TGF-β1 Protects Trauma-injured Murine Cortical Neurons by Upregulating L-type Calcium Channel Cav1.2 via the p38 Pathway

Abstract

Traumatic brain injury (TBI) is a leading cause of disability and death in adolescents, and there is a lack of effective methods of treatment. The neuroprotective effects exerted by TGF-β1 can ameliorate a range of neuronal lesions in multiple central nervous system diseases. In this study, we used an in-vitro TBI model of mechanical injury on murine primary cortical neurons and the neuro-2a cell line to investigate the neuroprotective role played by TGF-β1 in cortical neurons in TBI. Our results showed that TGF-β1 significantly increased neuronal viability and inhibited apoptosis for 24 h after trauma. The expression of Cav1.2, an L-type calcium channel (LTCC) isoform, decreased significantly after trauma injury, and this change was reversed by TGF-β1. Nimodipine, a classic LTCC blocker, abolished the protective effect of TGF-β1 on trauma-induced neuronal apoptosis. The knockdown of Cav1.2 in differentiated neuro-2a cells significantly inhibited the anti-apoptosis effect of TGF-β1 exerted on injured neuro-2a cells. Moreover, TGF-β1 rescued and enhanced the trauma-suppressed neuro-2a intracellular Ca2+ concentration, while the effect of TGF-β1 was partially inhibited by nimodipine. TGF-β1 significantly upregulated the expression of Cav1.2 by activating the p38 MAPK pathway and by inhibiting trauma-induced neuronal apoptosis. In conclusion, TGF-β1 increased trauma-injured murine cortical neuronal activity and inhibited apoptosis by upregulating Cav1.2 channels via activating the p38 MAPK pathway. Therefore, the TGF-β1/p38 MAPK/Cav 1.2 pathway has the potential to be used as a novel therapeutic target for TBI.