Division of System Neurophysiology, National Institute for Physiological Sciences, 38, Nishigonaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan; Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), 38, Nishigonaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan.
Division of System Neurophysiology, National Institute for Physiological Sciences, 38, Nishigonaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan; Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), 38, Nishigonaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan.
Neurochem Int. 2019 Mar;124:171-180. doi: 10.1016/j.neuint.2019.01.011. Epub 2019 Jan 11.
Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain and shows motor dysfunctions. Zonisamide (ZNS, 1,2-benzisoxazole-3-methanesulfonamide), which was originally developed as an antiepileptic drug, was also found to have beneficial effects on motor symptoms in PD. In the current study, we have investigated the behavioral and physiological effects of ZNS on L-DOPA-induced dyskinesia (LID) in PD model mice. Chronic administration of L-DOPA plus ZNS in PD model mice was shown to increase the duration and severity of LID compared with PD model mice that were treated with L-DOPA alone. To elucidate the neural mechanism of the effects of ZNS on LID, we examined neuronal activity in the output nuclei of the basal ganglia, i.e., the substantia nigra pars reticulata (SNr). Chronic administration of L-DOPA plus ZNS in PD mice decreased the firing rate in the SNr while they showed apparent LID. In addition, chronic treatment of L-DOPA plus ZNS in PD mice changed cortically evoked responses in the SNr during LID. In the control state, motor cortical stimulation induces the triphasic response composed of early excitation, inhibition, and late excitation. In contrast, L-DOPA plus ZNS-treated PD mice showed longer inhibition and reduced late excitation. Previous studies proposed that inhibition in the SNr is derived from the direct pathway and releases movements, and that late excitation is derived from the indirect pathway and stops movements. These changes of the direct and indirect pathways possibly underlie the effects of ZNS on LID.
帕金森病（PD）是一种由中脑多巴胺能神经元丧失引起的神经退行性疾病，表现为运动功能障碍。佐尼沙胺（ZNS，1,2-苯并异恶唑-3-甲磺酰胺）最初被开发为抗癫痫药物，也被发现对 PD 患者的运动症状有有益作用。在本研究中，我们研究了 ZNS 对 PD 模型小鼠 L-DOPA 诱导的运动障碍（LID）的行为和生理影响。与单独给予 L-DOPA 的 PD 模型小鼠相比，慢性给予 L-DOPA 加 ZNS 的 PD 模型小鼠的 LID 持续时间和严重程度增加。为了阐明 ZNS 对 LID 影响的神经机制，我们检查了基底神经节输出核即黑质网状部（SNr）中的神经元活动。慢性给予 L-DOPA 加 ZNS 的 PD 小鼠在出现明显 LID 的同时，SNr 的放电率降低。此外，慢性给予 L-DOPA 加 ZNS 的 PD 小鼠在 LID 期间改变了 SNr 中的皮质诱发反应。在对照状态下，运动皮层刺激诱导由早期兴奋、抑制和晚期兴奋组成的三相反应。相比之下，L-DOPA 加 ZNS 治疗的 PD 小鼠表现出更长的抑制和减少的晚期兴奋。先前的研究提出，SNr 中的抑制来自直接通路并释放运动，而晚期兴奋来自间接通路并停止运动。这些直接和间接通路的变化可能是 ZNS 对 LID 影响的基础。
