Abstract
Background: Neuroprotective effects of ketogenic diets (KD) have been reported in stroke models, and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome has also been implicated in the pathogenesis of stroke. This study aimed to investigate the effects of KD on NLRP3 inflammasome and explore the potential molecular mechanisms.Methods: In in vivo study, mice were fed with KD for 3 weeks and then subjected to middle cerebral artery occlusion/reperfusion (MCAO/R)-injury. In in vitro study, SH-SY-5Y cells were treated with β-hydroxybutyrate (BHB) followed by oxygen–glucose deprivation/reoxygenation (OGD/R). NLRP3 inflammasome activation and related regulatory mechanisms were evaluated.Results: Mice fed with KD had increased tolerance to MCAO/R. KD inhibited endoplasmic reticulum (ER) stress and suppressed TXNIP/NLRP3 inflammasome activation in the brain. The in vitro study showed BHB (10 mM) prevented the mitochondrial translocation of dynamin-related protein 1 (Drp1) to inhibit mitochondrial fission. Furthermore, BHB decreased reactive oxygen species (ROS) generation, inhibited ROS-NLRP3 pathway in OGD/R-treated cells, and suppressed ER stress-induced NLRP3 inflammasome activation.Conclusions: KD may suppress ER stress and protect mitochondrial integrity by suppressing the mitochondrial translocation of Drp1 to inhibit NLRP3 inflammasome activation, thus exerting neuroprotective effects. Our findings provide evidence for the potential application of KD in the prevention of ischemic stroke.
Highlights
Ischemic stroke, a leading cause of destructive cerebrovascular diseases, is characterized by disrupted blood flow and glucose/oxygen deprivation of brain cells, which may result in cellular dysfunction (Fisher and Saver, 2015)
Inflammation plays an important role in the pathogenesis of ischemic stroke, and the role of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in stroke has been a focus in current studies (Kawabori and Yenari, 2015)
Our results revealed that ketogenic diets (KD) and BHB were able to improve cerebral ischemia by inhibiting nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation, which was ascribed to the suppression of dynamin-related protein1 (Drp1)-mediated mitochondrial fission and the inhibition of endoplasmic reticulum (ER) stress
Summary
A leading cause of destructive cerebrovascular diseases, is characterized by disrupted blood flow and glucose/oxygen deprivation of brain cells, which may result in cellular dysfunction (Fisher and Saver, 2015). Inflammation plays an important role in the pathogenesis of ischemic stroke, and the role of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in stroke has been a focus in current studies (Kawabori and Yenari, 2015). The NLRP3 inflammasome is a molecular platform in which pro-inflammatory cytokines (such as caspase-1 and interleukin-1β [IL-1β]) are activated to induce inflammation (Ogura et al, 2006). NLRP3 and its adaptor apoptosis-associated Speck-like protein (ASC) translocate to the perinuclear space, where they co-localize with ER and mitochondrial organelle clusters (Jo et al, 2016). The mechanism by which Drp regulates NLRP3-mediated inflammation in ischemic stroke remains unclear. Neuroprotective effects of ketogenic diets (KD) have been reported in stroke models, and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome has been implicated in the pathogenesis of stroke. This study aimed to investigate the effects of KD on NLRP3 inflammasome and explore the potential molecular mechanisms
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