PGRN Can Improve The Anxiety And Learning And Memory Ability After Cerebral Ischemia By Promoting The Regeneration Of Hippocampal Nerve

Brain ischemia is a cerebrovascular disease which is a serious threat to human health and is characterized by high fatality rate and high disability rate.Stroke patients often endure post-stroke depression and cognitive impairment,and their learning memory is also severely affected.Cognitive impairment and learning and memory disorders caused by cerebral ischemia is closely related with neuronal damage in the hippocampus.Studies show that there is a continuous proliferation of neural stem cells(NSC)and neural progenitor cells(NPC)in adult mammals’ subventricular zone(SVZ)and subgranular zone(SGZ).The ischemic injury stimulates the neurogenesis of SGZ,and the newly proliferated neural stem cells or neural precursor cells migrate and differentiate into mature granular cell.Newly proliferated granular cells play an important role in learning and memory function of hippocampus.Therefore,promoting hippocampal neurogenesis and repairing damaged neurons in hippocampus become a significant to improve anxiety and learning and memory after ischemia.Progranulin(PGRN)is a kind of secretory glycoprotein,which is widely involved in many important pathological and physiological activities such as inflammatory response,injury repair,growth and development,and metabolic regulation.PGRN cast a protective effect on ischemic and hypoxic cerebra.PGRN can improve the memory deficits in Alzheimer’s disease by inhibiting the deposition of beta amyloid,and can also promote hippocampal neurogenesis by inhibiting inflammatory response.Our previous studies have shown that PGRN can promote the proliferation of SVZ neural stem cells after cerebral ischemia,and promote the migration of neural stem cells to the damaged areas and differentiate into mature neurons.However,the effect of PGRN on the neurogenesis in SGZ and its effects on anxiety and learning and memory after ischemia have not yet been reported.We speculate that PGRN can improve the learning and memory by promoting neurogenesis in SGZ after ischemia.In our present study,we first induced pMCAo models in C57BL/6 mice,PGRN expression in ischemic penumbra was is detected via immunohistochemical techniques.Then we explored the reverse effect of intraventricular injected exogenous recombinant PGRN on the neurobehaviour of ischemic mice;finally,the effects of PGRN on the proliferation,migration and differentiation of NSC/NPC in SGZ of ischemic mice were detected by immunohistochemistry and double immunolabeling staining.Results:1.The expression of PGRN in the posterior cerebral ischemia was increased:immunofluorescence staining of PGRN showed that PGRN in ischemic penumbra was up-regulated at 7d,14d and 28d after ischemia(P<0.01;P<0.01;P<0.01).PGRN in hippocampus CA1 was up-regulated at 7d after ischmia(P<0.05).While there was no significant difference in hippocampus CA3 and DG2.PGRN improved anxiety after cerebral ischemia in mice.(1)Open field test showed that there was no significant difference in locomotor capacity at 14d after ischemia compared with other group;and the time the animals spent in the central area increased significantly after the injection of PGRN(P<0.05).(2)The elevated plus maze test showed that the number of open arm entries and time spent by the animals in the open arm increased significantly at 14d after ischemia and after the injection of PGRN(P<0.05).3.PGRN improves learning and memory after cerebral ischemia in mice:The results of Morris water maze showed that escape latency and path latency were down-regulated,and there was a significant difference after two days training(26d,27d)(P<0.05).In the second stage,the time in the target quadrant significantly increased at the 28d day after ischemia and after PGRN injection(P<0.05).4.PGRN promotes the proliferation of neural stem cells in SGZ:BrdU immunohistochemical staining showed that PGRN could increase the number of BrdU positive cells in SGZ at 3d and 7d after cerebral ischemia(P<0.05;P<0.01).PGRN can also promote the BrdU/Nestin positive cell numbers in SGZ at 14 day after cerebral ischemia(P<0.05).5.PGRN promotes the migration and differentiation of neural stem cells to immature neuron in SGZ:PGRN can promote the expression of DCX in SGZ at 7d and 14d after cerebral ischemia(P<0.01).PGRN improved BrdU/DCX positive cells proportion in SGZ at 14d after cerebral ischemia(P<0.01).6.PGRN promotes the differentiation of neural stem cells into neurons in SGZ after ischemia:PGRN increased the number of BrdU/Neu N positive cells in hippocampal granular layer after ischemia.Conclusion:1.After cerebral ischemia,the expression of PGRN in the ischemic penumbra and hippocampus CA1 increased,while there was no significant difference in CA3 and DG.2.PGRN relieves anxiety and improves the ability of learning and memory capacity after cerebral ischemia.3.PGRN promotes the proliferation of NSC/NPC in SGZ and the differentiation of neural progenitor cells after cerebral ischemia.PGRN increased the number of mature neuron in ischemic granular layer.