Study About Losartan Protect Cerebral Injury At The Later Stage Of Mice Forebrain Ischemia/Reperfusion

Objective:Cerebral ischemia is a main type of stroke, which cause serious damage to thepatient’s health and doesn’t have a good treatment nowadays. AT1-receptorblockers can reduce the occurrence of stroke through controlling high bloodpressure which is a high risk factor of stroke. The study also found that brainangiotensin system has changed after cerebral ischemia, and the change of brainangiotensin system components can affect the brain injury of cerebral ischemia.Many animal experiments has confirmed the protective effect of the AT1receptorblockers on cerebral ischemia/reperfusion, and studied its possible mechanism inneuron apoptosis, oxidative stress, inflammation, etc. But all of these studys isabout the earlier stage of brain ischemia/reperfusion. This study in order to furtherproved that AT1receptor blocker losartan has protective effect at the later stage ofmice forebrain ischemia/reperfusion. Astrocytes have inhibitory effect on nerveregeneration and functional recovery at the later stage of brainischemia/reperfusion, and related studies also suggest AT1receptor has inhibitoryeffect on astrocytes. This study was continuing on this field. Methods:Normal mice were randomly divided into several groups, choose0.5mg/kg,1mg/kg and5mg/kg as the dose of losartan potassium which was administered byintraperitoneal injection, control group was given normal saline. Forebrainischemia model was established by blocking bilateral common carotid artery for60min. Mice was given forebrain ischemia or shame operation15d after firstdrug treatment. At different time points after reperfusion, the body weight, motorfunction, learning and memory in Morris water maze, neuronal density in striatumand hippocampal CA1region, and the expression of GFAP and GFAP-positiveastrocytes density in hippocampal CA1region were evaluated.Results:At1d after reperfusion, body weight loss was observed in forebrain ischemiagroup, significantly improved at3,7,14and21d after reperfusion byadministrated1mg/kg losartan, and wasn’t improved by administrated0.5mg/kgor5mg/kg losartan. But no obvious improvement of body weight was observed onmices simply administrated losartan.At3d and21d after reperfusion, time remained on the accelerating rotarodwas obviously shorter in forebrain ischemia group than control group, andsignificantly improved by administrated1mg/kg losartan, and wasn’t improved byadministrated0.5mg/kg or5mg/kg losartan. No obvious improvement of motor function was observed on mices simply administrated losartan.At3d and4d of Morris water maze which was performed at16d afterperfusion, escape latencies for platform were obviously longer in forebrainischemia group than control group, and significantly shortened by administrated1mg/kg losartan. But escape latencies for platform were significantly shortened byadministrated5mg/kg losartan only at4d of Morris water maze, and were notshortened by administrated0.5mg/kg. No obvious improvement of learning andmemory in Morris water maze was observed on mices simply administrated1mg/kg losartan.At21d after perfusion, serious neurological damage in striatum andhippocampal CA1region was observed in forebrain ischemia group, neuronaldensity in these areas was also significantly reduced, and can be reversed byadministrated1mg/kg losartan. The reduction of neuronal density was alsoreversed by administrated0.5mg/kg losartan only in hippocampal CA1region, butwas not improved by administrated5mg/kg losartan.And the expression of GFAP and GFAP-positive astrocytes density in thehippocampal CA1region were obviously higher in forebrain ischemia group thancontrol group, and significantly inhibited by administrated1mg/kg losartan.Conclusion:Losartan can promoted the recovery of the weight and motor function after forebrain ischemia/reperfusion, and improved the reduction of spatial learning andmemory ability and the loss of neurons at the later stage of reperfusion. Losartancan significantly inhibited the activation and proliferation of astrocytes, whichmay be one of its targets of neuroprotection at the later stage of reperfusion.