Sulforaphane alleviates ethanol-mediated central inhibition and reverses chronic stress-induced aggravation of acute alcoholism via targeting Nrf2-regulated catalase expression
Sulforaphane alleviates ethanol-mediated central inhibition and reverses chronic stress-induced aggravation of acute alcoholism via targeting Nrf2-regulated catalase expression
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萝卜硫素通过靶向 Nrf2 调节的过氧化氢酶表达，减轻乙醇介导的中枢抑制并逆转慢性应激诱导的急性酒精中毒加重。
DOI：
10.1016/j.neuropharm.2020.108235
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发表时间：
2020
影响因子：
4.7
通讯作者：
Wu Peng-Fei
中科院分区：
文献类型：
--
作者：
Xu Jun-Feng;Lu Jia-Jing;Cao Yu;Wang Wen;Li Hou-Hong;Chen Jian-Guo;Wang Fang;Wu Peng-Fei
过量饮酒引起的急性酒精中毒是酒精性死亡的重要原因。压力暴露已被确定为酗酒的风险因素之一。以前的报道表明，应激源可能会增强酒精的抑制作用，但其潜在机制仍不清楚。在这里，我们报告了慢性不可预测的应激通过损害核因子(红系衍生的2)-样2(NRF2)-过氧化氢酶信号通路增加了小鼠对急性乙醇中毒的敏感性。NRF2活性调节过氧化氢酶的表达，过氧化氢酶是大脑中介导乙醇氧化的关键抗氧化酶。药物阻断过氧化氢酶或NRF2活性可显著加重急性乙醇中毒。萝卜硫素是一种十字花科蔬菜衍生的NRF2激活剂，可显著减轻急性乙醇中毒。此外，萝卜硫素能迅速逆转应激所致的急性酒精中毒加重。我们的发现表明，Nrf2可能通过控制过氧化氢酶介导的乙醇氧化，作为预防急性酒精中毒的新药物靶点，特别是在精神疾病患者中。
Acute ethanol intoxication by excessive drinking is an important cause of alcohol-induced death. Stress exposure has been identified as one risk factor for alcohol abuse. Previous reports indicated that stressors may augment inhibitory effects of alcohol, but the underlying mechanism remains unknown. Here, we reported that chronic unpredictable stress increased the sensitivity to the acute ethanol intoxication in mice via impairing nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-catalase signaling. Nrf2 activity regulates the expression of catalase, a key antioxidant enzyme that mediates ethanol oxidation in the brain. Pharmacological blockade of catalase or Nrf2 activity significantly aggravated acute ethanol intoxication. Sulforaphane, a cruciferous vegetable-derived activator of Nrf2, significantly attenuated acute ethanol intoxication. Furthermore, the stress-induced aggravation of acute alcoholism was rapidly reversed by sulforaphane. Our findings suggest that Nrf2 may function as a novel drug target for the prevention of acute alcoholism, especially in psychiatric patients, by controlling catalase-mediated ethanol oxidation.