The Early Combining Therapeutic Effect On The Intra Cerebral Hematoma With Atorvastatin And Low-dose Dexamethasone

Objective:Intracerebral hemorrhage,the most severe and incurable form of stroke,not only presents a high mortality and disability rate,but also causes a series of pathological changes,leading the secondary brain injury.A large number of studies have confirmed that low-dose atorvastatin showed a positive efficacy on intracerebral hemorrhage.The mechanism is to promote angiogenesis around the hematoma and regulate hematoma-related inflammatory reactions,thus improving hematoma absorption and functional recovery.However,atorvastatin has a delayed effect and can't improve multiple pathological changes as early as possible,which is not conducive to early control of secondary brain injury.Inflammation is the main factor of secondary brain injury.Dexamethasone,a commonly used anti-inflammation drug in clinic,has been studied on intracerebral hemorrhage for a long while.However,high-dose dexamethasone can't be used to treat intracerebral hemorrhage clinically,because it may cause a series of complications,and even worsen the prognosis of patients.Therefore,we hypothesized that a new strategy for short-term atorvastatin combined with low-dose dexamethasone can promote angiogenesis and intensify anti-inflammatory effect,thus improving the therapeutic effect of intracerebral hemorrhage.This study was to investigate the early therapeutic effects of atorvastatin combined with lose-dose dexamethasone in intracerebral hemorrhage mice,evaluating whether its therapeutic effects faster and better than atorvastatin monotherapy or dexamethasone monotherapy.Methods:The collagenase-injected intracerebral hemorrhage mice models were established and randomly divided into five groups:(1)sham group;(2)vehicle group;(3)atorvastatin group;(4)dexamethasone group;(5)combine group(atorvastatin combined with dexamethasone).After successful modelling,the drug was administered orally every 24h for 72h according to the above-mentioned grouping and drug dosage of each group.The following experiments were conducted to evaluate the therapeutic effects of atorvastatin and dexamethasone combination treatment in intracerebral hemorrhage comprehensively:magnetic resonance imaging was used to monitor the hematoma absorption.Modified neurological severity score,foot-fault test,Rota-rod test and Morris water maze were performed to evaluate functional recovery in mice.We used laser speckle contrast imager,brain water content test and Evans blue extravasation method to measure cerebral blood flow,cerebral edema and blood-brain barrier dysfunction respectively.The expression of inflammatory and angiogenic cytokines were detected by the cytokine array kit and angiogenesis array kit.The oxidative stress responses were evaluated by enzyme-linked immunosorbent assay.Finally,neuronal apoptosis and proliferation surrounding the hematoma in brain tissue were completed by immunofluorescence co-staining.Results:After 72h administration,hematoma volume of combine group was significantly reduced,and neurological function recovery was significantly better compared with vehicle group.In addition,cerebral blood flow of combine group recovered rapidly,brain edema and blood-brain barrier dysfunction were less severe than vehicle group.Combine group's pro-inflammatory cytokines were significantly lower and angiogenic cytokines were significantly higher compared with vehicle group.The oxidative stress responses of combine group were reduced,and neuronal apoptosis around the hematoma was significantly reduced while the proliferation was significantly increased.More importantly,the therapeutic effects of combine group after a series of intracerebral hemorrhage pathological changes were faster than atorvastatin monotherapy and superior than dexamethasone monotherapy.However,the effect of atorvastatin monotherapy began to appear at 7-14 days after the treatment,and the therapeutic advantage of the combination drug was no longer obvious.Conclusion:The early short-term application of atorvastatin combined with low-dose dexamethasone could improve a series of pathological changes and neurological deficits in intracerebral hemorrhage mice,which was faster than atorvastatin monotherapy and superior than dexamethasone monotherapy.However,this effect was not durable,suggesting that the combination of statin and dexamethasone in the treatment of intracerebral hemorrhage required early application and application of appropriate time.