三醇抑制细胞内快速酸化和脑缺血性损伤：谷氨酸在神经元代谢重编程中的作用,ACS Chemical Neuroscience

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三醇抑制细胞内快速酸化和脑缺血性损伤：谷氨酸在神经元代谢重编程中的作用
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2022-06-30 , DOI: 10.1021/acschemneuro.2c00119
DongDong Xue ₁ , CaiLv Wei ₂ , YueHan Zhou ₁ , Kai Wang ₃ , YuWei Zhou ₁ , Chen Chen ₁ , Yuan Li ₁ , LongXiang Sheng ₁ , BingZheng Lu ₁ , Zhu Zhu ₁ , Wei Cai ₂ , XinPeng Ning ₂ , ShengLong Li ₂ , TianYu Qi ₂ , JiaKai Pi ₄ , SuiZhen Lin ₅ , GuangMei Yan ₁ , YiJun Huang ₁ , Wei Yin ₂

Affiliation

作为主要损伤事件之一，脑组织酸中毒在缺血性中风发作后的几分钟内迅速发生。据报道，谷氨酸是一种诱导神经元兴奋性毒性的兴奋性氨基酸，可通过调节质子相关的膜转运蛋白来触发神经元细胞内 pH 值 (pHi) 的降低。然而，谷氨酸通过调节代谢在神经元酸中毒中的可能作用仍不清楚。在这里，我们发现 200 μM 谷氨酸处理可在 15 分钟内快速促进糖酵解并抑制原代培养神经元的线粒体氧化磷酸化，从而导致显着的细胞溶质乳酸积累，从而导致细胞内快速酸化和神经元损伤。谷氨酸对神经元代谢的重编程依赖于单磷酸腺苷活化蛋白激酶 (AMPK) 信号传导，因为其选择性抑制剂化合物 C 对 AMPK 活化的抑制在体外显着逆转了这些有害事件。此外，我们之前报道的神经保护剂 5α-androst-3β,5α,6β-TRIOL (TRIOL) 还可以通过抑制 AMPK 信号传导显着逆转细胞内酸化并减轻神经元损伤。此外，在体内大脑中动脉闭塞的急性缺血性卒中模型中，TRIOL 显着减少了梗死体积并减轻了神经功能障碍。总之，我们揭示了谷氨酸在通过 AMPK 介导的神经元重编程由谷氨酸诱导的乳酸积累引起的快速细胞内酸化损伤中的新作用。而且，

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TRIOL Inhibits Rapid Intracellular Acidification and Cerebral Ischemic Injury: The Role of Glutamate in Neuronal Metabolic Reprogramming

As one of the key injury incidents, tissue acidosis in the brain occurs very quickly within several minutes upon the onset of ischemic stroke. Glutamate, an excitatory amino acid inducing neuronal excitotoxicity, has been reported to trigger the decrease in neuronal intracellular pH (pHi) via modulating proton-related membrane transporters. However, there remains a lack of clarity on the possible role of glutamate in neuronal acidosis via regulating metabolism. Here, we show that 200 μM glutamate treatment quickly promotes glycolysis and inhibits mitochondrial oxidative phosphorylation of primary cultured neurons within 15 min, leading to significant cytosolic lactate accumulation, which contributes to the rapid intracellular acidification and neuronal injury. The reprogramming of neuronal metabolism by glutamate is dependent on adenosine monophosphate-activated protein kinase (AMPK) signaling since the inhibition of AMPK activation by its selective inhibitor compound C significantly reverses these deleterious events in vitro. Moreover, 5α-androst-3β,5α,6β-TRIOL (TRIOL), a neuroprotectant we previously reported, can also remarkably reverse intracellular acidification and alleviate neuronal injury through the inhibition of AMPK signaling. Furthermore, TRIOL remarkably reduced the infarct volume and attenuated neurologic impairment in acute ischemic stroke models of middle cerebral artery occlusion in vivo. In summary, we reveal a novel role of glutamate in rapid intracellular acidification injury resulting from glutamate-induced lactate accumulation through AMPK-mediated neuronal reprogramming. Moreover, inhibition of the quick drop in neuronal pHi by TRIOL significantly reduces the cerebral damages, suggesting that it is a promising drug candidate for ischemic stroke.

更新日期：2022-06-30

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