Department of Neurosurgery, the Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.
Brain Res Bull. 2022 Jan;178:17-28. doi: 10.1016/j.brainresbull.2021.11.003. Epub 2021 Nov 11.
Traumatic brain injury (TBI) is still one of the main causes of death and disability worldwide. Bmal1 (brain and muscle Arnt-like protein-1) is the most central factor of the circadian rhythms that control life and cells. Studies have shown that Bmal1 is involved in inflammation, oxidative stress, vasodilation, glucose and lipid metabolism. This study explored the effect of Bmal1 on secondary brain injury after TBI in rats and the possible mechanism. We established a rat model of TBI induced by the free fall of a weight in rats. The Western blotting and immunofluorescence results showed that the Bmal1 levels decreased in the cerebral cortex after TBI, especially at 48 h. The effects of Bmal1 levels on rats after TBI were evaluated by brain oedema measurement, adhesive removal tests, behavioural tests, and TUNEL and FJC staining. We found that the recombinant Bmal1 protein increased Bmal1 levels after TBI and reduced brain oedema, neurobehavioural injury, somatosensory disturbances, and nerve cell necrosis and apoptosis. The ELISA results showed that Bmal1 overexpression could reduce the inflammatory factors IL-4 and TNF-α after TBI. In contrast, inhibiting Bmal1 expression had the opposite effect. The changes in Bmal1 levels were closely related to the phosphorylation of p38 MAPK after TBI. In conclusion, a decrease in Bmal1 after TBI may exacerbate pathological symptoms in vivo by activating p38 MAPK phosphorylation.
创伤性脑损伤（TBI）仍然是全球范围内主要的死亡和残疾原因之一。Bmal1（脑和肌肉 ARNT 样蛋白-1）是控制生命和细胞的昼夜节律的最核心因素。研究表明，Bmal1 参与炎症、氧化应激、血管舒张、葡萄糖和脂质代谢。本研究探讨了 Bmal1 对大鼠 TBI 后继发性脑损伤的影响及其可能的机制。我们建立了大鼠自由落体致 TBI 的模型。Western blot 和免疫荧光结果表明，TBI 后皮质中 Bmal1 水平下降，尤其是在 48 h 时。通过脑水肿测量、粘贴去除试验、行为测试以及 TUNEL 和 FJC 染色评估 Bmal1 水平对 TBI 后大鼠的影响。我们发现，重组 Bmal1 蛋白增加了 TBI 后 Bmal1 水平，减少了脑水肿、神经行为损伤、感觉障碍和神经细胞坏死和凋亡。ELISA 结果表明，Bmal1 过表达可减少 TBI 后促炎因子 IL-4 和 TNF-α。相反，抑制 Bmal1 表达则有相反的效果。Bmal1 水平的变化与 TBI 后 p38 MAPK 磷酸化密切相关。总之，TBI 后 Bmal1 的减少可能通过激活 p38 MAPK 磷酸化使体内病理症状恶化。
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