Combined bone marrow stromal cells and oxiracetam treatments ameliorates acute cerebral ischemia/reperfusion injury through TRPC6

Ischemic stroke has become one of the leading causes of deaths and disabilities all over the world. In this study, we investigated the therapeutic effects of combined bone marrow stromal cells (BMSCs) and oxiracetam treatments on acute cerebral ischemia/reperfusion (I/R) injury. A rat model of middle cerebral artery occlusion (MCAO) followed by complete reperfusion, as well as a cortex neuron oxygen-glucose deprivation (OGD) model was established. When compared with BMSCs or oxiracetam monotherapy, combination therapy significantly improved functional restoration with decreased infarct volume in observed ischemic brain. We propose that it may occur through the transient receptor potential canonical (TRPC)6 neuron survival pathway. The increased expression of TRPC6 along with the reduction of neuronal cell death in the OGD cortex neurons and combination therapy group indicated that the TRPC6 neuron survival pathway plays an important role in the combined BMSCs and oxiracetam treatments. We further tested the activity of the calpain proteolytic system, and the results suggested that oxiracetam could protect the integrity of TRPC6 neuron survival pathway by inhibiting TRPC6 degradation. The protein levels of phospho-cAMP response element binding protein (p-CREB) were tested. It was found that BMSCs play a role in the activation of the TRPC6 pathway. Our study suggests that the TRPC6 neuron survival pathway plays a significant role in the protective effect of combined BMSCs and oxiracetam treatments on acute cerebral I/R injury. Combined therapy could inhibit the abnormal degradation of TRPC6 via decreasing the activity of calpain and increasing the activation of TRPC6 neuron survival pathway.