Atorvastatin Administration After Stroke In Rats Enhances Neurogenesis And Improves Neurological Function

Objective: Experimental stroke induced by middle cerebral artery occlusion(MCAO)causes neurogenesis in the subventricular zone(SVZ),from where,the neuroblasts migrate along the blood vessel toward the ischemic penumbra and improve the neurological outcome.Although atorvastatin(Ator)has been widely used to treat and prevent ischemic stroke in the clinic and has been previously dementrated its neuro-protective function by Our laboratory,less is known about their role in regulating cerebral ischemia-induced neural progenitors proliferation,migration via the SDF-1/CXCR4 pathway during the process.Methods:1 All mice were randomly divided into 5 groups,including sham group,MCAo group,Atorvastatin group,AMD3100 group(a CXCR4 antagonist)AMD3100 + Atorvastatin group.Rats were treated with Atorvastatin(10mg/kg/d,i.g.)or the same volume of 0.9% saline or AMD3100(2.5mg/kg/d,i.p.)starting within 2 hours after MCAO daily for 14 consecutive days.The dosage of Atorvastatin and AMD3100 was chosen based on previous study and our pre-experiment.2 Young mice were subjected to the permanent MCAO by occluding the single lateral middle cerebral arteries(MCA)of C57BL/6 rats with electric heating coagulation following the ligation of ipsilateral common carotid artery(CCA).The infarct volume was determined with Hematoxylin and eosin(H&E)staining.The neurological functional recovery(functional motor outcome)was respectively evaluated at 1,3,7,14,21 and 28 days post-operation.To further explore the molecular machenism,the protein expression of SDF/CXCR4 axis,ERK1/2 and Akt were investigated by Western Blot,and also,the AMD3100(a chemokine(C-XC motif)receptor 4(CXCR4)antagonist)was used.Furthermore,nestin/Brd U,Dcx/Brd U,Neu N/Brd U,GFAP/Brd U was double immunostained to identify the prolifrating progenitors,migration neurobalsts and the new-born cells.Immunohistochemistry was applied to illustrate the migration patter as well.Confocal microscopy was used to determined the relation between the migrating neuroblasts and the vasculature.Twenty-four hours after ischaemia,mice prepared to tested in immunofluorescence received Brd U injection(50 mg/kg/day,i.p.)everyday for 14 days in a consecutive manner.Immuno-histochemistry measurement was performed14 days after stroke to analyze cell proliferation,neuroblast migration.Results:1 The three stages encompassed by neurogenesis: proliferation,migration and differentiation was improved by the administration of atrovastatin.Atrovastatin contribute to neurological recovery beginning from 14 days after cerebral infarction.2 AMD3100 largely blocked the beneficial effects of neuro-repair and the expression of SDF-1/CXCR4 downstream signaling pathway induced by atrovastatin(P<0.05).3 Functional recovery was beginning at 2,3 and 4 weeks after ischemic stroke.Atorvastatin-treated group stay on the rota-rod much longer than MCAO controls,while CXCR4 antagonist(AMD3100)significantly impede the recovery of motor function versus control group.Cotreatment of atorvastatin and AMD3100 significantly ameliorated the neuro-dysfunction compared with Atorvastatin group.There was no statistic significance in infarct size among groups.Conclusions : These results indicate that therapeutic effects ofatrovastatin may including the promotion of neurogenesis and angiogenesis and functional recovery after stroke,highlighting SDF-1/CXCR4 as a key mediator for atrovastatin.