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1
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Farchione TJ, Long LJ, Gallagher MW, Spencer-Laitt D, Torre M, Woodard LS, Curreri AJ, Brown B, Ross M, Barlow DH. Results from a randomized controlled trial of zonisamide in the treatment of alcohol use disorder. J Psychiatr Res 2024; 179:182-190. [PMID: 39306870 PMCID: PMC11773425 DOI: 10.1016/j.jpsychires.2024.08.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 08/20/2024] [Accepted: 08/29/2024] [Indexed: 11/05/2024]
Abstract
There is preliminary evidence that the anticonvulsant medication Zonisamide (ZON) may be an effective, well-tolerated treatment for alcohol use disorder (AUD). However, further evaluation of its efficacy for treating patients with AUD is needed, and much remains unknown about ZON's therapeutic mechanisms. The present study aimed to evaluate the efficacy and tolerability of ZON in a double-blind, placebo-controlled, randomized trial. Eighty-one adults (ages 21-65) diagnosed with AUD were randomly assigned to receive either ZON (at a target dose of 400 mg/d) or a pill placebo over 12 weeks, followed by a two-week taper. All participants also received a computerized alcohol reduction program, Take Control (TC). Primary drinking outcomes were average daily drinks, percentage drinking days, and percentage heavy drinking days. Further, we evaluated changes in AUD clinical severity and performance on neuropsychological measures. For both groups, drinking outcomes generally decreased, as did AUD clinical severity, though group differences were not statistically significant. Neuropsychological testing performance was similar for both groups at baseline; however, at post-treatment, participants in the ZON group demonstrated poorer working memory and lower performance on verbal fluency tests compared to the placebo group, and these differences were statistically significant with moderate-large effect sizes. One serious adverse event was reported among individuals receiving ZON. Study findings indicate that ZON combined with TC does not demonstrate superior effectiveness for reducing average daily drinks in this clinical sample with principal AUD compared to placebo and TC, and treatment with ZON may be associated with reduced neurocognitive performance over time.
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Affiliation(s)
- Todd J Farchione
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA.
| | - Laura J Long
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - Matthew W Gallagher
- Department of Psychology, Texas Institute for Measurement, Evaluation and Statistics, University of Houston, Houston, TX, USA
| | | | - Marie Torre
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - Lauren S Woodard
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - Andrew J Curreri
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - Bonnie Brown
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - Margaret Ross
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
| | - David H Barlow
- Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
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2
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Tóth K, S Nagy K, Güler Z, Juhász ÁG, Pállinger É, Varga G, Sarac AS, Zrínyi M, Jedlovszky-Hajdú A, Juriga D. Characterization of Electrospun Polysuccinimide-Dopamine Conjugates and Effect on Cell Viability and Uptake. Macromol Biosci 2023; 23:e2200397. [PMID: 36592964 DOI: 10.1002/mabi.202200397] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/14/2022] [Indexed: 01/04/2023]
Abstract
Biocompatible nanofibrous systems made by electrospinning have been studied widely for pharmaceutical applications since they have a high specific surface and the capability to make the entrapped drug molecule amorphous, which increases bioavailability. By covalently conjugating drugs onto polymers, the degradation of the drug as well as the fast clearance from the circulation can be avoided. Although covalent polymer-drug conjugates have a lot of advantages, there is a lack of research focusing on their nano-formulation by electrospinning. In this study, polysuccinimide (PSI) based electrospun fibrous meshes conjugated with dopamine (DA) are prepared. Fiber diameter, mechanical properties, dissolution kinetics and membrane permeability are thoroughly investigated, as these are crucial for drug delivery and implantation. Dopamine release kinetics prove the prolonged release that influenced the viability and morphology of periodontal ligament stem cells (PDLSCs) and SH-SY5Y cells. The presence of dopamine receptors on both cell types is also demonstrated and the uptake of the conjugates is measured. According to flow cytometry analysis, the conjugates are internalized by both cell types, which is influenced by the chemical structure and physical properties. In conclusion, electrospinning of PSI-DA conjugates alters release kinetics, meanwhile, conjugated dopamine can play a key role in cellular uptake.
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Affiliation(s)
- Krisztina Tóth
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Krisztina S Nagy
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.,Department of Oral Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Zeliha Güler
- Department of Nanoscience and Nanoengineering, Istanbul Technical University, Istanbul, 34469, Turkey.,Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development, Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, the Netherlands
| | - Ákos György Juhász
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Gábor Varga
- Department of Oral Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.,Centre for Translational Medicine, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary
| | - A Sezai Sarac
- Department of Nanoscience and Nanoengineering, Istanbul Technical University, Istanbul, 34469, Turkey
| | - Miklós Zrínyi
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Angéla Jedlovszky-Hajdú
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
| | - Dávid Juriga
- Laboratory of Nanochemistry, Department of Biophysics and Radiation Biology, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
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3
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Naito T, Satake W, Cha PC, Kobayashi K, Murata M, Toda T. Comparative whole transcriptome analysis of Parkinson's disease focusing on the efficacy of zonisamide. J Neurol Neurosurg Psychiatry 2022; 93:509-512. [PMID: 35264450 PMCID: PMC9016247 DOI: 10.1136/jnnp-2021-328742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Interindividual variations in responsiveness to zonisamide in patients with Parkinson's disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD. METHODS We selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of 'wearing-off'. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point. RESULTS Differentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10-3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10-3 and 8.2 × 10-3, respectively). CONCLUSIONS Our results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment.
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Affiliation(s)
- Tatsuhiko Naito
- Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Wataru Satake
- Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan .,Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Pei-Chieng Cha
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kazuhiro Kobayashi
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Miho Murata
- Department of Neurology, NCNP Hospital, Kodaira, Japan
| | - Tatsushi Toda
- Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan .,Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
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4
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He J, Zhang X, He W, Xie Y, Chen Y, Yang Y, Chen R. Neuroprotective effects of zonisamide on cerebral ischemia injury via inhibition of neuronal apoptosis. ACTA ACUST UNITED AC 2021; 54:e10498. [PMID: 33656055 PMCID: PMC7917778 DOI: 10.1590/1414-431x202010498] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 11/02/2020] [Indexed: 11/22/2022]
Abstract
It is known that neuronal apoptosis contributes to pathology of cerebral ischemia injury. Zonisamide (ZNS) has shown anti-apoptosis effects in recent studies. The present study investigated whether the anti-apoptotic effect can account for the neuroprotective action of ZNS on cerebral ischemia. Neuronal cells were maintained under oxygen-glucose deprivation conditions to simulate cerebral ischemia and treated with ZNS simultaneously. The apoptosis of the cells and expression of apoptosis-related proteins were investigated by flow cytometry and western blot analysis, respectively. A cerebral ischemia mouse model was created via middle cerebral artery occlusion, and the mice were treated with ZNS. Neurological deficit scores and infarct volumes of the cerebral ischemia mice were measured. The apoptosis status of the neuronal cells was evaluated by TUNEL staining. In vitro, the ZNS treatment inhibited both the apoptosis of the neuronal cells and apoptosis-related protein expression (caspase-3, caspase-8, and calpain-1) induced by the oxygen-glucose deprivation. The anti-apoptosis effect of ZNS could occur through the blocking of reactive oxygen species. Moreover, ZNS treatment significantly ameliorated neurological deficits and reduced infarct volumes in the cerebral ischemia mice model. In this study, ZNS exerted neuroprotective effects by inhibition of apoptosis in neuronal cells in cerebral ischemia. Therefore, ZNS might be a promising therapy for cerebral ischemia.
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Affiliation(s)
- Junna He
- Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiangjian Zhang
- Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Weiliang He
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yanzhao Xie
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yanxia Chen
- Department of Endocrinology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yang Yang
- Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Rong Chen
- Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei, China
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5
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Li C, Xue L, Liu Y, Yang Z, Chi S, Xie A. Zonisamide for the Treatment of Parkinson Disease: A Current Update. Front Neurosci 2020; 14:574652. [PMID: 33408605 PMCID: PMC7779619 DOI: 10.3389/fnins.2020.574652] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.
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Affiliation(s)
- Chengqian Li
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Li Xue
- Department of Medical Record, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yumei Liu
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhengjie Yang
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Song Chi
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Anmu Xie
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
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6
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Binvignat O, Olloquequi J. Excitotoxicity as a Target Against Neurodegenerative Processes. Curr Pharm Des 2020; 26:1251-1262. [PMID: 31931694 DOI: 10.2174/1381612826666200113162641] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/27/2019] [Indexed: 12/20/2022]
Abstract
The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington's disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.
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Affiliation(s)
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Instituto de Ciencias Biomedicas, Facultad de Ciencias de la Salud, Universidad Autonoma de Chile, Talca, Chile
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7
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Miyawaki Y, Samata B, Kikuchi T, Nishimura K, Takahashi J. Zonisamide promotes survival of human-induced pluripotent stem cell-derived dopaminergic neurons in the striatum of female rats. J Neurosci Res 2020; 98:1575-1587. [PMID: 32506530 PMCID: PMC7497107 DOI: 10.1002/jnr.24668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 05/15/2020] [Accepted: 05/17/2020] [Indexed: 11/12/2022]
Abstract
The transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease model animals. However, the survival of DA progenitors is low, and the final yield of DA neurons is only approximately 0.3%–2% the number of transplanted cells. Zonisamide (ZNS) increases the number of survived DA neurons upon the transplantation of mouse‐induced pluripotent stem (iPS) cell‐derived DA progenitors in the rat striatum. In this study, we induced DA progenitors from human iPS cells and transplanted them into the striatum of female rats with daily administration of ZNS. The number of survived DA neurons was evaluated 1 and 4 months after transplantation by immunohistochemistry, which revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. To assess the mechanism of action of ZNS, we performed a gene expression analysis to compare the gene expression profiles in striatum treated with or without ZNS. The analysis revealed that the expression of SLIT‐and NTRK‐like protein 6 (SLITRK6) was upregulated in rat striatum treated with ZNS. In conclusion, ZNS promotes the survival of DA neurons after the transplantation of human‐iPS cell‐derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain.
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Affiliation(s)
- Yoshifumi Miyawaki
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Bumpei Samata
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Tetsuhiro Kikuchi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Kaneyasu Nishimura
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Jun Takahashi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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8
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Takaku S, Sango K. Zonisamide enhances neurite outgrowth from adult rat dorsal root ganglion neurons, but not proliferation or migration of Schwann cells. Histochem Cell Biol 2019; 153:177-184. [PMID: 31879799 PMCID: PMC7060162 DOI: 10.1007/s00418-019-01839-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 01/06/2023]
Abstract
Zonisamide, an anti-epileptic and anti-Parkinson’s disease drug, displays neurotrophic activity on cultured motor neurons and facilitates axonal regeneration after peripheral nerve injury in mice, but its underlying mechanisms remain unclear. In this study, zonisamide enhanced neurite outgrowth from cultured adult rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner (1 μM < 10 μM < 100 μM), and its activity was significantly attenuated by co-treatment with a phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor LY294002 or a mitogen-activated protein kinase (MAPK) inhibitor U0126. In agreement with these findings, 100 μM zonisamide for 1 h induced phosphorylation of AKT and ERK1/2, key molecules of PI3K and MAPK signaling pathways, respectively in mouse neuroblastoma × rat DRG neuron hybrid cells ND7/23. In contrast, zonisamide failed to promote proliferation or migration of immortalized Fischer rat Schwann cells 1 (IFRS1). These findings suggest that the beneficial effects of zonisamide on peripheral nerve regeneration may be attributable to its direct actions on neurons through PI3K and MAPK pathways, rather than the stimulation of Schwann cells.
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Affiliation(s)
- Shizuka Takaku
- Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
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9
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Amo T, Oji Y, Saiki S, Hattori N. Metabolomic analysis revealed mitochondrial dysfunction and aberrant choline metabolism in MPP+-exposed SH-SY5Y cells. Biochem Biophys Res Commun 2019; 519:540-546. [DOI: 10.1016/j.bbrc.2019.09.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/09/2019] [Indexed: 11/29/2022]
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10
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Ueno SI, Saiki S, Fujimaki M, Takeshige-Amano H, Hatano T, Oyama G, Ishikawa KI, Yamaguchi A, Nojiri S, Akamatsu W, Hattori N. Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson's Disease. Cells 2018; 8:cells8010014. [PMID: 30597973 PMCID: PMC6356654 DOI: 10.3390/cells8010014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/20/2018] [Accepted: 12/25/2018] [Indexed: 12/03/2022] Open
Abstract
Although many experimental studies have shown the favorable effects of zonisamide on mitochondria using models of Parkinson’s disease (PD), the influence of zonisamide on metabolism in PD patients remains unclear. To assess metabolic status under zonisamide treatment in PD, we performed a pilot study using a comprehensive metabolome analysis. Plasma samples were collected for at least one year from 30 patients with PD: 10 without zonisamide medication and 20 with zonisamide medication. We performed comprehensive metabolome analyses of plasma with capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. We also measured disease severity using Hoehn and Yahr (H&Y) staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor section, and analyzed blood chemistry. In PD with zonisamide treatment, 15 long-chain acylcarnitines (LCACs) tended to be increased, of which four (AC(12:0), AC(12:1)-1, AC(16:1), and AC(16:2)) showed statistical significance. Of these, two LCACs (AC(16:1) and AC(16:2)) were also identified by partial least squares analysis. There was no association of any LCAC with age, disease severity, levodopa daily dose, or levodopa equivalent dose. Because an upregulation of LCACs implies improvement of mitochondrial β-oxidation, zonisamide might be beneficial for mitochondrial β-oxidation, which is suppressed in PD.
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Affiliation(s)
- Shin-Ichi Ueno
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Shinji Saiki
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Motoki Fujimaki
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Haruka Takeshige-Amano
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Taku Hatano
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Genko Oyama
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Kei-Ichi Ishikawa
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
- Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Akihiro Yamaguchi
- Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Shuko Nojiri
- Medical Technology Innovation Center, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Wado Akamatsu
- Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
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11
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The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Na v 1.6. Exp Neurol 2018; 308:111-119. [PMID: 30017881 DOI: 10.1016/j.expneurol.2018.07.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 06/22/2018] [Accepted: 07/11/2018] [Indexed: 11/23/2022]
Abstract
Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20 mg/kg, i.p. every 4 h × 3) following a single injection of MPTP (12.5 mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-α and gp91phox, and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation.
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12
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Uemura MT, Asano T, Hikawa R, Yamakado H, Takahashi R. Zonisamide inhibits monoamine oxidase and enhances motor performance and social activity. Neurosci Res 2017. [DOI: 10.1016/j.neures.2017.05.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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13
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Xicoy H, Wieringa B, Martens GJM. The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol Neurodegener 2017; 12:10. [PMID: 28118852 PMCID: PMC5259880 DOI: 10.1186/s13024-017-0149-0] [Citation(s) in RCA: 639] [Impact Index Per Article: 79.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/05/2017] [Indexed: 12/29/2022] Open
Abstract
Parkinson’s disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage. This cell line is frequently chosen because of its human origin, catecholaminergic (though not strictly dopaminergic) neuronal properties, and ease of maintenance. However, there is no consensus on many fundamental aspects that are associated with its use, such as the effects of culture media composition and of variations in differentiation protocols. Here we present the outcome of a systematic review of scientific articles that have used SH-SY5Y cells to explore PD. We describe the cell source, culture conditions, differentiation protocols, methods/approaches used to mimic PD and the preclinical validation of the SH-SY5Y findings by employing alternative cellular and animal models. Thus, this overview may help to standardize the use of the SH-SY5Y cell line in PD research and serve as a future user’s guide.
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Affiliation(s)
- Helena Xicoy
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboudumc, Nijmegen, The Netherlands.,Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Bé Wieringa
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboudumc, Nijmegen, The Netherlands
| | - Gerard J M Martens
- Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
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Affiliation(s)
- Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Yagi
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
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15
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Neuroprotection as a Potential Therapeutic Perspective in Neurodegenerative Diseases: Focus on Antiepileptic Drugs. Neurochem Res 2015; 41:340-52. [PMID: 26721507 DOI: 10.1007/s11064-015-1809-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/10/2015] [Accepted: 12/14/2015] [Indexed: 02/07/2023]
Abstract
Neuroprotection is conceived as one of the potential tool to prevent or slow neuronal death and hence a therapeutic hope to treat neurodegenerative diseases, like Parkinson's and Alzheimer's diseases. Increase of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation have been identified as main causes of neuronal death and adopted as targets to test experimentally the putative neuroprotective effects of various classes of drugs. Among these agents, antiepileptic drugs (AEDs), both the old and the newer generations, have shown to exert protective effects in different experimental models. Their mechanism of action is mediated mainly by modulating the activity of sodium, calcium and potassium channels as well as the glutamatergic and GABAergic (gamma-aminobutyric acid) synapses. Neurological pathologies in which a neuroprotective action of AEDs has been demonstrated in specific experimental models include: cerebral ischemia, Parkinson's disease, and Alzheimer's disease. Although the whole of experimental data indicating that neuroprotection can be achieved is remarkable and encouraging, no firm data have been produced in humans so far and, at the present time, neuroprotection still remains a challenge for the future.
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Yagi H, Ohkawara B, Nakashima H, Ito K, Tsushima M, Ishii H, Noto K, Ohta K, Masuda A, Imagama S, Ishiguro N, Ohno K. Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model. PLoS One 2015; 10:e0142786. [PMID: 26571146 PMCID: PMC4646494 DOI: 10.1371/journal.pone.0142786] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 10/27/2015] [Indexed: 12/25/2022] Open
Abstract
No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson’s disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.
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Affiliation(s)
- Hideki Yagi
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Nakashima
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenyu Ito
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mikito Tsushima
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hisao Ishii
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Hand Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kimitoshi Noto
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Hand Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kyotaro Ohta
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akio Masuda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shiro Imagama
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Ishiguro
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
- * E-mail:
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Maeda T, Takano D, Yamazaki T, Satoh Y, Nagata K. Zonisamide in the early stage of Parkinson's disease. ACTA ACUST UNITED AC 2015. [DOI: 10.1111/ncn3.167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Tetsuya Maeda
- Department of Neurology; Research Institute for Brain and Blood Vessels Akita; Akita Japan
| | - Daiki Takano
- Department of Neurology; Research Institute for Brain and Blood Vessels Akita; Akita Japan
| | - Takashi Yamazaki
- Department of Neurology; Research Institute for Brain and Blood Vessels Akita; Akita Japan
| | - Yuichi Satoh
- Department of Neurology; Research Institute for Brain and Blood Vessels Akita; Akita Japan
| | - Ken Nagata
- Department of Neurology; Research Institute for Brain and Blood Vessels Akita; Akita Japan
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18
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Abdel-Salam OME. Drug therapy for Parkinson’s disease: An update. World J Pharmacol 2015; 4:117. [DOI: 10.5497/wjp.v4.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 01/26/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
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Tsujii S, Ishisaka M, Shimazawa M, Hashizume T, Hara H. Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo. Eur J Pharmacol 2014; 746:301-7. [PMID: 25261037 DOI: 10.1016/j.ejphar.2014.09.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/16/2014] [Accepted: 09/16/2014] [Indexed: 11/15/2022]
Abstract
Zonisamide has been reported to have protective effects on epilepsy and Parkinson׳s disease and to work via various mechanisms of action, such as inhibition of monoamine oxidase-B and enhancement of tyrosine hydroxylase. Recently, it has been suggested that zonisamide itself shows neuroprotective actions. Therefore, in the present study we investigated the neuroprotective effects of zonisamide against endoplasmic reticulum (ER) stress. We used human neuroblastoma (SH-SY5Y) cells and investigated the protective effects of zonisamide against tunicamycin- and thapsigargin-induced neuronal cell death. In addition, we investigated the effect of zonisamide against 1-methyl-4-phenylpyridinium (MPP⁺)-induced cell death and the mechanism of protection against ER stress. In vivo, we investigated the effect of zonisamide (20 mg/kg, p.o.) in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson׳s disease. Zonisamide not only suppressed MPP⁺-induced cell death, but also inhibited ER stress-induced cell death and suppressed the expression of ER stress-related factors such as C/EBO homologous protein (CHOP) in vivo. Furthermore, zonisamide inhibited the activation of caspase-3 in vitro. These results suggest that zonisamide affected ER stress via caspase-3. We think that ER stress, particularly the mechanism via caspase-3, is involved in part of the neuroprotective effect of zonisamide against the experimental models of Parkinson׳s disease.
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Affiliation(s)
- Saori Tsujii
- Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan
| | - Mitsue Ishisaka
- Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan
| | - Masamitsu Shimazawa
- Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan
| | - Takanori Hashizume
- Laboratory of Drug Metabolism & Pharmacokinetics, Faculty of Pharmacy, Osaka Ohtani University, Japan
| | - Hideaki Hara
- Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan.
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20
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Kopecky BJ, Liang R, Bao J. T-type calcium channel blockers as neuroprotective agents. Pflugers Arch 2014; 466:757-65. [PMID: 24563219 DOI: 10.1007/s00424-014-1454-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/15/2014] [Accepted: 01/19/2014] [Indexed: 01/12/2023]
Abstract
T-type calcium channels are expressed in many diverse tissues, including neuronal, cardiovascular, and endocrine. T-type calcium channels are known to play roles in the development, maintenance, and repair of these tissues but have also been implicated in disease when not properly regulated. Calcium channel blockers have been developed to treat various diseases and their use clinically is widespread due to both their efficacy as well as their safety. Aside from their established clinical applications, recent studies have suggested neuroprotective effects of T-type calcium channel blockers. Many of the current T-type calcium channel blockers could act on other molecular targets besides T-type calcium channels making it uncertain whether their neuroprotective effects are solely due to blocking of T-type calcium channels. In this review, we discuss these drugs as well as newly developed chemical compounds that are designed to be more selective for T-type calcium channels. We review in vitro and in vivo evidence of neuroprotective effects by these T-type calcium channel blockers. We conclude by discussing possible molecular mechanisms underlying the neuroprotective effects by T-type calcium channel blockers.
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Affiliation(s)
- Benjamin J Kopecky
- Department of Otolaryngology, Center for Aging, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, MO, 63110, USA
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21
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Cataldi M. The changing landscape of voltage-gated calcium channels in neurovascular disorders and in neurodegenerative diseases. Curr Neuropharmacol 2013; 11:276-97. [PMID: 24179464 PMCID: PMC3648780 DOI: 10.2174/1570159x11311030004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 02/02/2013] [Accepted: 02/14/2013] [Indexed: 12/12/2022] Open
Abstract
It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca2+ in neurons. Also, some of them as L-type channels are essential for Ca2+-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the “harmless” VGCCs may become “toxic” for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca2+ when: a) their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca2+-dependent action potentials carry high Ca2+ loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca2+. This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca2+-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia.
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Affiliation(s)
- Mauro Cataldi
- Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Italy
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22
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Grover ND, Limaye RP, Gokhale DV, Patil TR. Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease. Indian J Pharmacol 2013; 45:547-55. [PMID: 24347760 PMCID: PMC3847242 DOI: 10.4103/0253-7613.121266] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/24/2013] [Accepted: 08/14/2013] [Indexed: 12/18/2022] Open
Abstract
The limitations of currently available therapies in addressing the non motor symptoms of Parkinson's disease (PD) have egged on the search for newer options. Zonisamide has been in use for epilepsy and it was serendipitously found to improve the symptoms of PD in a patient who had both epilepsy and PD. Thereafter, various trials were designed to assess the use of zonisamide in PD. The present article investigates the evidence for use of zonisamide in PD from the various clinical trials that were designed to address this issue. Furthermore, the article also summarizes the various mechanisms of its use in PD as described in various animal experiments. A search protocol was designed with predefined inclusion and exclusion criteria. The databases searched were Pubmed, Ovid medline, Cochrane and clinicaltrials.gov. The data thus generated, was fed into a predesigned format. Most of the clinical trials on zonisamide in PD have come from Japan. Most of these trials used the changes in the Unified Parkinson's Disease Rating Scale (UPDRS) score as the endpoints and the most conclusive evidence is for a dose of 25-50 mg, which caused a change in UPDRS part III (motor symptoms). These patients were on levodopa and other drugs used for PD during the trials. One of the clinical trials conducted in Spain investigates the use of zonisamide in impulse control disorders among 15 patients of PD. Among the many mechanisms postulated, a reduction in levodopa induced quinone formation, protection against mitochondrial impairment and an increase in astroglial cysteine transport, an inhibition of microglial activation, monoamine oxidase-B (MAO-B) inhibition, an increased dopamine release and blockade of calcium channels are the most cited. There is evidence for use of zonisamide in PD in addition to levodopa and other therapies for control of motor symptoms. For now, the evidence for its use in control of non motor symptoms in PD is not enough and needs to be investigated further.
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Affiliation(s)
- Neeta D. Grover
- Department of Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Sangli, Maharashtra, India
| | - Ramachandra P. Limaye
- Department of Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Sangli, Maharashtra, India
| | - Dilip V. Gokhale
- Department of Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Sangli, Maharashtra, India
| | - Tatyasaheb R. Patil
- Department of Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Sangli, Maharashtra, India
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Condello S, Currò M, Ferlazzo N, Costa G, Visalli G, Caccamo D, Pisani LR, Costa C, Calabresi P, Ientile R, Pisani F. Protective effects of zonisamide against rotenone-induced neurotoxicity. Neurochem Res 2013; 38:2631-9. [PMID: 24142350 DOI: 10.1007/s11064-013-1181-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 10/03/2013] [Accepted: 10/14/2013] [Indexed: 02/08/2023]
Abstract
Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson's disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10-100 μM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 μM) displayed significant protective effects against rotenone-induced ROS production and Δψm at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone-increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction.
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Affiliation(s)
- Salvatore Condello
- Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, AOU Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
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Abstract
We found that zonisamide (ZNS), an antiepileptic agent, has beneficial effects on Parkinson disease. A 25mg once a day of ZNS significantly improves motor function of advanced patients with Parkinson disease. Its effects maintained at least one year even in patients with advanced stage. It was finally approved as an anti parkinsonian agent in Japan on March 2009. ZNS increases dopamine contents in the striatum by activating dopamine synthesis through increasing the levels of tyrosine hydroxylase (TH) mRNA and TH protein. It moderately inhibits monoamine oxydase (MAO) activity. The inhibitory effect of ZNS on T-type Ca(++)channel may also affect the anti-parkinsonian effects. ZNS also showed neuroprotective effects on several parkinsonian models through effecting both neuron and glia. We will verify the neuroprotective effects of ZNS on patients with Parkinson disease and study the factors responsible for the individual difference of the effects of zonisamide by using genome wide association study (GWAS) in the near feature.
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Affiliation(s)
- Miho Murata
- Department of Neurology, National Center Hospital, National Center of Neurology & Psychiatry
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Choudhury ME, Sugimoto K, Kubo M, Iwaki H, Tsujii T, Kyaw WT, Nishikawa N, Nagai M, Tanaka J, Nomoto M. Zonisamide up-regulated the mRNAs encoding astrocytic anti-oxidative and neurotrophic factors. Eur J Pharmacol 2012; 689:72-80. [PMID: 22659113 DOI: 10.1016/j.ejphar.2012.05.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 04/27/2012] [Accepted: 05/15/2012] [Indexed: 01/28/2023]
Abstract
Zonisamide has been proven as an effective drug for the recovery of degenerating dopaminergic neurons in the animal models of Parkinson's disease. However, several lines of evidence have questioned the neuroprotective capacity of zonisamide in animal models of Parkinson's disease. Although it suppresses dopaminergic neurodegeneration in animal models, the cellular and molecular mechanisms underlying the effectiveness of zonisamide are not fully understood. The current study demonstrates the effects of zonisamide on astrocyte cultures and two 6-hydroxydopamine-induced models of Parkinson's disease. Using primary astrocyte cultures, we showed that zonisamide up-regulated the expression of mRNA encoding mesencephalic astrocyte-derived neurotrophic factor, vascular endothelial growth factor, proliferating cell nuclear antigen, metallothionein-2, copper/zinc superoxide dismutase, and manganese superoxide dismutase. Similar responses to zonisamide were found in substantia nigra where the rats were pre-treated with 6-hydroxydopamine. Notably, pharmacological inhibition of 6-hydroxydopamine-induced toxicity by zonisamide pre-treatment was also confirmed using rat mesencephalic organotypic slice cultures of substantia nigra. In addition to this, zonisamide post-treatment also attenuated the nigral tyrosine hydroxylase-positive neuronal loss induced by 6-hydroxydopamine. Taken together, these studies demonstrate that zonisamide protected dopamine neurons in two Parkinson's disease models through a novel mechanism, namely increasing the expression of some important astrocyte-mediated neurotrophic and anti-oxidative factors.
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Affiliation(s)
- M E Choudhury
- Department of Therapeutic Medicine (Clinical Pharmacology and Neurology), Ehime University Graduate School of Medicine, Shitsukawa, Toon-Shi, Ehime 791-0295, Japan
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HRD1 Levels Increased by Zonisamide Prevented Cell Death and Caspase-3 Activation Caused by Endoplasmic Reticulum Stress in SH-SY5Y Cells. J Mol Neurosci 2011; 46:527-35. [DOI: 10.1007/s12031-011-9638-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 08/21/2011] [Indexed: 10/17/2022]
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