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.

严重的厌食症限制了顺铂的临床应用，甚至导致治疗的中断。然而，顺铂引起厌食症的机制尚不清楚。在此，我们证明顺铂可以影响神经元伽马振荡并诱导下丘脑弓状核 (Arc) 神经元θ-伽马相位-振幅耦合异常，这些发现与小鼠食物摄入量显着减少和体重减轻有关。Arc中AgRP神经元的化学遗传激活逆转了顺铂诱导的小鼠食物摄入减少。我们进一步证明了内皮过氧亚硝酸盐（ONOO ^-) 在顺铂治疗后，Arc 中的形成诱导亚硝化应激，这是通过以前未表征的途径，涉及神经元 caspase-1 激活。引人注目的是，用 ONOO ^-清道夫尿酸 (UA) 治疗逆转了 AgRP 神经元降低的动作电位 (AP) 频率并增加了由 ONOO ^-供体 SIN1 诱导的 POMC 神经元的 AP 频率，如由以下确定的全细胞膜片钳电生理记录。与这些发现一致，UA 治疗有效缓解了顺铂诱导的小鼠 Arc 中神经元振荡和神经元 theta-γ 相位-幅度耦合的功能障碍。综上所述，这些结果首次表明，针对内皮 ONOO 的过度生产^- 可以通过神经元 caspase-1 调节顺铂诱导的神经毒性，从而作为减轻化疗诱导的厌食和体重减轻的潜在治疗方法。