Effects Of RO27-3225 On Neurogenesis And Neuroinflammation In A Mouse Model Of Cerebral Infarction

Objective:Cerebral infarction,which accounts for about 80%of all strokes,is one of the leading causes of death and disability in adults worldwide,and the treatment is currently limited.RO27-3225 is a highly selective melanocortin receptor 4 agonist that alleviates the damage in many nervous system diseases,such as cerebral hemorrhage,traumatic brain injury and chronic neurodegenerative diseases.However,the effect of RO27-3225 on cerebral infarction and its mechanism remain unclear.In this study,we used a mouse model of transient middle cerebral artery occlusion(tMCAO)and administered RO27-3225 or saline to the mice by intraperitoneal injection.We explored and discussed the effect of RO27-3225 on cerebral infarction and the possible mechanism from the aspects of neurogenesis,neuroinflammation and so on.Methods:108 mice(male,25?30g)were randomly assigned to four groups:(Sham+saline group,n=18),(Sham+RO27-3225 group,n=18),(tMCAO+saline group,n=36),(tMCAO+R027-3225 group,n=36).A mice-model of tMCAO was established via improved thread method.RO27-3225 or saline administrations were performed until 7 days after the surgery.We analyzed modified Neurological Severity Scores(mNSS),cerebral infarction volume,and brain water content of each group.Immunofluorescence(IF)was performed to evaluate proliferation and differentiation of neural stem cell,changes in the number of PDGFR?+cells and activated microglia.The expression of Iba1,TNF?,IL6,and iNOS were measured by Western blot.Statistical analysis was carried out with SPSS version 13.0.All results were expressed as mean±SD.Results:1.RO27-3225 increased Nestin+/BrdU+ cells and DCX+/BrdU+cells in the subventricular zone(SVZ)as well as DCX+/BrdU+ cells and PDGFR?+ cells in the peri-infarct zone after tMCAO,respectively.2.RO27-3225 decreased the number of activated microglia and the expression level of Iba1,TNF?,IL6,and iNOS protiens after tMCAO.3.RO27-3225-treated mice had significantly decreased infarct volumes,brain water contents and neurological deficits after tMCAO.Conclusions:RO27-3225 can promote neurogenesis in the SVZ,inhibit neuroinflammation in the peri-infarct,ameliorate brain damage and improve recovery of neurological function after cerebral infarction.