Beneficial effects of atorvastatin on sex‐specific cognitive impairment induced by a cerebral microhaemorrhage in mice

Abstract

Background and purposes Cerebral microhaemorrhages (CMH) are associated with cognitive decline in humans. In rodents, CMHs induce cognitive impairment in male mice only along with sex‐specific cortical and hippocampal modifications affecting neural, glial and vascular functions. Statins, prescribed in the context of cardiovascular risk factors, have been proposed to prevent cognitive decline thanks to their pleiotropic properties. We tested here the action of atorvastatin on CMH‐induced cognitive impairment in a murine model of CMH. Experimental approach Using a multimodal approach combining behavioural tests, in vivo imaging, biochemistry and molecular biology, the effects of oral administration of atorvastatin (AT) on the sex‐specific modifications induced by a cortical CMH were studied in male and female mice (C57BL/6J) at 6 weeks post‐induction using a collagenase‐induced model. Key results AT drove specific effects according to the sex‐specific CMH‐induced modifications. In males: AT improved the visuospatial memory, induced a local modulation of microglial response and enhanced BDNF‐TrkB and VEGF expression in the cortex. In the hippocampus, AT increased glucose metabolism and modulated astrocytes morphology. In females: AT did not modulate visuospatial memory despite the increased expression of cortical BDNF and the decrease of the number of hippocampal astrocytes. AT also induced a decrease in the expression of cortical oestrogen receptors. AT did not modify body weight nor serum cholesterol levels in both sexes. Conclusion and implications AT modulated the sex‐specific cognitive impairment induced by the CMH with a pathophysiological impact mainly within the cortical area. It could represent a promising candidate for future sex‐stratified clinical trials in patients with CMH.