Study Of Therapeutic Effect And Underlying Mechanisms Of Dexmedetomidine On Intracerebral Hemorrhage

Background and Objective: Intracerebral hemorrhage(ICH)is a devastating disease without effective treatment but with high rates of mortality and disability.The brain injury after ICH is divided into the primary injury and the secondary injury.Emerging evidence suggests that inflammatory cascade plays a key role in the progression of ICH-induced brain injury,including destroying the blood brain barrier(BBB),accelerating the formation of edema that surrounds hematomas,exacerbating the mass effect,and amplifying the cell death process,eventually resulting in the degradation of brain damage.Evidence has shown that NLRP3 inflammasome was activated after ICH and leads to the maturation of caspase-1,and caspase-1 can cleave the preforms of IL-1β and IL-18,which contribute to BBB disruption and lead to the influx of immune cells.Dexmedetomidine(DEX)is a highly effective α2 adrenergic receptor agonist that has sedative,analgesic,and anti-anxiety effects,and is regarded as a potential therapeutic for NLRP3-associated syndromes.In this study,we examined the therapeutic effects of dexmedetomidine in two mouse models of ICH.Methods: ICH models were induced via injecting bacterial collagenase or autologous blood.And then they were randomly assigned into two groups: ICH group and dexmedetomidine treatment group.We use modified Neurological Severity Score(m NSS),corner turn test to evaluate neurodeficits,evaluate the hematoma and the brain edema to assess the effective,the flow cytometry and RT-PCR to assess the brain and periphery immune cell infiltration,and also we use the Evans Blue and western blot to assess the BBB dysfunction.Results:1、Dexmedetomidine treatment attenuates neurodeficits after ICH.m NSS and corner test were performed at day 1 and day 3 after ICH induced by autologous blood injection or collagenase injection.Compared with ICH group,there was a significant improvement in neurological function scores in the dexmedetomidine group(P< 0.05).2、Compared with ICH group,dexmedetomidine treatment group reduced the brain water content and hematoma significantly(P < 0.05).3、Mice were given dexmedetomidine by daily i.p.injection,starting from12 h or 18 h after ICH.Compared with ICH group,12 h treatment group has a significant improvement in neurological function scores and brain water content(P < 0.05).4、The results of RT-PCR shows dexmedetomidine treatment group inhibit the activation of NLRP3 inflammasome components and IL-1β(P < 0.05).5、Flow cytometry analysis show dexmedetomidine treatment reduces infiltration of leukocytes and microglia activation significantly(P<0.05).6、Evans Blue shows,compared with ICH group,dexmedetomidine treatment group protects the permeability of BBB after ICH(P < 0.05).Western bolt analysis shows that dexmedetomidine preserved tight junction protein(claudin-5 and ZO-1)expression compared with the ICH group(P < 0.05).Conclusions: Our data demonstrated that dexmedetomidine can effectively attenuate brain inflammation and provide protection against ICH.Dexmedetomidine can significantly inhibit the activation of NLRP3 inflammasome,reduce microglial production of proinflammatory factors,decrease immune cells infiltration and enhance BBB integrity.All the results indicated that dexmedetomidine could be a potent candidate for treatment of ICH.