Ketogenic Diet Improves Brain Ischemic Tolerance and Inhibits NLRP3 Inflammasome Activation by Preventing Drp1-Mediated Mitochondrial Fission and Endoplasmic Reticulum Stress.
Ketogenic Diet Improves Brain Ischemic Tolerance and Inhibits NLRP3 Inflammasome Activation by Preventing Drp1-Mediated Mitochondrial Fission and Endoplasmic Reticulum Stress.
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生酮饮食通过防止 Drp1 介导的线粒体裂变和内质网应激来改善脑缺血耐受性并抑制 NLRP3 炎症小体激活
DOI：
10.3389/fnmol.2018.00086
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发表时间：
2018
影响因子：
4.8
通讯作者：
Cui M
中科院分区：
文献类型：
--
作者：
Guo M;Wang X;Zhao Y;Yang Q;Ding H;Dong Q;Chen X;Cui M
背景：生酮饮食(KD)在卒中模型中的神经保护作用已有报道，核苷酸结合域(NOD)样受体蛋白3(NLRP3)炎症体也参与了卒中的发病机制。本研究旨在研究KD对NLRP3炎症小体的影响，并探讨其可能的分子机制。方法：在体内实验中，给小鼠灌胃KD 3周后，造成小鼠大脑中动脉闭塞/再灌注损伤。在体外实验中，SH-SY-5Y细胞用β-羟基丁酸酯(BHB)处理，然后进行氧-葡萄糖剥夺/复氧(OGD/R)。评价NLRP3炎性小体激活及相关调控机制。结果：KD可提高小鼠对MCAO/R的耐受性，抑制内质网应激，抑制脑内TXNIP/NLRP3炎性小体的激活。体外研究表明，BHB(10 MM)可阻止动力蛋白相关蛋白1(Drp1)的线粒体易位，从而抑制线粒体分裂。此外，BHB还可减少OGD/R处理细胞中ROS的产生，抑制ROS-NLRP3途径，并抑制ER应激诱导的NLRP3炎性小体的激活。结论：KD可能通过抑制线粒体转位，抑制NLRP3炎性小体激活，从而抑制内质网应激，保护线粒体完整性，从而发挥神经保护作用。我们的发现为KD在预防缺血性卒中中的潜在应用提供了证据。
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.
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影响因子：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
影响因子：
--
作者：
Otera H;Mihara K
通讯作者：
Mihara K
影响因子：
48
作者：
Fisher, Marc;Saver, Jeffrey L.
通讯作者：
Saver, Jeffrey L.
影响因子：
4.1
作者：
Kawabori M;Yenari MA
通讯作者：
Yenari MA