The Role Of Mitochondrial Fission In Early Brain Injury In A Rat Model Of Subarachnoid Hemorrhage And Potential Mechanism

PurposeAberrant modulation of mitochondrial dynamic network,which shifts the balance of fusion and fission towards fission,is involved in brain damage of various neurodegenerative diseases including Parkinson’s disease,Huntington’s disease and Alzheimer’s disease.A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage,however,the underlying molecular mechanisms have remained to be elucidated.This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1(Drpl,a dominator of mitochondrial fission)on blood-brain barrier(BBB)disruption and neuronal apoptosis and the potential mechanisms in SAH rats.MethodsThe endovascular perforation models of SAH were performed in adult male Sprague Dawley rats.Experiment 1—A total of 168 rats were randomly divided into three groups:The sham group,the SAH + vehicle group and the SAH + Mdivi-1 group.Mdivi-1(1.2 mg/kg)or vehicle(0.9%NaCl)were administrated intravenously at 5 min after SAH induction.Experiment 2—One hundred and seven rats were randomly divided into 3 groups:the SAH + vehicle group,the SAH + Mdivi-1 group and the SAH+ Mdivi-1 + Rotenone group.Mdivi-1,vehicle or Rotenone were administrated at 5 min after SAH induction.The survival rate after SAH was observed until 72h.Mortality,SAH grades,neurological function,brain edema,BBB permeability,transmission electron microscopy,ROS assay,immunofluorescence staining and western blot were respectively performed at 24h after SAH.ResultsThe results indicated Mdivi-1(a selective Drpl inhibitor)reversed the morphologic changes of mitochondria and Drpl translocation,reduced ROS levels,ameliorated the BBB disruption and brain edema remarkably,decreased the expression of MMP-9 and prevented degradation of tight junction proteins—Occludin,Claudin-5 and ZO-1.Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B(NF-κB),leading to decreased expressions of TNF-α,IL-6 and IL-1β.Moreover,Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome.To investigate the underlying mechanisms further,we determined that Mdivi-1 reduced p-PERK,p-eIF2a,CHOP,cleaved Caspase-3 and Bax expression as well as increased Bcl-2 expression.Rotenone(a selective inhibitor of mitochondrial complexes I)abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1.ConclusionIn conclusion,these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH,and the inhibition of Drpl by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.