Department of Neurology, Philipps-University of Marburg, Baldingerstrasse, Marburg, Germany.
J Parkinsons Dis. 2013;3(2):161-72. doi: 10.3233/JPD-120157.
Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons and an accompanying neuroinflammatory process in the substantia nigra (SN). The cholinergic anti-inflammatory signalling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. A major component of this pathway is the α7 nicotinic acetylcholine receptor (α7 nACh receptor), which is expressed on immune cells such as microglia.
To determine the role of this cholinergic anti-inflammatory signalling pathway, we investigated the effects of the selective α7 nACh agonist PNU-282987 and of the non-competitive nACh antagonist mecamylamine on microglia-induced neuroinflammation and toxin-induced degeneration of dopaminergic neurons in a mouse model of PD.
PNU-282987, mecamylamine or placebo administration was started one day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57Bl/6 mice were injected intraperitoneally four times at 2 h intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or seven days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis.
Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion. Unexpectedly, mecamylamine lowered neuroinflammation as well, though it did not show a neuroprotective potential at the nigral level.
Our results demonstrate the therapeutic potential of the selective α7 nicotinic acetylcholine agonist PNU-282987 in attenuating neuroinflammation and toxin-induced loss of dopaminergic neurons in the acute MPTP mouse model of PD.
帕金森病（PD）与多巴胺能神经元的神经退行性变以及黑质（SN）中的伴随神经炎症过程有关。胆碱能抗炎信号通路使自主神经系统能够调节免疫刺激和炎症过程。该途径的主要组成部分是α7 烟碱型乙酰胆碱受体（α7 nACh 受体），其在免疫细胞（如小胶质细胞）上表达。
为了确定该胆碱能抗炎信号通路的作用，我们研究了选择性α7 nACh 激动剂 PNU-282987 和非竞争性 nACh 拮抗剂美金刚胺对 PD 小鼠模型中小胶质细胞诱导的神经炎症和毒素诱导的多巴胺能神经元变性的影响。
PNU-282987、美金刚胺或安慰剂给药于 MPTP 中毒前一天开始，每天重复直至 MPTP 中毒后处死。C57Bl/6 小鼠经腹腔注射 4 次，间隔 2 小时，每次 20 mg/kg MPTP-HCl 或相应体积的生理盐水。MPTP 中毒结束后 2 天或 7 天，处死动物并处理其大脑进行进一步分析。
PNU-282987 治疗可减轻 MPTP 损伤 SN 中的神经炎症。此外，PNU-282987 减轻了 MPTP 诱导的 SN 中多巴胺能神经元丢失，并减少了纹状体多巴胺耗竭。出乎意料的是，美金刚胺也降低了神经炎症，尽管它在黑质水平没有表现出神经保护潜力。
我们的研究结果表明，选择性α7 烟碱乙酰胆碱激动剂 PNU-282987 具有治疗潜力，可减轻急性 MPTP 小鼠 PD 模型中的神经炎症和毒素诱导的多巴胺能神经元丢失。
