缺氧诱导因子-1靶基因参与生酮饮食提高大脑中动脉闭塞模型小鼠脑缺血耐受作用

Ketogenic diet may improve ischemic tolerance of middle cerebral artery occlusion mice through up-regulation of hypoxia inducible factor-1 target genes

目的探究生酮饮食对大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)模型小鼠的作用及缺氧诱导因子-1靶基因参与机制。方法小鼠随机分为正常对照组及标准饮食组、高碳水化合物饮食组、生酮饮食组,建模前通过3周饮食干预后,饮食干预的3组小鼠建造MCAO模型,正常对照组给予标准饮食但不进行MCAO造模。2,3,5-三苯基氯化四氮唑染色观察脑梗死体积,Longa评分法对模型鼠进行神经功能评分,聚合酶链反应检测缺血区脑组织缺氧诱导因子-1下游靶基因红细胞生成素、血管内皮生长因子、葡萄糖转运体1、单羧酸转运体4的mRNA表达量。结果生酮饮食组小鼠脑组织梗死体积更小,神经功能评分更低,缺血区脑组织中红细胞生成素、血管内皮生长因子、葡萄糖转运体1、单羧酸转运体4的mRNA表达显著增加。结论生酮饮食可能是通过增加缺血区缺氧诱导因子-1靶基因表达,从而提高MCAO小鼠脑组织对缺血的耐受性。

Objective To explore the effects of ketogenic diet on middle cerebral artery occlusion( MCAO) mice and the role of hypoxia inducible factor-1( HIF-1) target genes in this process. Methods C57 BL / 6 mice were randomly allocated into four groups: standard diet group,high carbohydrate diet group,ketogenic diet group and control group. Mice of the 3 intervention groups were fed with corresponding diets for 3 weeks and were afterwards made into MCAO mice models. Control group was fed with standard diet for 3 weeks without MCAO treatment. Stroke volume was measured by 2,3,5-triphenyl tetrazolium chloride( TTC) staining. Neurological function was accessed by Longa scoring method. Polymerase chain reaction( PCR) was used to detect mRNA expression quantity of HIF-1 downstream target genes including erythropoietin( EPO),vascular endothelial growth factor( VEGF),glucose transport 1( GLUT1) and monocarboxylic transporter 4( MCT4) in the ischemic region. Results Compared with the other 3 groups,ketogenic diet group showed smaller stroke volume,better neurological score and higher mRNA expression quantity of HIT-1 downstream target genes. Conclusion Ketogenic diet may improve brain ischemic tolerance of MCAO mice through up-regulation of HIF-1 target genes.