Branch of cerebral vascular diseases, Department of Neurosurgery, General Hospital of Southern Theater Command of PLA, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, China; Department of Neurology, Chenzhou No. 1 People's Hospital, Chenzhou, 423000, Hunan, China.
Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, 400000, China; Institute of Brain and Intelligence, Army Medical University, Chongqing, 400000, China.
Behav Brain Res. 2022 Sep 5;433:113997. doi: 10.1016/j.bbr.2022.113997. Epub 2022 Jul 5.
Effective treatment for cognitive dysfunction after traumatic brain injury (TBI) is lacking in clinical practice. Increased brain-derived neurotrophic factor (BDNF) expression in cognitive circuits can significantly alleviate cognitive dysfunction in animal models of TBI. Selective 5-hydroxytryptamine receptor 6 (5-HTR) agonists significantly increase BDNF expression and improve cognitive function. Therefore, we evaluated the protective effect of a highly selective 5-HTR agonist, WAY-181187, on cognitive dysfunction after TBI. We established a controlled cortical impact model of moderate TBI in rats and performed drug intervention for five consecutive days. Rats had spatial reference memory impairment in the Morris water maze one and four weeks after TBI. BDNF expression in the medial prefrontal cortex (mPFC) and hippocampus decreased two and five weeks after TBI. Additionally, five weeks after TBI, decreases in neuronal dendritic spine density and the proportion of thin, mushroom-shaped dendritic spines and an increased proportion of stubby-type dendritic spines were observed. WAY-181187 administration (3 mg/kg) for five consecutive days after TBI significantly alleviated cognitive dysfunction at one and four weeks (P < 0.001 and P < 0.01), upregulated BDNF expression in the mPFC and hippocampus at two (P < 0.01 and P < 0.05) and five (P < 0.01 and P < 0.001) weeks and increased the dendritic spine density and the proportions of thin, mushroom-shaped dendrites in the mPFC (P < 0.05, P < 0.001 and P < 0.01) and hippocampus (P < 0.05, P < 0.001 and P < 0.05) at five weeks after TBI. Our results confirm that WAY-181187 administration (3 mg/kg) in the acute phase alleviated cognitive dysfunction after TBI, possibly by upregulating BDNF expression in the mPFC and hippocampus, enhancing neuroplasticity.
创伤性脑损伤（TBI）后认知功能障碍的有效治疗方法在临床实践中仍缺乏。增加认知回路中的脑源性神经营养因子（BDNF）表达可显著缓解 TBI 动物模型中的认知功能障碍。选择性 5-羟色胺受体 6（5-HTR）激动剂可显著增加 BDNF 表达并改善认知功能。因此，我们评估了高度选择性 5-HTR 激动剂 WAY-181187 对 TBI 后认知功能障碍的保护作用。我们在大鼠中建立了中度 TBI 的皮质撞击模型，并连续五天进行药物干预。TBI 后 1 周和 4 周，大鼠在 Morris 水迷宫中出现空间参考记忆障碍。TBI 后 2 周和 5 周，内侧前额叶皮质（mPFC）和海马中的 BDNF 表达下降。此外，TBI 后 5 周，神经元树突棘密度降低，薄蘑菇状树突棘的比例降低，短粗型树突棘的比例增加。TBI 后连续 5 天给予 WAY-181187（3mg/kg）治疗可显著改善 1 周和 4 周时的认知功能障碍（P<0.001 和 P<0.01），并上调 mPFC 和海马中 BDNF 的表达在 2 周（P<0.01 和 P<0.05）和 5 周（P<0.01 和 P<0.001），增加 mPFC（P<0.05，P<0.001 和 P<0.01）和海马（P<0.05，P<0.001 和 P<0.05）中薄蘑菇状树突棘的比例。我们的结果证实，TBI 急性期给予 WAY-181187（3mg/kg）治疗可减轻 TBI 后的认知功能障碍，可能是通过上调 mPFC 和海马中的 BDNF 表达，增强神经可塑性。
