Hippocampal HMGB1/TLR4 Pathway Mediates Cognitive Dysfunction in Chronic Stress Mice

海马HMGB1/TLR4通路介导慢性应激小鼠的认知功能障碍

Objective Chronic stress can induce cognitive dysfunction,but the underlying mechanisms remain unknown.Studies have confirmed that the high mobility group box 1/Toll-like receptor 4(HMGB1/TLR4)pathway is closely associated with cognitive impairment.Therefore,this research aimed to explore whether the HMGB1/TLR4 pathway involves in chronic stress-induced cognitive dysfunction.Methods The chronic unpredictable mild stress(CUMS)mouse model was established by randomly giving different types of stress every day for four consecutive weeks.Cognitive function was detected by novel object recognition test,Y-maze test,and Morris water maze test.The protein expressions of HMGB1,TLR4,B-cell lymphoma 2(BCL2),and BCL2 associated X(BAX)were determined by Western blot.The damage of neurons in the hippocampal CA1 region was observed by hematoxylin-eosin(HE)staining.Results The protein expressions of HMGB1 and TLR4 were significantly increased in the hippocampus of chronic stress mice.Furthermore,inhibition of the HMGB1/TLR4 pathway induced by ethyl pyruvate(EP,a specific inhibitor of HMGB1)and TAK242(a selective inhibitor of TLR4)treatment attenuated cognitive impairment in chronic stress mice,according to the novel object recognition test,Y-maze test,and Morris water maze test.In addition,administration of EP and TAK242 also mitigated the increase of apoptosis in the hippocampus of chronic stress mice.Conclusion These results indicate that the hippocampal HMGB1/TLR4 pathway contributes to chronic stress-induced apoptosis and cognitive dysfunction.

目的慢性应激可引起认知功能障碍,但其机制尚不清楚。研究已经证实,HMGB1/TLR4通路与认知障碍密切相关。本研究旨在探讨HMGB1/TLR4通路是否参与慢性应激诱导的认知功能障碍。方法采用慢性不可预知应激(CUMS)小鼠模型,连续4周每天随机给予不同类型的应激。采用新物体识别实验、Y迷宫实验和Morris水迷宫实验检测认知功能。蛋白质印迹法(Western blot)检测HMGB1、TLR4、BCL2和BAX蛋白的表达。苏木精-伊红(HE)染色观察海马CA1区神经元损伤。结果暴露于CUMS的小鼠海马HMGB1和TLR4蛋白表达明显升高。此外,根据新物体识别实验、Y迷宫和Morris水迷宫实验,丙酮酸乙酯(EP,HMGB1的特异性抑制剂)和TAK242(TLR4的选择性抑制剂)抑制HMGB1/TLR4通路可减轻慢性应激小鼠的认知障碍。此外,注射EP和TAK242还能缓解慢性应激小鼠海马细胞凋亡的增加。结论海马HMGB1/TLR4通路参与了慢性应激诱导的细胞凋亡和认知功能障碍。