The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, The First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu, China.
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Jiangsu, China.
Neuroscience. 2022 Jul 1;494:51-68. doi: 10.1016/j.neuroscience.2022.02.003. Epub 2022 Feb 11.
Neuron apoptosis is a feature of secondary injury after traumatic brain injury (TBI). Evidence implies that excess calcium (Ca) ions and reactive oxidative species (ROS) play critical roles in apoptosis. In reaction to increased ROS, the anti-oxidative master transcription factor, Transient receptor potential Ankyrin 1 (TRPA1) allows Ca ions to enter cells. However, the effect of TBI on the expression of TRPA1 and the role of TRPA1 in TBI are unclear. In the present study, TBI in the mouse brain was simulated using the weight-drop model. The process of neuronal oxidative stress was simulated in HT22 neuronal cells by treatment with hydrogen peroxide. We found that TRPA1 was significantly upregulated in neurons at 24 h after TBI. Neuronal apoptosis was increased in the in vivo and in vitro models; however, this increase was reduced by the functional inhibition of TRPA1 in both models. After TBI, TRPA1 was upregulated via nuclear factor, erythroid 2 like 2 (Nrf2) in neurons. TRPA1-mediated neuronal apoptosis after TBI might be achieved in part through the CaMKII/AKT/ERK signaling pathway. To sum up, TBI-triggered TRPA1 upregulation in neurons is mediated by Nrf2 and the functional blockade of TRPA1 attenuates neuronal apoptosis and improves neuronal dysfunction, partially mediated through the activation of the calcium/calmodulin dependent protein kinase II (CaMKII) extracellular regulated kinase (ERK)/protein kinase B (AKT) signaling pathway. Our results suggest that functional blockade of TRPA1 might be a promising therapeutic intervention related to ROS and Nrf2 in TBI.
神经元凋亡是创伤性脑损伤 (TBI) 后继发性损伤的一个特征。有证据表明，过量的钙离子 (Ca) 和活性氧 (ROS) 在细胞凋亡中发挥关键作用。为了应对增加的 ROS，抗氧化主转录因子瞬时受体电位锚蛋白 1 (TRPA1) 允许 Ca 离子进入细胞。然而，TBI 对 TRPA1 表达的影响以及 TRPA1 在 TBI 中的作用尚不清楚。在本研究中，使用重物坠落模型模拟小鼠脑损伤。通过用过氧化氢处理 HT22 神经元细胞来模拟神经元氧化应激过程。我们发现，TBI 后 24 小时神经元中 TRPA1 表达显著上调。体内和体外模型中神经元凋亡增加；然而，在两种模型中，TRPA1 的功能抑制均可减少这种增加。TBI 后，神经元中核因子，红系 2 样 2 (Nrf2) 上调 TRPA1。TRPA1 介导的 TBI 后神经元凋亡可能部分通过钙调蛋白依赖性蛋白激酶 II (CaMKII)/蛋白激酶 B (AKT)/细胞外调节激酶 (ERK) 信号通路实现。总之，TRPA1 在神经元中的上调是由 Nrf2 介导的，TRPA1 的功能阻断可减轻神经元凋亡和改善神经元功能障碍，部分通过钙调蛋白依赖性蛋白激酶 II (CaMKII)/蛋白激酶 B (AKT)/细胞外调节激酶 (ERK) 信号通路的激活来实现。我们的结果表明，TRPA1 的功能阻断可能是一种有前途的治疗干预措施，与 TBI 中的 ROS 和 Nrf2 有关。
