Transplantation Of Bone Marrow Stromal Cells Promotes The Recovery Of Spatial Learning And Memory And Impacts The Expressions Of Bdnf And P75NTR In Rats With Chronic Cerebral Ischemia

Chronic ischemic in central nervous system can lead to dendritic and axonal injuries, and demyelinating lesions, which affecting spatial learning and memory capacity. Brain-derived neurotrophic factor (BDNF) is an important neurotrophin which has pleiotropic effects on modulating activity-dependent forms of synaptic plasticity, neuronal survival, neuronal development, dendritic arborization and axon growth. P75neurotrophin receptor (P75NTR) is a transmembrane receptor that is identified as a low-affinity receptor for BDNF. P75NTR plays as a negative regulator that involves in activity-dependent forms of synaptic plasticity when it bands with BDNF. Studies also showed that P75NTR was required for the signaling pathway of myelin-associated inhibitors (Nogo-A, MAG, OMgp) that inhibited neurite outgrowth. It was reported that expression of BDNF in the the rat brain with hypoxia-ischemia was lower than that in the normal rat brain. While another study pointed out that the level of P75NTR in rat hippocampus with transient global cerebral ischemia was sharp increased.Numbers of studies demonstrated that bone marrow stromal cells (BMSCs) may provide an adequate source for individualized cell transplantation and can circumvent problems which come from ethics and immunogenicity. BMSCs may improve cognitive function through the following mechanisms:neurons that differentiate from BMSCs might replace the damaged and missing neurons due to chronic hypoperfusion; BMSCs might secrete some neurotrophic factors which play a neuroprotective function; BMSCs may up-regulate some endogenous proteins which can activate self-repair process.Study demonstrated that BMSCs could protect oligodendrocytes from injury of oxygen-glucose deprivation though reducing the expression of P75NTR. It was still unclear whether BMSCs transplantation could influence the expression of p75NTR, which might play critical roles in the pathogenesis of chronic cerebral ischemia.In the present study, first we induced a rat chronic cerebral ischemia model by permanent occlusion of bilateral common carotid arteries. Then we transplanted BMSCs into the rat model and estimated the protective effects of BMSCs against the deficiency of spatial learning and memory ability caused by chronic cerebral ischemia. We also observe the changes of the expression of BDNF and P75NTR in the CAl region of hippocampus of rats in different groups. The mechanism of recovery of spatial learning and memory after BMSCs transplantation may be relevant to the expressions of BDNF and P75NTR.Objective:To investigate the the effects of intravenous administration of rat BMSCs on spatial memory and expressions of BDNF and P75NTR in hippocampal CAl region of rats with chronic cerebral ischemia.Material and Methods:1. Rat BMSCs was isolated by whole bone marrow adherent culture. After cultured for several passages, flow cytometry was used to identify the surface markers and cell purity of BMSCs. Cells of passage5to8were used for transplantation. Before transplantion, cells were transfected with lentivirus carrying a green fluorescent protein (GFP) gene for tracing in vivo.2. Thirty-six Sprague-Dawley rats were randomly divided into sham group, model group and transplantation group. The rat model of chronic cerebral ischemia in the latter two groups were established by permanent occlusion of bilateral common carotid arteries(2-VO).Rats in the transplantation group were transfused with BMSCs which had been transfected with GFP via tail vein at48hours after surgery.3. Rats in each group were tested space learning and memory abilities by Morris water maze after30days of trasplantation.The expressions of BDNF and P75NTR protein in hippocampal were determined by immunohistochemistry and western blot.Results:1. Compared with the sham group,the average escape latency of the rats in model group were significantly longer(P<0.01) while the target quadrant residence time and the number of times across platforms position were significantly fewer (P <0.05) in water maze test.Compared with model group, the average escape latency of the rats in transplantation group were shorter(P<0.01), while the target quadrant residence time and the number of times across platforms position were increased (P <0.05).2. The results of immunohistochemistry and western blot showed that the expression of BDNF decreased (P<0.05) and the expression of P75NTR increased (P <0.05) more in model group than that in sham group. The expression of BDNF increased (P<0.05) and the expression of P75NTR decreased (P<0.05) in transplantation group compared with model group.Conclusions:1. Transplantation of bone marrow stromal cells via intravenous route can significantly promote the recovery of neurological function in rats with chronic cerebral ischemia.2. The expression of BDNF decreased, while the expression of P75NTR increased in hippocampal CA1region of rat model with chronic cerebral ischemia.3. BMSCs transplantation can significantly raise BDNF expression and down-regulate P75NTR expression in hippocampal CA1region of rat model with chronic cerebral ischemia. This may be associated with the recovery of neurological function.