Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Republic of Korea; Graduate Training Program of Korean Medical Therapeutics for Healthy Aging, Pusan National University, Yangsan, 50612, Republic of Korea.
School of Healthcare and Biomedical Engineering, Chonnam National University, Yeosu, 59626, Republic of Korea.
Brain Stimul. 2022 May-Jun;15(3):645-653. doi: 10.1016/j.brs.2022.04.002. Epub 2022 Apr 13.
Therapeutic effects of transcranial alternating current stimulation (tACS) for treating Parkinson's disease (PD) are limited to modulating abnormally synchronized oscillations; however, long-lasting tACS effects may involve non-neuronal mechanisms like the regulation of neurotrophic factors.
OBJECTIVES/HYPOTHESIS: We investigated whether tACS exerts neuroprotective effects on dopaminergic neurons in a mouse model of PD by regulating endogenous glial cell line-derived neurotrophic factor (GDNF).
Repeated high-definition tACS (HD-tACS, 20 min, 89.1 μA/mm) was administered over the primary motor cortex of C57BL/6J 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Behavioral tests assessing motor function, immunohistochemistry, western blots, enzyme-linked immunosorbent assays, and flow cytometric analyses were performed to examine suitable tACS conditions and its underlying mechanisms.
Stimulation at representative frequencies (theta to gamma; 20-Hz beta frequency, in particular) attenuated motor dysfunction and protected the dopaminergic neurons with increased GDNF production. Beta-frequency (20 Hz) tACS application significantly attenuated motor deficits to levels comparable with those of levodopa treatment. Moreover, beta-frequency tACS induced the survival of dopaminergic neurons in the substantia nigra with upregulated production of endogenous GDNF in striatal parvalbumin-positive interneurons. An inhibitor of the GDNF receptor-associated rearranged during transfection (RET) kinase suppressed most aspects of the tACS-induced behavioral recovery, dopaminergic cell survival, and GDNF production. Beta-frequency tACS activated RET-related survival signaling for dopaminergic neurons in the substantia nigra.
Application of tACS over the primary motor cortex may exert protective effects on dopaminergic neurons in the substantia nigra via activation of endogenous GDNF production by striatal parvalbumin-positive interneurons and its survival signaling.
经颅交流电刺激（tACS）治疗帕金森病（PD）的疗效仅限于调节异常同步振荡；然而，tACS 的持久效应可能涉及非神经元机制，如神经营养因子的调节。
目的/假设：我们通过调节内源性胶质细胞系衍生的神经营养因子（GDNF），研究 tACS 是否对 PD 小鼠模型中的多巴胺能神经元产生神经保护作用。
对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠的初级运动皮层进行重复高清晰度 tACS（HD-tACS，20 分钟，89.1μA/mm）。进行行为测试以评估运动功能、免疫组织化学、Western 印迹、酶联免疫吸附测定和流式细胞术分析，以检查合适的 tACS 条件及其潜在机制。
在代表性频率（θ到γ；特别是 20-Hz β频率）下刺激可减轻运动功能障碍并增加 GDNF 产生来保护多巴胺能神经元。β频率（20 Hz）tACS 应用可显著减轻运动缺陷，使其达到与左旋多巴治疗相当的水平。此外，β频率 tACS 诱导黑质中多巴胺能神经元的存活，并上调纹状体中 Parvalbumin 阳性中间神经元中内源性 GDNF 的产生。GDNF 受体相关转染后重排（RET）激酶抑制剂抑制了 tACS 诱导的行为恢复、多巴胺能细胞存活和 GDNF 产生的大部分方面。β频率 tACS 激活了黑质中多巴胺能神经元的 RET 相关存活信号。
初级运动皮层的 tACS 应用可能通过激活纹状体 Parvalbumin 阳性中间神经元的内源性 GDNF 产生及其存活信号，对黑质中的多巴胺能神经元发挥保护作用。
