Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Cell Rep. 2023 Apr 25;42(4):112294. doi: 10.1016/j.celrep.2023.112294. Epub 2023 Mar 21.
Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that β-hydroxybutyrate (β-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of β-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilateral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical approaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.
中风是全球导致成年人残疾的主要原因，需要更好的药物来促进中风后的功能恢复。越来越多的证据表明，网络兴奋性在中风修复阶段对于中风恢复起着关键作用。在这里，我们表明β-羟基丁酸（β-HB），一种必需的酮体（KB）成分，与中风患者的改善结果呈正相关，并在中风修复阶段促进中风啮齿动物的功能恢复。β-HB 的这些有益作用取决于 HDAC2/HDAC3-GABA 转运蛋白 1（GAT-1）信号介导的兴奋增强和梗死周围皮层中的相发性 GABA 抑制，以及同侧皮层、对侧皮层和皮质脊髓束的结构和功能可塑性。与现有的提高 KB 水平的临床方法相结合，我们的结果提供了一种可临床转化的方法来促进中风恢复。此外，GAT-1 可以作为开发药物促进中风后功能恢复的药理学靶点。
