Endothelial peroxynitrite causes disturbance of neuronal oscillations by targeting caspase-1 in the arcuate nucleus.
Endothelial peroxynitrite causes disturbance of neuronal oscillations by targeting caspase-1 in the arcuate nucleus.
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内皮过氧亚硝酸盐通过靶向弓状核中的 caspase-1 引起神经元振荡紊乱
DOI：
10.1016/j.redox.2021.102147
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发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
Han F
中科院分区：
文献类型：
--
作者：
Sun M;Mao XF;Li ZM;Zhu ZH;Gong DM;Lu L;Chen X;Zhang Y;Fukunaga K;Ji Y;Gu AH;Lu YM;Han F
严重的厌食症限制了顺铂的临床应用，甚至导致停药。然而，顺铂诱导厌食的机制尚不清楚。在此，我们证明，顺铂可以影响神经元γ振荡，并诱导异常的神经元θ-γ相位振幅耦合在弓状核（Arc）的下丘脑，这些发现与小鼠的摄食量和体重减轻显着减少。Arc中AgRP神经元的化学发生激活逆转了顺铂诱导的小鼠摄食量减少。我们进一步证明，内皮过氧亚硝酸盐（ONOO−）的形成在弧诱导亚硝化应激顺铂治疗后，通过以前未知的途径，涉及神经元caspase-1激活。引人注目的是，用ONOO−清除剂尿酸（UA）处理逆转了AgRP神经元降低的动作电位（AP）频率，并增加了由SIN 1（ONOO−的供体）诱导的POMC神经元的AP频率。与这些发现一致，UA治疗有效地减轻了顺铂诱导的小鼠Arc中神经元振荡和神经元θ-γ相位振幅耦合的功能障碍。总之，这些结果首次表明，靶向内皮ONOO-的过度产生可以通过神经元caspase-1调节顺铂诱导的神经毒性，从而作为一种潜在的治疗方法来缓解化疗诱导的厌食症和体重减轻。血管内皮细胞ONOO通过caspase-1介导了顺铂诱导的Arc神经元异常振荡。ONOO-清除剂UA可减轻顺铂对Arc的神经毒性和caspase-1的激活。靶向内皮ONOO-提供了一种有希望的方法来减轻化疗诱导的厌食症和体重减轻。
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. Endothelial ONOO– induced the abnormal neuronal oscillations following cisplatin treatment through caspase-1 in the Arc. ONOO– scavenger UA could attenuate cisplatin-induced neurotoxicity and caspase-1 activation in the Arc. Targeting endothelial ONOO– provided a promising approach to alleviate chemotherapy-induced anorexia and weight loss.
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影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
Harrison, DG
影响因子：
15.9
作者：
Krashes, Michael J.;Koda, Shuichi;Lowell, Bradford B.
通讯作者：
Lowell, Bradford B.
DOI：
10.1523/jneurosci.4122-11.2012
发表时间：
2012-01-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Belluscio MA;Mizuseki K;Schmidt R;Kempter R;Buzsáki G
通讯作者：
Buzsáki G
影响因子：
16.2
作者：
Cowley, MA;Pronchuk, N;Cone, RD
通讯作者：
Cone, RD
内皮细胞中过氧亚硝酸盐通量的可视化揭示了脑血管损伤的动态进展
影响因子：
15
作者：
Li, Xin;Tao, Rong-Rong;Hu, You-Hong
通讯作者：
Hu, You-Hong