在实验性帕金森病中，沙芬酰胺对谷氨酸能纹状体网络的影响。
Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease.
机构信息
Neurological Clinic, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, via Gambuli, 1, 06132, Perugia, Italy.
Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, Piazza G. Ermini, 1, 06123, Perugia, Italy; Laboratory of Neurophysiology, Santa Lucia Foundation IRCCS, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
出版信息
Neuropharmacology. 2020 Jun 15;170:108024. doi: 10.1016/j.neuropharm.2020.108024. Epub 2020 Mar 3.
OBJECTIVE
The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (l-DOPA) treatment.
BACKGROUND
Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and l-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of l-DOPA therapy in PD.
METHODS
Electrophysiological effects of safinamide (1-100 μM) were investigated by patch-clamp recordings in striatal slices of naïve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with l-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the l-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test.
RESULTS
Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC) values in the therapeutic range (3-5 μM). Chronic co-administration of safinamide plus l-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs.
CONCLUSIONS
Safinamide, at a clinically relevant dose, optimizes the effect of l-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and l-DOPA ameliorates motor deficits.
目的
本研究旨在评估沙芬酰胺对纹状体棘状投射神经元（SPN）固有和突触特性的电生理作用，并在左旋多巴（l-DOPA）治疗前后，在多巴胺（DA）去神经大鼠中描述该药物可能的抗帕金森治疗作用。
背景
目前帕金森病（PD）的治疗选择主要是 DA 替代策略，这通常会导致 SPN 谷氨酸诱导的过度兴奋引起进行性运动波动和 l-DOPA 诱导的运动障碍（LIDs）。作为一种可逆的、电压门控钠离子通道的使用依赖性抑制剂，沙芬酰胺可减少谷氨酸的释放，并可能优化 PD 中 l-DOPA 治疗的效果。
方法
通过在未经处理的、6-羟多巴胺（6-OHDA）损伤的 DA 去神经大鼠和慢性给予 l-DOPA 的 DA 去神经动物的纹状体切片中进行膜片钳记录，研究沙芬酰胺（1-100 μM）的电生理作用。体内通过和不通过慢性沙芬酰胺治疗评估 LIDs，并通过评分 l-DOPA 诱导的异常不自主运动（AIMs）来测量。运动缺陷通过步测法进行评估。
结果
沙芬酰胺降低了所有组的 SPN 放电率和谷氨酸能突触传递，表现出剂量依赖性效应，半数最大抑制浓度（IC）值在治疗范围内（3-5 μM）。在 DA 去神经动物中，慢性给予沙芬酰胺加 l-DOPA 有利于皮质纹状体长时程突触增强（LTP）的恢复和兴奋性突触传递的去增强，也减少了 LIDs 发作前的运动缺陷。
结论
沙芬酰胺在临床相关剂量下，通过降低 SPN 兴奋性和调节突触传递，优化了 l-DOPA 治疗实验性 PD 的效果。沙芬酰胺和 l-DOPA 的联合给药可改善运动缺陷。
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