Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Exp Neurol. 2010 Feb;221(2):329-34. doi: 10.1016/j.expneurol.2009.11.018. Epub 2009 Dec 4.
Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na(+) channels and T-type Ca(2+) channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC(50) of 25 muM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP(+)), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.
唑尼沙胺是一种获得美国食品药品监督管理局批准的抗癫痫药物，它可以阻断电压依赖性钠离子通道和 T 型钙离子通道，当与其他帕金森病（PD）治疗方法联合使用时，可以改善 PD 患者的临床预后。唑尼沙胺还可以调节多巴胺（DA）活性，在缺血模型中提供保护，并影响抗氧化系统。因此，我们测试了它在 PD 小鼠模型中保护 DA 神经元的能力，并研究了其保护作用的机制。同时用唑尼沙胺和 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗小鼠，可减轻纹状体中 DA、其代谢物 DOPAC 和酪氨酸羟化酶（TH）含量的减少。我们还发现，唑尼沙胺在体外以 25 μM 的 IC50 抑制单胺氧化酶 B（MAO-B）的活性，这个浓度在用于治疗人类癫痫的治疗范围内。此外，通过离体测定，唑尼沙胺可减弱系统给予的司来吉兰与 MAO-B 的不可逆结合。单独用唑尼沙胺治疗不会对离体 MAO-B 活性产生任何持久影响，表明它是该酶的可逆抑制剂。与唑尼沙胺对 MAO-B 的作用一致，通过 MAO-B 作用从给予的 MPTP 衍生而来的 1-甲基-4-苯基吡啶鎓（MPP+）的纹状体含量在用 MPTP 和唑尼沙胺治疗的小鼠中显著降低。唑尼沙胺阻断 MAO-B 的效力和可逆性可能有助于该药物改善 PD 患者的临床症状的能力。结果还表明，在治疗癫痫或 PD 时，尤其是与其他药物联合使用时，需要谨慎使用。
