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Endothelial peroxynitrite causes disturbance of neuronal osci
AAV-hM3Dq was used for chemogenetic activation of AgRP neurons in the Arc. (From BrainVTA)
The viruses used in this article from BrainVTA are in the table below
Chemogenetics  PT-0019 AAV-hSyn-DIO-hM3Dq-mCherry
Control  PT-0115 AAV-hSyn-DIO-mCherry
Meiling Sun, Xing-Feng Mao, Zheng-Mao Li, Zhi-Hui Zhu, Dong-Mei Gong, Lu Lu, Xiang Chen, Yu Zhang, Kohji Fukunaga, Yong Ji, Ai-Hua Gu, Ying-Mei Lu, Feng Han
Pub Date: 2021-09-27, DOI: 10.1016/j.redox.2021.102147, Email: [email protected]
Severe anorexia limits the clinical application of cisplatin, and even leads to the discontinuation of treatment. However, the mechanisms underlying cisplatin-induced anorexia are unknown. Herein, we demonstrated that cisplatin could affect neuronal gamma oscillations and induce abnormal neuronal theta-gamma phase-amplitude coupling in the arcuate nucleus (Arc) of the hypothalamus, and these findings were associated with significantly decreased food intake and weight loss in mice. Chemogenetic activation of AgRP neurons in the Arc reversed the cisplatin-induced food intake reduction in mice. We further demonstrated that endothelial peroxynitrite (ONOO−) formation in the Arc induced nitrosative stress following cisplatin treatment via a previously uncharacterized pathway involving neuronal caspase-1 activation. Strikingly, treatment with the ONOO− scavenger uric acid (UA) reversed the reduced action potential (AP) frequency of AgRP neurons and increased the AP frequency of POMC neurons induced by SIN1, a donor of ONOO−, in the Arc, as determined by whole-cell patch-clamp electrophysiological recording. Consistent with these findings, UA treatment effectively alleviated cisplatin-induced dysfunction of neuronal oscillations and neuronal theta-gamma phase-amplitude coupling in the Arc of mice. Taken together, these results suggest, for the first time, that targeting the overproduction of endothelial ONOO− can regulate cisplatin-induced neurotoxicity through neuronal caspase-1, and thereby serve as a potential therapeutic approach to alleviate chemotherapy-induced anorexia and weight loss.
In this study, the authors provide direct evidence of abnormal neuronal gamma oscillations and neuronal theta-gamma phase-amplitude coupling in the Arc after cisplatin exposure. Notably, endothelial ONOO generation by cisplatin mediates neuronal caspase-1 activation, which induces abnormal neuronal action potential in the Arc. They further show that an ONOO scavenger (UA) can eliminate cisplatin-induced neurotoxicity and consequently alleviate the feeding behavior disorder associated with cisplatin-based chemotherapy.
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