The Effect And Mechanism Of Drp1 In A Mouse Model Of Traumatic Brain Injury

Objective: Traumatic brain injuries is caused by outside forcing inducing visible head injury,general can lead to serious consequences.It has been reported that brain injury can cause mitochondrial dysfunction which induce secondary injury.While,mitochondrial dynamin-related protein 1(Drp1)plays an important role in the process of mitochondrial fission,participating in maintaining the balance of mitochondria.This research focus on the role of Mdivi-1,a selective inhibitor of Drp1,in mitochondrial balance,mitochondrial autophagy and cell death even the effect of nerve dysfunction after TBI.Moreover discusses the mechanism in order to find a new therapeutic targets.Methods: TBI model was established by weight drop device in adult mice based on procedures previously reported.Mdivi-1,a selective inhibitor of Drp1,was administered by intraperitoneal injection 10 mins after TBI as experimental group.Accordingly,the control group inject asepsis PBS salt solution.Animals were sacrificed at different time after surgery except the behavior group.First using Western Blot to evaluate the expression level of Drp1 after TBI.Mitochondrial morphology in neuron cell were observed by electron microscopy.PI-positive cells was used to identify the effects of cytoplasm membrane integrity.The tissue lesion volume and brain water content were used to evaluate brain injury after TBI.The levels of apoptosis,autophagy and mitochondria related proteins were measured by Western Blot.Finally,Motor Test and Morris water maze Test were performed to detect learning and memory functions.Results:(1)In TBI group,Drp1 expression levels and the number of PI-positive cells were increased from 1 h and peaked at 24 h after injury.Compared with the Sham group,the Mdivi-1 group were significantly lower.(2)In contrast with small and granular mitochondria in neuron cells,mitochondria with longer diameter and bigger size were appeared after Mdivi-1 treatment,moreover,the level of Drp1 is decreased.(3)TBI-induced apoptosis related proteins,mitophagy related proteins expression changes were detected,and the experimental group reversed these changes.(4)TBI induced brain edema,lesion volume increases and behavioral deficits,while the administration of Mdivi-1 can effectively reverse these changes.Conclusion:(1)Mdivi-1 through inhibiting the function of Drp1 to regulate the balance of mitochondrial dynamic and reverse mitochondrial morphological changes after TBI.(2)Mdivi-1 can dramatically reduce the level of mitophagy and cell apoptosis.(3)Mdivi-1 can reverse the changes of brain edema,behavioral deficits and lesion volume after TBI.