Journal
FRONTIERS IN MOLECULAR NEUROSCIENCE
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2018.00086
Keywords
ketogenic diet; beta-hydroxybutyrate; mitochondrial fission; endoplasmic reticulum stress; NLRP3 inflammasome; Drp1
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Funding
- National Natural Science Foundation of China [81471173, 81571109, 81571033]
- Science and Technology Commission of Shanghai Municipality [16411970200]
- Key Basic Research Grant from the Science and Technology Commission of Shanghai Municipality [16JC1400500]
- International Science and Technology Cooperation Program of China [2014DFA32830]
- Key Research and Development Plants of Jiangsu Province [BE2016726]
- National Key Research and Development Program of China [2017YFC0907002, 2017YFC0907501]
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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 beta-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.
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