Chen Dongdong, Jiang Yunzhao, Ge Feng, Liu Xiaoyong, Huang Qingqing, Gong Yan
Department of Neurosurgery, The Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214000, China.
Department of Neurosurgery, The Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214000, China.
Neuroscience. 2025 Jul 23;579:129-143. doi: 10.1016/j.neuroscience.2025.05.307. Epub 2025 May 30.
Synaptic dysfunction exists before symptoms occur in Parkinson's disease, and restoring synaptic function as a promising therapeutic approach. Brain-derived neurotrophic factor serves as a key neuroregulatory factor in regulating synaptic function. Studies have shown that the protein levels of brain-derived neurotrophic factor is low in Parkinson's disease mice. However, repetitive transcranial magnetic stimulation (rTMS) can mitigate this decline. We explored the protective role of rTMS on brain-derived neurotrophic factor and synaptic function in a mouse Parkinson's disease model. The bioinformatics analysis further confirmed the regulation of synaptic function. Behavioral tests, Western blot tests, and immunofluorescence were performed. In 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine mouse model, low, medium, and high frequency magnetic stimulation were used at the same time, and we found that only the high frequency group improved dopaminergic neuron loss and the expression of brain-derived neurotrophic factor. Meanwhile, high frequency rTMS treatment alleviated motor dysfunction by alleviating the loss of dopaminergic neurons within the substantia nigra. In addition, high frequency treatment induced the phosphorylation of Ca2+/calmodulin-dependent protein kinase II and cAMP response element-binding protein, but the total protein level did not change significantly. After further use of KN93 antagonism, it was observed that P- Ca2+/calmodulin-dependent protein kinase II, P-cAMP response element-binding protein, brain-derived neurotrophic factor, and synapse-related protein expression were decreased, and rTMS protection was no longer effective. Therefore, rTMS therapy may upregulate brain-derived neurotrophic factor through the Ca2+/calmodulin-dependent protein kinase II-cAMP response element-binding protein pathway, improve synaptic function, and protect dopaminergic neurons, thereby enhancing motor function.
在帕金森病症状出现之前就存在突触功能障碍，恢复突触功能是一种有前景的治疗方法。脑源性神经营养因子是调节突触功能的关键神经调节因子。研究表明，帕金森病小鼠中脑源性神经营养因子的蛋白水平较低。然而，重复经颅磁刺激（rTMS）可以减轻这种下降。我们在小鼠帕金森病模型中探讨了rTMS对脑源性神经营养因子和突触功能的保护作用。生物信息学分析进一步证实了对突触功能的调节。进行了行为测试、蛋白质免疫印迹测试和免疫荧光检测。在1-甲基-4-苯基-1,2,3,6-四氢吡啶小鼠模型中，同时使用低、中、高频磁刺激，我们发现只有高频组改善了多巴胺能神经元丢失和脑源性神经营养因子的表达。同时，高频rTMS治疗通过减轻黑质内多巴胺能神经元的丢失来缓解运动功能障碍。此外，高频治疗诱导了Ca2+/钙调蛋白依赖性蛋白激酶II和环磷酸腺苷反应元件结合蛋白的磷酸化，但总蛋白水平没有显著变化。进一步使用KN93拮抗后，观察到磷酸化的Ca2+/钙调蛋白依赖性蛋白激酶II、磷酸化的环磷酸腺苷反应元件结合蛋白、脑源性神经营养因子和突触相关蛋白表达下降，rTMS的保护作用不再有效。因此，rTMS治疗可能通过Ca2+/钙调蛋白依赖性蛋白激酶II-环磷酸腺苷反应元件结合蛋白途径上调脑源性神经营养因子，改善突触功能，保护多巴胺能神经元，从而增强运动功能。
