Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.
Neurotox Res. 2018 Jul;34(1):16-31. doi: 10.1007/s12640-017-9846-2. Epub 2017 Dec 7.
Parkinson's disease (PD) is conventionally seen as resulting from single-system neurodegeneration affecting nigrostriatal dopaminergic neurons. However, accumulating evidence indicates multi-system degeneration and neurotransmitter deficiencies, including cholinergic neurons which degenerate in a brainstem nucleus, the pedunculopontine nucleus (PPN), resulting in motor and cognitive impairments. The neuropeptide galanin can inhibit cholinergic transmission, while being upregulated in degenerating brain regions associated with cognitive decline. Here we determined the temporal-spatial profile of progressive expression of endogenous galanin within degenerating cholinergic neurons, across the rostro-caudal axis of the PPN, by utilizing the lactacystin-induced rat model of PD. First, we show progressive neuronal death affecting nigral dopaminergic and PPN cholinergic neurons, reflecting that seen in PD patients, to facilitate use of this model for assessing the therapeutic potential of bioactive peptides. Next, stereological analyses of the lesioned brain hemisphere found that the number of PPN cholinergic neurons expressing galanin increased by 11%, compared to sham-lesioned controls, and increasing by a further 5% as the neurodegenerative process evolved. Galanin upregulation within cholinergic PPN neurons was most prevalent closest to the intra-nigral lesion site, suggesting that galanin upregulation in such neurons adapt intrinsically to neurodegeneration, to possibly neuroprotect. This is the first report on the extent and pattern of galanin expression in cholinergic neurons across distinct PPN subregions in both the intact rat CNS and lactacystin-lesioned rats. The findings pave the way for future work to target galanin signaling in the PPN, to determine the extent to which upregulated galanin expression could offer a viable treatment strategy for ameliorating PD symptoms associated with cholinergic degeneration.
帕金森病（PD）通常被认为是由影响黑质纹状体多巴胺能神经元的单一系统神经退行性变引起的。然而，越来越多的证据表明多系统退化和神经递质缺乏，包括在脑干核团即脑桥被盖核（PPN）中退化的胆碱能神经元，导致运动和认知障碍。神经肽甘丙肽可以抑制胆碱能传递，同时在与认知能力下降相关的退化脑区中上调。在这里，我们通过利用乳白蛋白诱导的 PD 大鼠模型，确定了内源性甘丙肽在退化的胆碱能神经元中的时空表达模式，横跨 PPN 的头尾部。首先，我们显示出影响黑质多巴胺能和 PPN 胆碱能神经元的进行性神经元死亡，反映了 PD 患者的情况，从而促进了该模型用于评估生物活性肽的治疗潜力。接下来，对损伤大脑半球的体视学分析发现，与假损伤对照相比，表达甘丙肽的 PPN 胆碱能神经元数量增加了 11%，随着神经退行性过程的发展，进一步增加了 5%。PPN 胆碱能神经元内甘丙肽的上调最为常见，最接近内侧黑质病变部位，表明此类神经元内甘丙肽的上调内在适应神经退行性变，可能具有神经保护作用。这是首次在完整大鼠中枢神经系统和乳白蛋白损伤大鼠中报告 PPN 不同亚区胆碱能神经元中甘丙肽表达的程度和模式。这些发现为进一步研究 PPN 中的甘丙肽信号奠定了基础，以确定上调的甘丙肽表达在多大程度上可以为改善与胆碱能退化相关的 PD 症状提供可行的治疗策略。
