BackgroundParkinson’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.ResultsIn 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.ConclusionsChABC 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.

中文翻译：

---

软骨素酶 ABC 减少帕金森病 6-羟基多巴胺部分病变小鼠模型中的多巴胺能黑质细胞死亡和纹状体终末丢失

背景帕金森病 (PD) 的特征是黑质致密部 (SNc) 内的多巴胺能细胞丢失，导致纹状体多巴胺含量减少并导致运动障碍。因此，确定保护这些细胞免于变性并保留纹状体多巴胺能神经支配的新策略非常重要。硫酸软骨素蛋白聚糖 (CSPG) 是公认的抑制性细胞外环境的贡献者，已知会阻碍 CNS 损伤后的组织恢复。细菌裂解酶软骨素酶 ABC (ChABC) 对这些分子的消化已被证明可促进神经损伤动物模型的功能恢复。尽管 ChABC 已被证明可以促进黑质纹状体通路横断后多巴胺能轴突的萌芽，它在基于毒素的模块中防止黑质纹状体变性的能力对 PD 具有更好的结构有效性还有待探索。在这里，我们检查了 ChABC 治疗在 PD 的全部和部分 6-羟基多巴胺 (6-OHDA) 损伤小鼠模型中的神经保护功效。结果在具有完整 6-OHDA 损伤的小鼠中，ChABC 治疗未能防止黑质细胞的丢失或纹状体终端。相比之下，在带有部分 6-OHDA 损伤的小鼠中，ChABC 治疗显着保护了嘴部 SNc 的细胞，其数量仍是载体治疗动物的两倍多。在部分病变模型中，ChABC 治疗还显着保留了头侧纹状体的多巴胺能纤维，从生理盐水治疗动物的完整半球的 15.3 ± 3.5% 增加到 36.3 ± 6。ChABC 治疗组为 5%。ChABC 治疗的这些保护作用并没有伴随着圆柱体或苯丙胺诱导的运动功能旋转测试的改善。结论 ChABC 治疗对黑质纹状体束的部分 6-OHDA 病变提供了显着的保护，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。结论 ChABC 治疗对黑质纹状体束的部分 6-OHDA 损伤提供了显着的保护，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。结论 ChABC 治疗对黑质纹状体束的部分 6-OHDA 损伤提供了显着的保护，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。