Atorvastatin Reduces Neuroinflammation In Focal Cerebral Infarction Mice And Its Related Mechanisms

Stroke is a major chronic non-communicable disease that seriously endangers the health of Chinese residents,but the current treatment is still limited.Inflammation damage after stroke is the main cause for the aggravation of the disease.The diversity and dynamics of the gut microbiota play an important role in the outcome of stroke.The gut microbiota dysbiosis after stroke aggravates the inflammatory response in brain.Therefore,it is of great significance to explore the mechanism of gut microbiota in inflammatory damage after stroke.The previous studies have shown that atorvastatin exerts anti-inflammatory properties in ischemic stroke,and recent studies have revealed that intestinal microbiota plays a vital role in the pathogenesis of stroke.However,it is not clear whether the anti-inflammatory effects of atorvastatin against ischemic stroke is related to gut function and microbiota.We report herein that atorvastatin significantly ameliorated the defects in sensorimotor behaviors and reduced microglia-mediated neuroinflammation by inhibiting proinflammatory polarization of microglia in the peri-infarct cortex of the mice with permanent middle cerebral artery occlusion(p MCAO).Moreover,atorvastatin reversed microbial composition(characterized by increased abundance of Firmicutes and Lactobacillus and decreased Bacteroidetes abundance),increased fecal butyrate level,promoted intestinal barrier function(elevated protein levels of claudin-1,occludin and mucoprotein 2),as well as regulated intestinal immune function(decreased MCP-1,TNF-? and increased IL-10).Atorvastatin also significantly reduced the level of circulating endotoxin(lipopolysaccharide-binding protein),which is a biomarker of leaky gut.Transplantation of fecal microbiota collected from atorvastatin treated mice potently attenuated neuroinflammation in p MCAO mice,and the anti-inflammatory effects of fecal microbiota transplantation were similar to those of oral atorvastatin administration.These results suggested that the atorvastatin-mediated restoration of gut microbiota,improvement of intestinal barrier function and regulation of intestinal immunity were involved in the anti-inflammatory function in stroke mice.