Department of Microbiology and Immunology, Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China.
Department of Neurosurgery, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Neuroscience. 2022 Jun 1;492:47-57. doi: 10.1016/j.neuroscience.2022.04.010. Epub 2022 Apr 20.
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 Ca1.2, 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 Ca1.2 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 Ca concentration, while the effect of TGF-β1 was partially inhibited by nimodipine. TGF-β1 significantly upregulated the expression of Ca1.2 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/Ca 1.2 pathway has the potential to be used as a novel therapeutic target for TBI.
创伤性脑损伤（TBI）是青少年残疾和死亡的主要原因，目前缺乏有效的治疗方法。TGF-β1 的神经保护作用可以改善多种中枢神经系统疾病中的一系列神经元损伤。在本研究中，我们使用体外机械损伤的原代鼠皮质神经元和神经-2a 细胞系 TBI 模型，研究了 TGF-β1 在皮质神经元中的神经保护作用。结果表明，TGF-β1 可显著提高神经元活力并抑制创伤后 24 小时的细胞凋亡。创伤后 Ca1.2 的表达（一种 L 型钙通道（LTCC）同工型）显著降低，TGF-β1 可逆转这种变化。尼莫地平，一种经典的 LTCC 阻滞剂，可消除 TGF-β1 对创伤诱导的神经元凋亡的保护作用。分化的神经-2a 细胞中 Ca1.2 的敲低显著抑制了 TGF-β1 对损伤神经-2a 细胞的抗凋亡作用。此外，TGF-β1 通过激活 p38 MAPK 通路和抑制创伤引起的神经元凋亡来挽救和增强神经-2a 细胞内的 Ca 浓度。TGF-β1 可部分抑制。TGF-β1 通过激活 p38 MAPK 通路显著上调 Ca1.2 的表达，从而增加损伤的鼠皮质神经元的活性并抑制凋亡。因此，TGF-β1/p38 MAPK/Ca1.2 通路有可能成为 TBI 的新治疗靶点。
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