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Safinamide inhibits in vivo glutamate release in a rat model of Parkinson's disease.
Neuropharmacology ( IF 4.7 ) Pub Date : 2020-02-10 , DOI: 10.1016/j.neuropharm.2020.108006
Clarissa A Pisanò 1 , Alberto Brugnoli 1 , Salvatore Novello 1 , Carla Caccia 2 , Charlotte Keywood 2 , Elsa Melloni 2 , Silvia Vailati 2 , Gloria Padoani 2 , Michele Morari 1
Affiliation  

To investigate whether the reversible MAO-B inhibitor and sodium channel blocker safinamide impairs glutamate release under parkinsonian conditions in vivo, and this effect is dependent on MAO-B inhibition, safinamide (and rasagiline as a comparator) were administered to 6-hydroxydopamine hemilesioned rats, a model of Parkinson's disease, and haloperidol-treated rats, a model of neuroleptic-induced parkinsonism. A microdialysis probe was implanted in the dopamine-depleted dorsolateral striatum, globus pallidus, subthalamic nucleus or substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats. Glutamate and GABA release was stimulated by reverse dialysis of veratridine, and safinamide or rasagiline were acutely administered before veratridine at doses inhibiting MAO-B >50%. A microdialysis probe was implanted in the substantia nigra reticulata of naïve rats to monitor glutamate and GABA release following acute haloperidol and safinamide administration. Safinamide inhibited the veratridine-evoked glutamate release in the globus pallidus and subthalamic nucleus but not in the striatum and substantia nigra. Moreover, it reduced pallidal and nigral GABA release. Conversely, rasagiline failed to modify the veratridine-induced glutamate and GABA release in the basal ganglia. Safinamide also inhibited the haloperidol-induced nigral glutamate release. MAO-B inhibitors safinamide and rasagiline differ in their abilities to inhibit depolarization-evoked glutamate release in the basal ganglia of parkinsonian rats. The ineffectiveness of rasagiline suggests that MAO-B inhibition does not contribute to the antiglutamatergic activity of safinamide. The glutamate-inhibiting action of safinamide within the subthalamo-external pallidal loop, which shows abnormal activity in Parkinson's disease, might contribute to its therapeutic actions of improving motor performance without provoking troublesome dyskinesia.

中文翻译:

在帕金森氏病大鼠模型中,沙芬酰胺抑制体内谷氨酸的释放。

为了研究可逆的MAO-B抑制剂和钠通道阻滞剂沙芬酰胺是否在体内帕金森病条件下削弱了谷氨酸的释放,并且这种作用取决于MAO-B抑制作用,将沙芬酰胺(和雷沙吉兰作为比较剂)施用于6-羟基多巴胺大鼠,帕金森氏症模型和氟哌啶醇治疗的大鼠,是精神安定药诱发的帕金森氏症模型。将微渗析探针植入到6-羟基多巴胺成年大鼠的多巴胺消耗的背外侧纹状体,苍白球,丘脑下核或黑质网状组织中。通过对维他命啶的逆透析刺激谷氨酸和GABA的释放,并在给予维他命前以抑制MAO-B> 50%的剂量急性给予沙非酰胺或雷沙吉兰。将微透析探针植入幼稚大鼠的黑质网状组织中,以监测急性氟哌啶醇和沙非酰胺给药后谷氨酸和GABA的释放。沙芬酰胺抑制苍白球引起的苍白球和丘脑下核中谷氨酸的释放,而抑制纹状体和黑质中的谷氨酸的释放。此外,它减少了苍白和黑质GABA的释放。相反,雷沙吉兰未能改变维拉替丁诱导的基底节中谷氨酸和GABA的释放。沙非酰胺还抑制氟哌啶醇诱导的谷氨酸释放。MAO-B抑制剂沙芬酰胺和雷沙吉兰在抑制帕金森病大鼠基底神经节中去极化诱发的谷氨酸释放方面的能力不同。雷沙吉兰的无效性表明,MAO-B抑制作用无助于沙芬酰胺的抗谷氨酸能活性。沙芬酰胺在丘脑外下苍白环中的谷氨酸抑制作用,在帕金森氏病中表现出异常活性,可能有助于其改善运动能力而不引起麻烦的运动障碍的治疗作用。
更新日期:2020-02-10
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