Effects And Mechanism Of Neuregulin On Oxidative Stress Injury And Nrf2-ARE Signaling Pathway In Intracerebral Hemorrhage

Objective:In this study,a rat model of intracerebral hemorrhage was established,to investigate the effect of neuregulin-1?(NRG-1?)on neurological dysfunction and brain edema after intracerebral hemorrhage in rats.Endogenous antioxidant pathway nuclear factor related factor 2(Nrf2)/antioxidant response element(ARE)and downstream key molecules were detected,and to explore the mechanism of antioxidative effect of NRG-1? in rat model of intracerebral hemorrhage.Method:The male Sprague-Dawley rats were randomly divided into sham operation group,model group and treatment group.Each group was divided into 3 subgroups after modeling at day 1,and days 3 and 5.The model of intracerebral hemorrhage in rats was established by injection of collagenase type IV(0.5 U).The model group and the treatment group were injected with type IV collagenase.After 2 hours of treatment,the rats in the treatment group were treated with NRG-1?(2ug/Kg)injection through tail vein,and the volume of 0.1mol/L PBS solution was injected into the model group and sham operation group.The neurological deficit scores of each group were measured,and the brain water content was detected by dry wet weight method.The expression of Nrf2 and HO-1 protein in the tissues of around the hematoma were detected by immunohistochemistry and Western blot.Results:1,Neurological deficit score: At 1 day,model group appeared obvious neurologic impairment,3 days to reach the peak,and nerve function defect is most serious.And 5 days it was obvious neurologic impairment,but symptom relief compared with peak period,and compared to the model group and the sham operation.At different time points,the difference was statistically significant(P < 0.01).The level of exercise,sensory,balance and reflex dysfunction in the treatment group was lower than that in the model group at the observation time points,and the difference between the treatment group and the model group was statistically significant(P < 0.05).2,Brain water content: In the model group,the brain water content first increased and then decline.The brain edema occurred in the model group,which was increased rapidly and reached the peak at 3 days,and compared with sham operated group and model group,the difference was statistically significant(P < 0.01).After treatment,the brain edema at each time point was reduced,the treatment group compared with the model group,and the difference was statistically significant(P < 0.05).3,Immunohistochemical detection results: The expression of Nrf2 and HO-1 in the model group first increased and then decline,and then increased from 1 day,peaked at the end of the 3 days,then decreased gradually.Compared with sham operation group,the difference of each time point was statistically significant(P < 0.05).After treatment,the protein expression was increased at each time point.The difference between the treatment group and the model group was statistically significant(P < 0.05).4,Western Blot results: In the model group,the expression of Nrf2 and HO-1 protein were increased at 1 days,peaked at 3 days,and the peak value was increased at 5 days.After correction by reference value,the difference was statistically significant(P < 0.05).The expression of Nrf2 and HO-1 protein in the treatment group were significantly higher than that in the model group at each time point,and the difference was statistically significant(P < 0.05).Conclusion:The Nrf2-ARE pathway was activated in the model of intracerebral hemorrhage in rats,and the intervention of NRG-1? can further up-regulate the expression of Nrf2-ARE pathway.NRG-1? regulated the transcription of downstream antioxidant enzymes,and it plays an important role in anti-oxidative stress.Moreover,the degree of brain edema and neurological deficits were significantly improved by the intervention of NRG-1?.These results suggest that NRG-1? was effective in relieving secondary injury of intracerebral hemorrhage.The possible mechanism of this neuroprotective effect may be related to Nrf2-ARE pathway which was activation and it's the antioxidant activity.