Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
Neuropharmacology. 2018 Aug;138:371-380. doi: 10.1016/j.neuropharm.2018.06.028. Epub 2018 Jun 22.
Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of α5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and α5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of α5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian α5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in α5-KO mice. Decreased striatal dopamine uptake in α5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not α5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian α5-KO mice suggests potential for α5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease.
临床前研究表明，各种亚型的烟碱型乙酰胆碱受体参与了帕金森病的病理生理学过程，帕金森病是一种神经退行性疾病，其特征是黑质致密部（SNC）中的多巴胺能神经元死亡。我们首次研究了α5 型烟碱受体亚单位基因缺失对帕金森病小鼠模型和左旋多巴诱导的运动障碍的运动行为和神经退行性变的影响。通过将 6-羟多巴胺注射到纹状体或中脑边缘束中，在野生型和α5-KO 小鼠中诱导单侧多巴胺能损伤。随后，测量多巴胺能药物诱导的旋转行为。一部分动物接受了左旋多巴和尼古丁的慢性治疗，以评估尼古丁对左旋多巴诱导的运动障碍和抗运动障碍的作用。通过酪氨酸羟化酶免疫组织化学和立体学细胞计数评估 SNC 损伤程度。通过测量体外纹状体多巴胺转运蛋白功能和蛋白表达、多巴胺和代谢物组织浓度以及多巴胺受体 mRNA 表达，研究了α5 基因缺失对多巴胺系统的影响。半帕金森病的α5-KO 小鼠在安非他命注射后表现出旋转行为减弱，左旋多巴诱导的运动障碍减弱。在纹状体损伤模型中，α5-KO 小鼠 SNC 内侧簇的多巴胺能细胞丢失程度较轻。α5-KO 动物的纹状体多巴胺摄取减少表明多巴胺转运蛋白功能降低，这是神经毒性减弱的一种机制。尼古丁降低了野生型小鼠但没有降低α5-KO 小鼠的运动障碍严重程度。半帕金森病的α5-KO 小鼠观察到的多巴胺能神经退行性变和运动功能障碍减弱表明，含有α5 亚基的烟碱受体可能成为帕金森病治疗的新靶点。
