TrkA Pathway(s) are Involves in the Regulation of TRPM2 and TRPM7 Expression in the Substantia Nigra of the Parkinson’s Disease Rat Model Induced by 6-Hydroxydopamine

Abstract

Recently, it was demonstrated that the transient receptor potential melastatin 2 (TRPM2) and melastatin 7 (TRPM7) played a key role in ROS-induced neuronal death. Meanwhile, nerve growth factor (NGF), through activating tropomyosin-related kinase A (TrkA) pathway, is known to have survival and differentiation effects on neuronal cells. To mediate these actions, NGF binds to the high affinity neurotrophin receptor TrkA to trigger the intracellular signaling cascades. Two kinases whose activities mediate these processes are phosphatidylinositol 3-kinase (PI-3K) and ras/mitogen-activated protein kinase (MAPK). In this study, the Parkinson’s disease rat model induced by 6-hydroxydopamine (6-OHDA) was employed. TRPM7 and TRPM2 were found residing on dopaminergic neuronal body and process, and the effect of TrkA was concurrently observed on TRPM2 and TRPM7 in the cell body by immunohistochemistry staining. There was an increasing up-regulation of TRPM7 and TRPM2 expressions in the substantia nigra (SN) of the Parkinson’s disease (PD) rat model at one week after 6-OHDA injection. The levels of TRPM2 and TRPM7 in the PD group were reversed by intracerebroventricular injection of NGF (500ng) 30 min before 6-OHDA injection, and the effect of NGF was completely abolished by co-injection of TrkA inhibitor K252a. In addition, when Wortmannin and U0126 were introduced to block PI-3K and MAPK pathways respectively, only PI-3K inhibitor wortmannin substantially abolished NGF effects. These results suggest that TrkA, after being activated by NGF, can inhibit up-regulation of TRPM2 and TRPM7 expressions in the SN neurons injured by 6-OHDA through PI-3K signal pathway. These findings open a new way for further investigation of the potential roles of TRPM2, TRPM7 and NGF in the pathogenesis of PD.