Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling

Lin, Yu Hui; Yang, Di; Ni, Huan‐Yu; Xu, Xiang; Wu, Feng; Liu, Lin; Chen, Jie; Sun, Yanyu; Huang, Zhen-Quan; Li, Shiyi; Jiang, Peilin; Wu, Hai‐Yin; Chang, Lei; Hu, Bo; Luo, Chunxia; Wu, Jin; Zhu, Dong‐Ya

doi:10.1016/j.celrep.2023.112294

Cited by 8 publications

(3 citation statements)

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“…The potential mechanisms involve nerve, humoral, and immune aspects, such as regulating autophagy, inhibiting neuronal apoptosis, inhibiting the inflammatory response and regulating the immune response, reducing mitochondrial oxidative stress and inflammation, etc. Lately, 3-OHB promoting stroke recovery has been confirmed, as 3-OHB increased neural excitability and phasic GABA inhibition . Impaired energy metabolism and less ATP production are critical pathological hallmarks of IS, caused by reduced oxygen and glucose supply.…”

Section: Discussionmentioning

confidence: 96%

“…Lately, 3-OHB promoting stroke recovery has been confirmed, as 3-OHB increased neural excitability and phasic GABA inhibition. 29 Impaired energy metabolism and less ATP production are critical pathological hallmarks of IS, 30 caused by reduced oxygen and glucose supply. Increasing studies show that the strategy targeting energy metabolism improves stroke outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition

Huang,

Zhang,

Liu

et al. 2024

ACS Chem. Neurosci.

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Neuronal death resulting from ischemic stroke is the primary cause of adult mortality and disability, and effective neuroprotective agents for poststroke intervention are still lacking. Remote ischemic postconditioning (RIPostC) has demonstrated significant protective effects against ischemia in various organs; however, the specific mechanisms are not fully understood. This study investigated the potential neuroprotective mechanisms of RIPostC in the context of ischemic stroke. Using a rat model of middle cerebral artery occlusion, we found that RIPostC mitigated neurological damage, improved movement in the open-field test, and protected against neuronal apoptosis. In terms of energy metabolism, RIPostC enhanced ATP levels, suppressed lactate content, and increased the production of ketone bodies (KBs). In the ferroptosis assay, RIPostC protected against lipoperoxidation, reversed the reduction of glutathione peroxidase 4 (GPX4), and mitigated the excessive expression of long-chain acyl-CoA synthetase family member 4 (ACSL4). In oxygen-glucose deprivation/reoxygenationtreated HT22 cells, KBs maintained GPX4 levels, suppressed ACSL4 expression, and preserved the mitochondrial cristae number. However, the effect of KBs on the expression of GPX4, ACSL4, and the number of mitochondrial cristae was blocked by erastin. Moreover, both RIPostC and KBs reduced total iron and ferrous ion content by repressing iron transporters both in vitro and in vivo. In conclusion, KBs-induced mitigation of ferroptosis could represent a new therapeutic mechanism for RIPostC in treating stroke.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition

Huang,

Zhang,

Liu

et al. 2024

ACS Chem. Neurosci.

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“…KBs promote hyperacetylation of histones and non-histone proteins by increasing acetyl-CoA, a substrate for p300 histone acetyltransferase (HAT) [ 10 , 147 ]. Recent studies have shown that BHB promotes stroke recovery in rodents by reversing stroke-induced GABA transporter-1 (GAT-1) downregulation and dysfunction through HDAC2/3 inhibition, enhancing neural circuit excitability and functional plasticity [ 148 ]. Consistently, BHB has been shown to mediate exercise-stimulated expression of brain-derived neurotrophic factor (BDNF) through HDAC2/3 inhibition and H3 acetylation in the hippocampus [ 149 ].…”

Section: Molecular Mechanisms Of the Neuroprotective Effects Of Kbs A...mentioning

confidence: 99%

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

Jang,

Kim,

Lee

et al. 2023

IJMS

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Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

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Astrocyte Regulation of Neuronal Function and Survival in Stroke Pathophysiology

Boyle,

Berghella,

Blanco-Suarez

2024

Advances in Neurobiology

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Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling

Cited by 8 publications

References 50 publications

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition

Remote Ischemic Postconditioning-Mediated Neuroprotection against Stroke by Promoting Ketone Body-Induced Ferroptosis Inhibition

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

Astrocyte Regulation of Neuronal Function and Survival in Stroke Pathophysiology

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