mezza E, Morisco F, Fogliano V, Caporaso N. Garlic extract prevents CCl(4)-induced liver fibrosis in rats: The role of tissue transglutaminase. Dig Liver Dis 2010; 42:571-7. [PMID: 20004152 DOI: 10.1016/j.dld.2009.11.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 10/30/2009] [Accepted: 11/04/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Tissue transglutaminase contributes to liver damage in the development of hepatic fibrosis. In a model of neurodegeneration, the therapeutic benefit of cystamine has been partly attributed to its inhibition of transglutaminase activity. Garlic extract contains many compounds structurally related to cystamine. We investigated the anti-fibrotic effect of garlic extract and cystamine as specific tissue transglutaminase inhibitors. METHODS Rat liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl(4)) for 7 weeks. Cystamine or garlic extract was administrated by daily intraperitoneal injection, starting from the day after the first administration of CCl(4). Hepatic function, histology, tissue transglutaminase immunostaining and image analysis to quantify Red Sirius stained collagen deposition were examined. Reverse transcription-polymerase chain reaction to detect alpha-SMA, IL-1beta and tissue transglutaminase expression and Western blot for tissue transglutaminase protein amount were performed. Transglutaminase activity was assayed on liver homogenates by a radio-enzymatic method. RESULTS Transglutaminase activity was increased in CCl(4) group and reduced by cystamine and garlic extract (p<0.05). Treatment with cystamine and garlic extract reduced the liver fibrosis and collagen deposition, particularly in the garlic extract group (p<0.01). Moreover, the liver damage improved and serum alanine aminotransferase was decreased (p<0.05). Tissue transglutaminase immunolocalised with collagen fibres and is mainly found in the ECM of damaged liver. Alpha-SMA, IL-1beta, tissue transglutaminase mRNA and tissue transglutaminase protein were down-regulated in the cystamine and garlic extract groups compared to controls. CONCLUSION These findings concurrently suggest that transglutaminase may play a pivotal role in the pathogenesis of liver fibrosis and may identify garlic cystamine-like molecules as a potential therapeutic strategy in the treatment of liver injury.
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Affiliation(s)
- Giuseppe D'Argenio
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
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Sun L, Xu S, Zhou M, Wang C, Wu Y, Chan P. Effects of cysteamine on MPTP-induced dopaminergic neurodegeneration in mice. Brain Res 2010; 1335:74-82. [DOI: 10.1016/j.brainres.2010.03.079] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 03/22/2010] [Accepted: 03/22/2010] [Indexed: 01/13/2023]
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Cystamine and intrabody co-treatment confers additional benefits in a fly model of Huntington's disease. Neurobiol Dis 2010; 40:130-4. [PMID: 20399860 DOI: 10.1016/j.nbd.2010.04.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 03/16/2010] [Accepted: 04/09/2010] [Indexed: 01/13/2023] Open
Abstract
Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.
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Gibrat C, Bousquet M, Saint-Pierre M, Lévesque D, Calon F, Rouillard C, Cicchetti F. Cystamine prevents MPTP-induced toxicity in young adult mice via the up-regulation of the brain-derived neurotrophic factor. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:193-203. [PMID: 19913065 DOI: 10.1016/j.pnpbp.2009.11.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Revised: 11/04/2009] [Accepted: 11/05/2009] [Indexed: 01/01/2023]
Abstract
Preclinical data suggest that cystamine stands as a promising neuroprotective agent against Huntington's and Parkinson's diseases. To decipher the mechanisms of action of cystamine, we investigated the effects of various doses of cystamine (10, 50, and 200mg/kg) on the regulation of the brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-receptor-kinase B (TrkB) and on the heat shock protein 70 (Hsp70) brain mRNA expression in relation to the time after administration. We have determined that the lower cystamine dose is the most efficient to promote putative neuroprotective effects. Indeed, an acute administration of 10mg/kg of cystamine increased the expression of BDNF mRNA in the substantia nigra compacta (SNc), although it did not significantly influence TrkB or Hsp70 mRNA. Higher cystamine doses resulted in the absence of activation of any of these markers or led to non-specific effects. We have also substantiated the neuroprotective effect of a 21-day treatment of 10mg/kg/day of cystamine in young adult mice against MPTP-induced loss of tyrosine hydroxylase-striatal fiber density, nigral dopamine cells and nigral Nurr1 mRNA expression. The neuroprotective action of cystamine in the same animals was associated with an up-regulation of BDNF in the SNc. Taken together, these results strengthen the neuroprotective potential of cystamine in the treatment of Parkinson's disease and point towards the up-regulation of BDNF as an important mechanism of action.
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Affiliation(s)
- C Gibrat
- Centre de Recherche du CHUL (CHUQ), Axe neurosciences, 2705 Boulevard Laurier, Québec, QC, Canada G1V 4G2
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Abstract
Huntington's disease (HD) is a relentless neurodegenerative disease that results in profound disability through a triad of motor, cognitive and neuropsychiatric symptoms. At present, there are very few therapeutic interventions available with the exception of a limited number of drugs that offer mild symptomatic relief. Although the genetic basis of the disease has been identified, the mechanisms behind the cellular pathogenesis are still not clear and as a result no candidate drugs with the potential for disease modification have been found clinically until now. One of the major limitations in assessing the usefulness of drug treatments in HD is the lack of well-designed, double-blind, placebo-controlled clinical trials. Most studies have been open-label, using a small number of patients and tend to concentrate on the motor features of the disease, primarily the chorea. This review discusses the treatments now used for HD before evaluating the newer drugs at present being explored in both the clinic and in the laboratory in mouse models of the disease.
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Affiliation(s)
- Sarah L Mason
- Cambridge Centre for Brain Repair, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB20PY, UK.
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49
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Transglutaminase 2 expression levels regulate sensitivity to cystamine plus TRAIL-mediated apoptosis. Cancer Lett 2009; 287:224-30. [PMID: 19632032 DOI: 10.1016/j.canlet.2009.06.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Revised: 06/11/2009] [Accepted: 06/16/2009] [Indexed: 12/30/2022]
Abstract
In this study, we demonstrate for the first time that cystamine, an inhibitor of transglutaminase 2 (TG2), enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Caki cells, but not in normal human mesangial cells. Cystamine plus TRAIL-induced down-regulation of c-FLIP was recovered to basal levels by addition of the pancaspase inhibitor, z-VAD. The forced expression of c-FLIP attenuated cystamine plus TRAIL-mediated apoptosis in Caki cells. Although, cells expressing high levels of TG2 were more sensitive to cystamine plus TRAIL-mediated apoptosis than were cells expressing low levels of TG2, cystamine plus TRAIL-mediated apoptosis in the cell line expressing high levels of TG2 was reduced when TG2 levels were knocked down with siRNA. These results indicate that the level of TG2 modulates cystamine plus TRAIL-induced apoptosis. Taken together, the present findings suggest that cystamine may be an effective sensitizer of TRAIL-induced apoptosis in cancer cells expressing high levels of TG2.
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50
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Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C, Cochrane Movement Disorders Group. Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev 2009; 2009:CD006455. [PMID: 19588392 PMCID: PMC7390161 DOI: 10.1002/14651858.cd006455.pub2] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with an average onset between the fourth and fifth decade of life; it leads to death 15 to 20 years after the onset of symptoms. Although several drugs seem effective in controlling the incapacitating manifestations of HD, no specific therapy is known. The present review aims at analysing the best available data on therapeutic interventions investigated with the goal of modifying the progression of the disease as measured in terms of survival, disability or progression of HD core symptoms. OBJECTIVES Evaluate the effectiveness of therapeutic interventions aimed at modifying disease progression in HD. SEARCH STRATEGY The search strategy developed for the Movement Disorders Group was undertaken. The Cochrane Controlled Trials Register, Medline, EMBASE and Clinical Trials Database of the United States National Institute of Health were thoroughly searched until December 2007. SELECTION CRITERIA All randomised, double-blinded, placebo-controlled clinical trials of therapeutics investigated with the goal of modifying disease progression in HD were included. Participants should have genetically confirmed diagnosis of HD or compatible symptoms and a family history. Trials had a follow-up duration of more than three months and at least ten participants. All pharmacological and non-pharmacological interventions were included. DATA COLLECTION AND ANALYSIS Two reviewers independently assessed the eligibility of identified trials. The methodological quality was assessed and eligible data were registered onto standardised forms. An intention-to-treat analysis was conducted, when feasible. If data were not available in the original publication, the principal investigator of the trial was contacted for further information. A meta-analysis was to be conducted when possible; otherwise, a descriptive summary of the results was provided. The software Revman 5.0.15 was used for statistical analysis. MAIN RESULTS Eight trials were included involving a total of 1366 HD patients. The duration of the studies ranged between 30 and 144 weeks (median: 52 weeks). The following interventions were selected: vitamin E, Idebenone, Baclofen, Lamotrigine, creatine, coenzyme Q10 + Remacemide, ethyl-eicosapentanoic acid and Riluzole. No trials produced positive results for the selected efficacy outcome measures. A descriptive summary of the trials is provided. The selected interventions were found to be generally safe and well tolerated. AUTHORS' CONCLUSIONS Only pharmacological interventions were included and none proved to be effective as a disease-modifying therapy for HD. Further trials with greater methodological quality should be conducted using more sensitive biological markers. Pre-symptomatic mutation carriers should be included in future studies.
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Affiliation(s)
- Tiago Mestre
- Institute of Molecular MedicineNeurological Clinical Research UnitHospital de Santa MariaAv. Prof. Egas MonizLisboaPortugal1649‐028
| | - Joaquim Ferreira
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaHospital de Santa MariaAv. Prof. Egas MonizLisboaPortugal1649‐028
| | - Miguel M Coelho
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaHospital de Santa MariaAv. Prof. Egas MonizLisboaPortugal1649‐028
| | - Mário Rosa
- Institute of Molecular MedicineNeurological Clinical Research UnitHospital de Santa MariaAv. Prof. Egas MonizLisboaPortugal1649‐028
| | - Cristina Sampaio
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaHospital de Santa MariaAv. Prof. Egas MonizLisboaPortugal1649‐028
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