Fasudil Ameliorates Oxidative Stress And Mitochondrial Fission-fusion Imbalance Via Inhibiting ROCK/MAPK And Activating Nrf2 Signaling Pathways In APP/PS1 Mice

Objective:The pathogenesis of Alzheimer’s disease(AD)is closely related to oxidative stress response and abnormal mitochondrial dynamics.And our previous research demonstrated that Fasudil has neuroprotective effect.But it is needed to explore whether Fasudil has inhibits oxidative stress and regulates mitochondiral dynamics.The main purpose of this study is to investigate the effect and underlying mechanism of ROCK inhibitor Fasudil on cognitive function and neuronal apoptosis in AD mice.Methods:Sixteen APP/PS1 mice of 8 months old were divided into model(NS group)and Fasudil treatment groups(F group)and 8 wild-type mice were used as normal control group(WT group).After behavioral test,all mice were sacrificed for related tests.Results:The results showed that the administration of Fasudil improved learning and memory ability,inhibited neuronal apoptosis by increasing the expression of Bcl-2,reducing Bax and Cleaved Caspase-3,as well as elevated the concentration of antioxidative substances and decreased lipid peroxides,down-regulated the expression of p-DRP1 and FIS1 and up-regulated the expression of OPA1,Mfn1 and Mfn2 in APP/PS1 mice.Moreover,Fasudil treatment also ameliorated the phosphorylation of p38,JNK and ERK,and accelerated Nrf2 expression and its antioxidative downstream molecules.Conclusion:Data from present study demonstrate that Fasudil significantly restored cognitive function,and reduced neuronal apoptosis in hippocampus in APP/PS1 mice,by restraining oxidative stress and regulating mitochondrial fission-fusion imbalance,which are probably related to the inhibition of ROCK/MAPK and the activation of Nrf2 signaling pathways.