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

ACS CHEMICAL NEUROSCIENCE(2022)

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摘要
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 protonrelated 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 mu M 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, 5 alpha-androst-3 beta,5 alpha,6 beta-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 glutamateinduced 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.
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关键词
glycolysis,intracellular acidification,lactate,5?-androst-3?,5?,6?-TRIOL,ischemic stroke,glutamate
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