| Objective: Traumatic brain injury(TBI)has a high incidence rate,and still has high morbidity and mortality,and secondary inflammatory changes after treatment of brain injury,blood brain Studies of secondary damage such as blood-brain barrier(BBB)destruction and cerebral edema remain stagnant,leading to further improvement in morbidity and mortality.Therefore,secondary injury after TBI is still a difficult problem to be solved so far.Valproic acid VPA is a histone deacetylase inhibitor(HDACI)that is effective against a variety of seizures.Recent studies have shown that VPA also has protective effects in tumor suppression,bipolar disorder,migraine,hemorrhagic shock resuscitation and treatment of central nervous system diseases,especially in the application of neuroprotective applications after TBI,but currently it has There is considerable debate about the doses that play a role in neuroprotection.In this study,the protective effects of different doses of valproic acid(VPA)on experimental traumatic brain injury in rats were studied,and the appropriate doses and related protective mechanisms were investigated.Methods : 1.A total of 100 adult male rats were randomly divided into 5 groups(n=20)by controlled cortex impact CCI.Sham group,TBI group,TBI + 30 mg VPA group,TBI + 150 mg VPA group,TBI + 300 mg VPA group.TBI+30mg VPA,TBI+150mg VPA,TBI+300mg VPA group were given VPA 30mg/kg,150mg/kg,300mg/kg daily for 7 days after TBI model awake,and Sham and TBI groups were given stomach feeding,etc.Volume of normal saline.2.20 rats in each group were sacrificed into 4 subgroups at 24 h,3d,7d and 14 d after operation,and 5 rats in each group were treated with modified neurological severity scores(mNSS).The internal venous blood was taken to detect the blood concentration of VPA.The brain was debrided and the brain was removed from the contused area.HE staining was used to observe the brain contusion and immunohistochemistry to detect aquaporin 4(AQP4)and matrix metalloproteinase-9(MMP-9),apolipoprotein J(ApoJ),parallel immunoblotting(western-blot)were used to measure the content of AQP4,MMP-9,ApoJ and the water content of brain tissue by dry and wet weight method.Results:1.Compared with Sham group,the mNSS scores of TBI group increased at 1,3,7 and 14 days after injury,the difference was statistically significant(P<0.05),and gradually decreased after 1,3,7 and 14 days after injury.Compared with TBI group,the mNSS scores of TBI+150mg VPA group and TBI+300mg VPA group decreased on the 1st,3rd,7th and 14 th day after injury,the difference was statistically significant(P<0.05),among which TBI The decrease of +300mg VPA group was the most obvious;compared with TBI group,the change of modified neurological deficit score in TBI+30mgVPA group was not statistically significant;2.Compared with Sham group,the water content of brain tissue in TBI group increased at 1,3,and 7 days after injury,the difference was statistically significant(P<0.05),and the difference of brain water content between groups in the 14 th day after injury.There was no statistical significance.Compared with the TBI group,the brain water content of the TBI+150VPA and TBI+300VPA groups decreased significantly on the 1st,3rd,and 7th day after injury,and the difference was statistically significant(P<0.05).Compared with the TBI group,there was no significant difference in brain tissue water content between the two groups(P>0.05).After the injury,the time was significantly lower in the TBI+300mg VPA group.There was no significant difference in brain water content between TBI+30mg VPA group and TBI group(P>0.05).3.Compared with the Sham group,the expression of MMP-9 in the TBI group increased at 1 day after surgery,peaked at 3 days,and showed no significant expression at 7 days and 14 days.Compared with the TBI group,the TBI+VPA group was 1 and 3 days after surgery.The expression of MMP-9 in brain tissue decreased,the difference was statistically significant(P<0.05).The higher the dose,the more obvious the difference was statistically significant(P<0.05).There was no obvious difference in the 14 d group.MMP-9 positive expression.4.Compared with Sham group,the expression of AQP4 in TBI group was the highest at 24 h after operation,and decreased at 3d,and returned to the baseline at 7d and 14 d.Compared with TBI group,AQP4 expression in brain tissue of TBI+VPA group was 1 and 3 days after operation.The difference was statistically significant(P<0.05).The higher the dose,the more obvious the difference was statistically significant(P<0.05).The difference of AQP4 expression in brain tissue of each group at 7 and 14 days after surgery did not has statistical significane.5.Compared with Sham group,the expression of ApoJ in TBI group increased at 1d,3d expression is still higher,decreased at 7d,and returned to normal at 14 d.Compared with TBI group,ApoJ expression in brain tissue of TBI+VPA group was 1 and 3 days after operation.The difference was statistically significant(P<0.05).The higher the dose,the more obvious the difference was statistically significant(P<0.05).On the 14 th day after operation,there was no difference in the expression of ApoJ between the experimental groups.In conclusion:1.Sodium valproate can alleviate brain edema in rats with brain injury and protect neuronal cells,which has a brain protective effect on rat brain injury model;2.Sodium valproate inhibited the expression of ApoJ,AQP4 and MMP-9 in brain tissue of rats with brain injury model.The doses of 30mg/kg,150 mg/kg and 300 mg/kg/d showed that the higher the dose,the inhibition The more obvious the effect;3.The brain protective effect of VPA may be the result of the combination of VPA inhibition of brain damage factor expression and inhibition of brain protective factor expression;4.High-dose sodium valproate is more advantageous in the brain protection of rat brain injury model,but drug poisoning should be avoided. |
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