| Ischemic cerebrovascular disease is highly prevalent worldwide and one of the leading causes of death and permanent disability and has increased the financial burden on patients and society.The increasing incidence and younger of ischemic stroke is related to harmful habits,the ageing of society.Prevention and treatment of ischemic stroke face more seriously situation.Intravenous recombinant tissue plasminogen activator(rt-PA)is the only approved treatment for acute cerebral ischemic within 4.5 h from symptoms onset,as currently approved treatments by Food and Drugs Administration(FDA)and supported by observational studies.However,many patients are still short of treatment,mainly due to the narrow time window and other contraindications for rt-PA.Beyond the time window of thrombolysic therapy significantly increased the risk of cerebral hemorrhage and severe brain edema caused by reperfusion-induced brain damage,and this risk increases with progressive delays in treatment initiation seriously.The cerebral blood flow recanalization is significant for patients.The functional recovery of lesion area required oxygen and other nutrients by cerebral blood flow recanalization.Therefore,seeking effective measures to extending the time window of thrombolysis focal cerebral ischemia has attracted more attention.It is also mean that extending the time window of thrombolytic is also essential.Thus,effective prevention and controlling of cerebral ischemia/reperfusion(I/R)injury is a pressing concern.The cerebellar fastigial nucleus electrical stimulation(FNS)in rat confers remarkable protection from brain injury.However,little is known about the effects of pre-FNS on time window of thrombolytic therapy.Therefore,we sought to determine whether FNS exerts its neuroprotective effect to prolong the therapeutic window in cerebral ischemia/reperfusion and related mechanisms.Objective:To investigate the effect of neurogenic neuroprotection conferred by FNS and the role of PPAR?-mediated inflammation in a rat model of cerebral ischemia-reperfusion.Methods:A cerebral middle cerebral artery ischemia/reperfusion model by self-thrombus was used in the study.After a continuous 1 hour fastigial nucleus electric stimulation,the male Sprague-Dawley(SD)rats were given middle cerebral artery occlusion(MCAO)for 1,3,6,9,12 and 15 hours undergoing reperfusion with intravenous recombinant tissue plasminogen activator(rt-PA),while the control group received without FNS.After 72 h of reperfusion,the neurological deficits,infarct volume was evaluated by TTC trainning and brain edema were evaluated by detecting wet weight-dry weight.The brain tissue in ischemic penumbra was determined the myeloperoxidase(MPO)activity by a spectrophotometer and expression of PPAR? was measured by Rt-PCR and Western blotting.Results:Our findings showed that neurologic deficits increased gradually in the two groups.In 15 h reperfusion subgroup,the scores of FNS group(1.90±0.54)were significantly decreased compared to the control group(2.74±0.55).In the FNS group,the infracted volume and the brain water content were significantly reduced as compared with the control group,especially at 6h and 9h reperfusion(P < 0.05).The results suggested that PPAR? levels were mainly located in the 6h and 9h reperfusion subgroup.Compared with control group,the levels of PPAR? was significantly higher in 3h,6h,9h,12 h and 15 h reperfusion subgroup(P < 0.05).Rt-PCR analysis further confirmed this result.A significantly higher expression of PPAR? were found in the FNS group compared with the control group at 3h?6h?9h?15h reperfusion.the MPO activity was significantly higher in the control group than those of the FNS group at 3h,6h,9h and 12 h reperfusion(P < 0.05).Compared with control group,FNS has shown obvious signs of alleviating the increase of inflammatory mediators in a time-dependent manner.Conclusions:1.The neuroprotective effects of FNS have been shown to prolong the therapeutic window in cerebral ischemia/reperfusion.This study indicate that pre-FNS produces neuroprotective effects via inhibiting inflammatory response in cerebral ischemia/reperfusion rats beyond the time window of thrombolysis,but not significant.2.The mechanisms underlying the protection exhibited by FNS seem to involve the up-regulated the expression of PPAR? and inhibition for neutrophil infiltration to against inflammatory damage.It aiso indicated that PPAR? antiinflammatory effect in penumbral region plays an important role in brain ischemia.3.It suggested that FNS still has certain protective effect but not significant beyond the time window of rt-PA,this may also suggest that antiinflammatory reaction mediated by FNS in cerebral ischemic penumbra may have a delayed effect.4.FNS would be desirable to improve the efficacy and safety of stroke therapy and to prolong the effective time window of it after stroke. |
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