The Protective Effect Of PGRN On The Neuronal Cells Damaged By Hypoxia And Hypoglycemia And The Influence Of Proliferation And Differentiation

Brain ischemia is one of the leading causes of death and disability in the world,which is a serious threat to human health.The injury area after cerebral ischemia were divied into inchemic core and ischemic penumbra which is still in reversible injury state.The key to treat cerebral ischemia is to protect ischemic penumbra.It has been reported that injury after cerebral ischemia induced nerve regeneration.Neural stem cell(NSC)/neural precursor cells(neural progenitor cell,NPC)can proliferate and migrate to the damaged area,differentiate into different types of nerve cells and integrate into the neural network,so that the structure and function of the brain are restored.Therefore,promoting the formation of neonatal neurons also plays an crucial role in the endogenous repairment of brain after cerebral ischemia.Neuroprotection and nerve regeneration after cerebral ischemia are regulated by many factors.PGRN(progranulin)is reported to have many physiological functions,such as growth factor,neurotrophic factor,anti-inflammatory factor and so on.It can participate in a variety of cascade reactions of cerebral ischemia injury.It has been shown that PGRN participates in the process of neuroprotection and nerve regeneration after cerebral ischemia.Its mechanism may be related to neuroprotection,blood brain barrier and inflammatory response.However,its molecular mechanism remains unclear.Thus,we hypothesizes that PGRN plays a protective role in promoting brain regeneration and cerebral ischemia.However,the protective effect of PGRN on nerve injury after cerebral ischemia and the mechanism of nerve regeneration are not clear.In the present study,PC 12 cell lines and neural stem cells(NSCs)were used to establish related cell models.The protective mechanism of PGRN on different cell modes was studied by cell experiments,immunofluorescence and immunoblotting and other molecular biology techniques.Results:1.The protective effect of PGRN on PC 12 cells:The oxygen glucose deprivation(OGD)model of PC 12 cells was established.The results were as follows:(1)PGRN can significantly reduce the apoptosis ratio of PC 12 cells induced by OGD,down-regulated Caspase 3(P<0.01),and maintained the balance of Bcl-2/Bax.(2)PGRN regulated the expression of Cyclin D1 in PC12 cells(P<0.01)under OGD condition.PGRN up-regulated the phosphorylation levels of Akt and Erkl/2 thus activated proliferation related signaling pathways,thus enhanced the proliferation of PC 12 cells.PGRN can protect OGD induced PC 12 cell injury from two aspects:decreasing apoptosis and promoting proliferation.2.The effect of PGRN on NSCs in hypoxic condition:The hypoxia model was established on primary culture of NSCs.The results were as follows:(1)After hypoxia 12h,the proliferation of NSCs was remarkablely enhanced,and PGRN could further enhance the proliferation of NSCs(P<0.05).PGRN could increase the phosphorylation levels of Akt and Erkl/2(P<0.01)to regulate NSCs proliferation.PGRN made the morphology of NSCs more closely related to neurons after hypoxia,and upregulated the expression of ?-tublin,DCX(P<0.01).PGRN can promote the proliferation and differentiation of NSCs after hypoxia,and may promote nerve regeneration after brain ischemia.Conclusions:1.PGRN protected OGD induced PC 12 cell injury by reducing apoptosis and promoting proliferation in two aspects.2.PGRN promoted the proliferation and differentiation of NSCs under hypoxia.