King's College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, SE1 1UL, UK.
BMC Neurosci. 2019 Dec 20;20(1):61. doi: 10.1186/s12868-019-0543-3.
Parkinson's disease (PD) is characterised by dopaminergic cell loss within the substantia nigra pars compacta (SNc) that leads to reduced striatal dopamine content and resulting motor deficits. Identifying new strategies to protect these cells from degeneration and retain striatal dopaminergic innervation is therefore of great importance. Chondroitin sulphate proteoglycans (CSPGs) are recognised contributors to the inhibitory extracellular milieu known to hinder tissue recovery following CNS damage. Digestion of these molecules by the bacterial lyase chondroitinase ABC (ChABC) has been shown to promote functional recovery in animal models of neurological injury. Although ChABC has been shown to promote sprouting of dopaminergic axons following transection of the nigrostriatal pathway, its ability to protect against nigrostriatal degeneration in a toxin-based module with better construct validity for PD has yet to be explored. Here we examined the neuroprotective efficacy of ChABC treatment in the full and partial 6-hydroxydopamine (6-OHDA) lesion mouse models of PD.
In mice bearing a full 6-OHDA lesion, ChABC treatment failed to protect against the loss of either nigral cells or striatal terminals. In contrast, in mice bearing a partial 6-OHDA lesion, ChABC treatment significantly protected cells of the rostral SNc, which remained at more than double the numbers seen in vehicle-treated animals. In the partial lesion model, ChABC treatment also significantly preserved dopaminergic fibres of the rostral dorsal striatum which increased from 15.3 ± 3.5% of the intact hemisphere in saline-treated animals to 36.3 ± 6.5% in the ChABC-treated group. These protective effects of ChABC treatment were not accompanied by improvements in either the cylinder or amphetamine-induced rotations tests of motor function.
ChABC treatment provided significant protection against a partial 6-OHDA lesion of the nigrostriatal tract although the degree of protection was not sufficient to improve motor outcomes. These results support further investigations into the benefits of ChABC treatment for providing neuroprotection in PD.
帕金森病（PD）的特征是黑质致密部（SNc）内多巴胺能细胞丧失，导致纹状体多巴胺含量降低，并导致运动功能障碍。因此，寻找新的策略来保护这些细胞免受变性并保留纹状体多巴胺能神经支配非常重要。硫酸软骨素蛋白聚糖（CSPGs）是抑制性细胞外基质的公认贡献者，已知该基质会阻碍中枢神经系统损伤后的组织恢复。细菌溶菌素软骨素酶 ABC（ChABC）消化这些分子已被证明可促进神经损伤动物模型的功能恢复。尽管 ChABC 已被证明可促进黑质纹状体通路横断后多巴胺能轴突的发芽，但尚未探索其在具有更好 PD 构建有效性的基于毒素的模块中防止黑质纹状体变性的能力。在这里，我们研究了 ChABC 治疗在全 6-羟多巴胺（6-OHDA）损伤 PD 小鼠模型中的神经保护作用。
在全 6-OHDA 损伤的小鼠中，ChABC 治疗未能防止黑质细胞或纹状体末端的丧失。相比之下，在部分 6-OHDA 损伤的小鼠中，ChABC 治疗显著保护了 rostral SNc 的细胞，其数量超过了载体处理动物的两倍以上。在部分损伤模型中，ChABC 治疗还显著保留了 rostral 背侧纹状体的多巴胺能纤维，其从盐水处理动物的完整大脑半球的 15.3±3.5%增加到 ChABC 处理组的 36.3±6.5%。ChABC 治疗的这些保护作用不伴有运动功能的圆筒或安非他命诱导旋转测试的改善。
ChABC 治疗对黑质纹状体束的部分 6-OHDA 损伤提供了显著的保护，尽管保护程度不足以改善运动结果。这些结果支持进一步研究 ChABC 治疗在 PD 中提供神经保护的益处。
