临床应用Zonisamide(唑尼沙胺）治疗帕金森症的最新机制解释
Zonisamide(唑尼沙胺）是一种新型的治疗帕金森症药物，在经历2001-2009年的临床后，日本卫生部已于2009年1月批准唑尼沙胺正式用于帕金森症的治疗，在这几年的研究及临床中，唑尼沙胺对于帕症的治疗中，发现有30%-40%的患者运动功能显著恢复，特别是应用左旋多巴制剂时间比较长，而有剂末和开关现象的患者。由于这只药物的治疗机制完全不同于现有的帕症药物，所以有必要做一个跟进，这只药物的主要功能在于二个方面。
一：神经保护，帕症的疾病进展牵涉到Tau蛋白介导的细胞毒性，异常的Tau蛋白聚集即过度表达和高度磷酸化是疾病不断进展的一个主要因素，而唑尼沙胺治疗帕金森症的机制是通过通过提高Hrd1泛素连接酶的水平而介导Tau蛋白的降解从而提供神经保护和解除疾病进展的诱因，从而彻底减缓疾病的进展。
二:在日本爱媛大学的一项研究中发现，Zonisamide可以诱导多巴胺能神经元的恢复，这一点比第一点更为重要，也就是揭示了一种积极的治疗方式，而不是对症的消极治疗。Zonisamide可能比雷沙吉兰这只目前最为有效的神经保护剂更为接近严格意义上讲的治疗二个字。
Zonisamide目前的一般治疗指引是每天25mg-75mg,最佳剂量为50mg,不建议每天用多于100mg，原厂是Eisai公司，即以前讨论过的VitK2的原厂厂家。
需要注意的是，如果病人有磺胺类药物过敏的是不适合用唑尼沙胺的。
J Mol Neurosci. 2012 Mar;46(3):527-35. Epub 2011 Sep 3.
HRD1 levels increased by zonisamide prevented cell death and caspase-3 activation caused by endoplasmic reticulum stress in SH-SY5Y cells.
Omura T, Asari M, Yamamoto J, Kamiyama N, Oka K, Hoshina C, Maseda C, Awaya T, Tasaki Y, Shiono H, Shimizu K, Matsubara K.
SourceDepartment of Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.
Abstract
Zonisamide, which is commonly prescribed at high doses (200-400 mg/day) for the treatment of partial seizures, has recently been used at a low dose (25 mg/day) for improving parkinsonian syndrome. However, the molecular mechanisms that underlie the antiparkinsonian effects of zonisamide have not been clarified. Here we show that low micromolar concentrations of zonisamide prevented cleavage of caspase-3 and cell death in human dopaminergic SH-SY5Y neuroblastoma cells that were subjected to endoplasmic reticulum stress induced by tunicamycin or 6-hydroxydopamine. Hypodense zonisamide increased the expression levels of SEL1L, which is known to stabilize the ubiquitin ligase HRD1. Indeed, upregulation of HRD1 protein was observed. Thus, the results of this study strongly suggest that low concentrations of zonisamide inhibit neuronal cell death by increasing HRD1 protein levels in patients with Parkinson’s disease. Consequently, in addition to the treatment of Parkinson’s disease, the therapeutic potential of zonisamide should be considered for the treatment of several neurodegenerative disorders with pathophysiological mechanisms involving endoplasmic reticulum stress.
PMID:21892618[PubMed - in process]
Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity.
Choudhury ME, Moritoyo T, Kubo M, Kyaw WT, Yabe H, Nishikawa N, Nagai M, Matsuda S, Nomoto M.
SourceDepartment of Therapeutic Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon-Shi, Ehime 791-0295, Japan.
Abstract
Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinson’s disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg×4 every 2h; 3) MPTP and zonisamide, 40 mg/kg×1, 1h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100β-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP-induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100β secretion.
Copyright © 2011 Elsevier B.V. All rights reserved.
PMID:21320474[PubMed - indexed for MEDLINE]
这是2007年的文章，有必要再重温一下，发表在当年美国神经学会会刊上的文章。
Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study.
Murata M, Hasegawa K, Kanazawa I; Japan Zonisamide on PD Study Group.
SourceDepartment of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan. mihom@ncnp.go.jp
Erratum in
Neurology. 2007 Jul 3;69(1):120.
Abstract
OBJECTIVE: To evaluate the efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of zonisamide (ZNS) administered as adjunctive treatment in patients with Parkinson disease (PD).
METHODS: We conducted a multicenter, randomized, double-blind, parallel-treatment, placebo-controlled study in Japan. Patients with PD who showed insufficient response to levodopa treatment were given placebo for 2 weeks and then treated for 12 weeks with 25, 50, or 100 mg/day of ZNS or placebo, in addition to levodopa, followed by a 2-week dose-reduction period. The primary endpoint was change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at the final assessment point. Secondary endpoints included changes from baseline in total daily "off" time; total scores of UPDRS Parts I, II, and IV; and Modified Hoehn and Yahr Scale score. Safety analysis was based on the incidence of adverse events.
RESULTS: There was significant improvement in the primary endpoint in the 25-mg and 50-mg groups vs placebo. The duration of "off" time was significantly reduced in the 50-mg and 100-mg groups vs placebo. Dyskinesia was not increased in ZNS groups. The incidence of adverse effects was similar between the 25-mg, 50-mg, and placebo groups but higher in the 100-mg group.
CONCLUSIONS: Zonisamide is safe, effective and well tolerated at 25 to 100 mg/day as an adjunctive treatment in patients with Parkinson disease.
