The mechanism of electroacupuncture-mediated improvement of Parkinson's disease by inhibiting ferroptosis through activating Nrf2/GPX4 signal pathway

Min Wang¹He-Sheng Zheng¹Weiliang Ye¹Jin-Dong Mao¹Kun Zhang¹Le Yang²Ming-gao Zhao²Shui-bing Liu¹Rui Liu^2*Yu-Mei Wu^1*

• ¹School of Pharmacy, Fourth Military Medical University, Xi’an, China
• ²Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi Province, China

Ferroptosis, a novel regulated iron-dependent cell death pathway, is consistent with several features of Parkinson's disease (PD) physiopathology, and efficient neuroprotective therapies are required for preventing DAergic neurons death initiated by ferroptosis. Electroacupuncture (EA), a treasure of Traditional Chinese Medicine, exerted therapeutic effects against PD to avoid the side effects of dopamine (DA)-based therapies. However, its underlying mechanisms are not yet fully understood. This study explored the role of EA in fighting the symptoms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model and the mechanisms involved in ferroptosis. We found that EA therapy attenuated the loss of DAergic neurons induced by ferroptosis, which was evaluated as increased malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), iron, and reduced levels of glutathione (GSH) and ferroptosis marker proteins including SLC7A11, glutathione peroxidase 4 (GPX4), the main iron storage protein ferritin heavy chain 1 (FTH1) and nuclear factor erythroid 2-related factor 2 (Nrf2), along with mitochondrial dysfunction upon MPTP insult. Furthermore, the inhibition of Nrf2 by alkaloid trigonelline (AT) administration abolished the neuroprotection of EA against ferroptosis induced by MPTP injury demonstrated above. Taken together, these results suggest that EA alleviated MPTPinduced DAergic neurons loss induced by ferroptosis via activating the Nrf2/SLC7A11/FTH1/GPX4 pathway. This study provided new ideas exploring the mechanism of EA in PD treatment.