School of Pharmacy, Yantai University, Yantai 264005, PR China.
School of Pharmacy, Yantai University, Yantai 264005, PR China.
Life Sci. 2015 Mar 1;124:136-43. doi: 10.1016/j.lfs.2015.01.014. Epub 2015 Jan 30.
The aim of the study is to evaluate the neuroprotective effects of continuous dopaminergic stimulation (CDS) by rotigotine-loaded microspheres (RoMS) in a mouse model of MPTP-induced Parkinson's disease (PD) and to elucidate the potential mechanism underlying these effects.
Male C57BL/6 mice were treated either intramuscularly once with RoMS or twice daily for two weeks with rotigotine, and from the 9th day, MPTP (30 mg/kg, i.p.) was injected for the last 5 days. Following treatment, Parkinsonism scores were calculated and oxidative stress-related indicators in the striatum were performed. Neuroinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were detected in the striatum. Expression of apoptosis-related proteins B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX) was measured in the striatum by Western blot. Nigral tyrosine hydroxylase (TH)-positive neurons and microglial cell markers, i.e., ionized calcium binding adaptor molecule-1 (Iba-1) and neuronal synaptosomes, were quantified to assess the neuroprotective efficacy of RoMS.
The administration of rotigotine significantly improved the Parkinsonism score, protected dopaminergic neurons with antioxidants, reduced microglial cell activation and the release of neuroinflammatory cytokines, and balanced the expression of Bcl-2 and Bax in MPTP-treated mice. Interestingly, the neuroprotective properties of rotigotine were remarkably amplified by CDS treatment with RoMS.
These results suggest that CDS therapy can play a neuroprotective role in an MPTP mouse model. Neuroprotective disease-modifying therapy may have the potential benefits of early treatment by normalizing compensatory mechanisms and may also help to delay dyskinesia in the later stages of PD.
本研究旨在评估罗替高汀微球（RoMS）持续多巴胺能刺激（CDS）在 MPTP 诱导的帕金森病（PD）小鼠模型中的神经保护作用，并阐明其潜在机制。
雄性 C57BL/6 小鼠肌肉注射 RoMS 一次或每天两次共两周，从第 9 天开始，腹腔注射 MPTP（30mg/kg），共 5 天。治疗后，计算帕金森病评分，并检测纹状体中与氧化应激相关的指标。检测纹状体中的神经炎症细胞因子，如肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）。通过 Western blot 检测纹状体中凋亡相关蛋白 B 细胞淋巴瘤/白血病 2（Bcl-2）和 Bcl-2 相关 X 蛋白（BAX）的表达。用尼氏染色法检测黑质酪氨酸羟化酶（TH）阳性神经元和小胶质细胞标志物，即离子钙结合衔接分子 1（Iba-1）和神经元突触体，以评估 RoMS 的神经保护效果。
罗替高汀的给药显著改善了帕金森病评分，用抗氧化剂保护多巴胺能神经元，减少小胶质细胞激活和神经炎症细胞因子的释放，并平衡 MPTP 处理小鼠中 Bcl-2 和 Bax 的表达。有趣的是，RoMS 的 CDS 治疗显著放大了罗替高汀的神经保护作用。
这些结果表明，CDS 治疗在 MPTP 小鼠模型中具有神经保护作用。神经保护疾病修饰治疗可能具有通过正常化代偿机制进行早期治疗的潜在益处，并且还有助于延缓 PD 后期的运动障碍。
