Department of Anatomy, University of Rostock, Gertrudenstr. 9, 18057 Rostock, Germany.
Neurobiol Dis. 2011 Feb;41(2):291-8. doi: 10.1016/j.nbd.2010.09.017. Epub 2010 Oct 16.
Central pathophysiological pathways of basal ganglia dysfunction imply a disturbed interaction of dopaminergic and cholinergic circuits. In Parkinson's disease (PD) imbalanced cholinergic hyperactivity prevails in the striatum. Interruption of acetylcholine (ACh) release in the striatum by locally injected botulinum neurotoxin A (BoNT-A) has been studied in the rat 6-hydroxydopamine (6-OHDA) model of PD (hemi-PD). The hemi-PD was induced by injection of 6-OHDA into the right medial forebrain bundle. Motor dysfunction provoked by apomorphine-induced contralateral rotation was completely reversed for more than 3 months by ipsilateral intrastriatal application of 1-2 ng BoNT-A. Interestingly, BoNT-A injected alone into the right striatum of naïve rats caused a slight transient ipsilateral apomorphine-induced rotation, which lasted only for about one month. Immunohistochemically, large axonal swellings appeared within the striatum injected with BoNT-A, which we tentatively named BoNT-A-induced varicosities. They contained either choline acetyltransferase or tyrosine hydroxylase. These findings suggest a selective inhibition of evoked release of ACh by locally applied BoNT-A. Intrastriatal application of BoNT-A may antagonize localized relative functional disinhibited hypercholinergic activity in neurodegenerative diseases such as PD avoiding side effects of systemic anti-cholinergic treatment.
基底神经节功能障碍的中心病理生理途径暗示多巴胺能和胆碱能回路的相互作用受到干扰。在帕金森病（PD）中，纹状体中胆碱能活性亢进失衡。通过在大鼠 6-羟多巴胺（6-OHDA）PD 模型（半 PD）中局部注射肉毒杆菌神经毒素 A（BoNT-A）来中断纹状体中乙酰胆碱（ACh）的释放已经进行了研究。半 PD 通过将 6-OHDA 注射到右侧中脑束中诱导。通过阿扑吗啡诱导的对侧旋转引起的运动功能障碍通过同侧纹状体中 1-2ng BoNT-A 的应用完全逆转超过 3 个月。有趣的是，单独将 BoNT-A 注射到 naïve 大鼠的右侧纹状体中会引起轻微的短暂同侧阿扑吗啡诱导的旋转，持续时间仅约一个月。免疫组织化学显示，在注射 BoNT-A 的纹状体中出现了大的轴突肿胀，我们暂将其命名为 BoNT-A 诱导的膨体。它们含有胆碱乙酰转移酶或酪氨酸羟化酶。这些发现表明局部应用的 BoNT-A 选择性抑制了诱发的 ACh 释放。BoNT-A 向纹状体的内注射可能拮抗神经退行性疾病（如 PD）中局部相对功能去抑制的高胆碱能活性，避免了全身性抗胆碱能治疗的副作用。
