Abstract
Background and Aims: Aberrant alterations of the circulating amino acid profile have been observed in patients with acute ischemic stroke. However, whether cerebral ischemia disrupts amino acid metabolism in brain tissues and subsequently potentiates cellular stress and cerebral injury has never been explored. Impaired catabolism and significant enrichment of branched-chain amino acids (BCAAs) were identified in Neuron 2α cells upon oxygen-glucose deprivation. This study is trying to clarify the role of cerebral BCAAs catabolism in ischemic stroke and clarify whether manipulation of cerebral BCAAs catabolism by pharmaco-logical and genetic methods could mitigate cerebral ischemia injury.
Methods: A Metabolomics approach combined with metabolic flux anal-ysis was adopted to analyze the BCAAs catabolism in the N2α cells. BCAAs catabolism was restored by suppressing BCKDK via pharmaco-logical inhibitor or silencing RNA approach. Additionally, the correlation between plasma BCAAs levels and the infarct volume of patients was evaluated accordingly.
Results: Impaired catabolism and significant enrichment of branched-chain amino acids (BCAAs) were identified in Neuron 2α cells upon oxygen-glucose deprivation and in the brain of mice with acute ischemic stroke. Furthermore, restoration of BCAAs catabolism by suppressing BCKDK via pharmacological inhibitor or silencing RNA approach dramatically alleviates ischemia-reperfusion injury in mice. Mechanistically, ischemia induces the expression of BCKDK via HIF-1α-mediated tran-scriptional activation leading to impaired adenosine triphosphate production and enhanced glutamate excitotoxicity. Meanwhile, a close correlation of elevated levels of circulating BCAAs with infarct volume was observed in patients with ischemic stroke.
Conclusions: Collectively, this study identified BCKDK as a novel hypoxia-responsive factor and a promising therapeutic target for cerebral ischemia injury.
Methods: A Metabolomics approach combined with metabolic flux anal-ysis was adopted to analyze the BCAAs catabolism in the N2α cells. BCAAs catabolism was restored by suppressing BCKDK via pharmaco-logical inhibitor or silencing RNA approach. Additionally, the correlation between plasma BCAAs levels and the infarct volume of patients was evaluated accordingly.
Results: Impaired catabolism and significant enrichment of branched-chain amino acids (BCAAs) were identified in Neuron 2α cells upon oxygen-glucose deprivation and in the brain of mice with acute ischemic stroke. Furthermore, restoration of BCAAs catabolism by suppressing BCKDK via pharmacological inhibitor or silencing RNA approach dramatically alleviates ischemia-reperfusion injury in mice. Mechanistically, ischemia induces the expression of BCKDK via HIF-1α-mediated tran-scriptional activation leading to impaired adenosine triphosphate production and enhanced glutamate excitotoxicity. Meanwhile, a close correlation of elevated levels of circulating BCAAs with infarct volume was observed in patients with ischemic stroke.
Conclusions: Collectively, this study identified BCKDK as a novel hypoxia-responsive factor and a promising therapeutic target for cerebral ischemia injury.
| Original language | English |
|---|---|
| Pages (from-to) | 345-346 |
| Number of pages | 2 |
| Journal | International Journal of Stroke |
| Volume | 18 |
| Issue number | 3, suppl. |
| DOIs | |
| Publication status | Published - 10 Oct 2023 |
| Event | 15th World Stroke Congress, WSC 2023 - Metro Toronto Convention Centre, Toronto, Canada Duration: 10 Oct 2023 → 12 Oct 2023 https://worldstrokecongress.org/ https://journals.sagepub.com/doi/full/10.1177/17474930231192010 |
