帕金森病(PD)的动物模型对于了解PD的发病机制和筛选新的治疗方法非常有用。本研究比较了两种常用的神经毒素诱导的慢性PD小鼠模型,以指导模型选择,探索PD的发病机制和潜在机制,并开发有效的治疗方法。通过用鱼藤酮或1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)治疗6周建立慢性PD小鼠模型。通过评估神经行为来比较鱼藤酮和MPTP对小鼠的影响,通过使用极点的神经病理学和线粒体功能,旋转杆和开放式现场测试,酪氨酸羟化酶(TH)的免疫组织化学,胶质纤维酸性蛋白(GFAP),离子化钙结合接头分子1(Iba-1),神经元核抗原(NeuN)和(p)S129α-突触核蛋白,GFAP的免疫荧光,Iba‑1和NeuN,TH的西方印迹,耗氧量,复合物I酶活性。运动活动,与对照组相比,鱼藤酮和MPTP组的运动协调和探索行为均显着降低。然而,行为测试在两组间无显著差异.在MPTP组中,黑质(SN)中多巴胺能(DA)神经元的丢失,与鱼藤酮组相比,SN和纹状体中酪氨酸羟化酶含量的降低以及SN中星形胶质细胞的增殖和小胶质细胞的活化更为显着。值得注意的是,与MPTP组相比,鱼藤酮组的线粒体依赖性耗氧量和SN中的复合物I酶活性显着降低。此外,路易体仅存在于鱼藤酮组的SN神经元中。尽管在两种小鼠模型之间没有观察到神经行为的显着差异,MPTP模型在DA神经元丢失方面更精确地再现了PD的病理特征,多巴胺水平降低和SN中的神经炎症。另一方面,鱼藤酮模型更适合研究线粒体功能障碍(复合物I活性缺失)和路易体形成在SN中的作用,这是PD的特征性病理特征。结果表明,MPTP和鱼藤酮PD模型各有优缺点,因此,应根据研究目的选择一个或两个。
Animal models for Parkinson\'s disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. The present study compared two commonly used
neurotoxin‑induced mouse models of chronic PD to guide model selection, explore the pathogenesis and mechanisms underlying PD and develop effective treatments. The chronic PD mouse models were established via treatment with rotenone or 1‑methyl‑4‑phenyl‑1,2,3,6-tetrahydropyridine (MPTP) for 6 weeks. The effects of rotenone and MPTP in the mice were compared by assessing neurobehavior, neuropathology and mitochondrial function through the use of the pole, rotarod and open field tests, immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calcium‑binding adapter molecule 1 (Iba‑1), neuronal nuclear antigen (NeuN) and (p)S129 α‑synuclein, immunofluorescence for GFAP, Iba‑1 and NeuN, western blotting for TH, oxygen consumption, complex I enzyme activity. The locomotor activity, motor coordination and exploratory behavior in both rotenone and MPTP groups were significantly lower compared with the control group. However, behavioral tests were no significant differences between the two groups. In the MPTP group, the loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta, the reduction of the tyrosine hydroxylase content in the SN and striatum and the astrocyte proliferation and microglial activation in the SN were more significant compared with the rotenone group. Notably, mitochondrial‑dependent oxygen consumption and complex I enzyme activity in the SN were significantly reduced in the rotenone group compared with the MPTP group. In addition, Lewy bodies were present only in SN neurons in the rotenone group. Although no significant differences in neurobehavior were observed between the two mouse models, the MPTP model reproduced the pathological features of PD more precisely in terms of the loss of DA neurons, decreased dopamine levels and neuroinflammation in the SN. On the other hand, the rotenone model was more suitable for studying the role of mitochondrial dysfunction (deficient complex I activity) and Lewy body formation in the SN, which is a characteristic pathological feature of PD. The results indicated that MPTP and rotenone PD models have advantages and disadvantages, therefore one or both should be selected based on the purpose of the study.