The Role And Mechanism Of PPARα In Neuronal Apoptosis And Nerve Function Recovery After Ischemic Stroke

Objective:To investigate the role and mechanism of PPARα in neuronal apoptosis and neurological function recovery after ischemic stroke.Methods:Firstly,the cerebral ischemia-reperfusion injury(IRI)was induced through middle cerebral artery occlusion(MCAO)model.The cerebral infarct volume,degree of cerebral edema and neurological function were detected in PPARα knockout mice and conditional gene knockout mice.The neurological function of mice was detected through behavioral tests such as Morris water maze,new object recognition experiment and accelerated rod.TUNEL staining and Golgi staining were used to examine cell apoptosis and dendritic structure.Secondly,adeno-associated virus(AAV)was stereotactically injected into mouse brain mediating the exogenous expression of PPARα,following exploring its effect on neuronal apoptosis and synaptic plasticity.Thirdly,the transport of mitochondria in axons was detecting by using live cell online culture technology.RNA-seq analysis and co-immunoprecipitation experiments were used to explore the molecular mechanism of PPARα in regulating neuronal apoptosis.At last,the immunofluorescence staining and flow cytometry were used to detect the effect of PPARα on microglia polarization after stroke.The model expressing exogenous PPARα in microglia in vivo was constructed to detect the effect of PPARα on the damage of blood-brain barrier after stroke.Results:Loss of PPARα led to aggravating IRI,motor dysfunction,increase of TUNEL+apoptotic cells and decrease of dendritic complexity in mice after stroke.However,AAV-mediated exogenous expression of PPARα resulted in partial recovery of motor dysfunction in mice after MCAO.Additionally,PPARα knockout resulted in a significant decrease in the expression of Dynlt1a according to RNA-seq.The results of live cell culture experiments showed that PPARα knockout resulted in reducing the transport of axonal mitochondria after OGD.PPARα promoted the polarization of microglia to the anti-inflammatory phenotype after stroke.Overexpression of PPARαin microglia led to a decrease in the damage of blood-brain barrier after MCAO.Conclusion:PPARa regulated mitochondrial axon transport by interacting with Dynlt1 and exerted a direct protective effect on neurons after stroke.In addition,PPARα regulated the transformation of microglia into anti-inflammatory phenotype after stroke,reduced inflammation,reduced the damage degree of blood-brain barrier,and exerted a neuroprotective effect.These results indicated that PPARa was a key target for neuroprotection after stroke.