Hyperactivation of TRPV4 causes the hippocampal pyroptosis pathway and results in cognitive impairment in LPS-treated mice

上睑下垂 海马结构 基因敲除 海马体 神经科学 神经炎症 TRPV4型 促炎细胞因子 药理学 炎症体 医学 化学 炎症 生物 免疫学 内科学 瞬时受体电位通道 细胞凋亡 受体 生物化学
作者
Dongming Guo,Yang Xu,Yingge Wang,Xiaolin Zhong,Zhenghai Liu,Suyun Li,Xiaofan Xu,Jingwen Zhang,Tianqing Xiong,Wenyu Cao,Jingyan Liang
出处
期刊:Behavioural Brain Research [Elsevier BV]
卷期号:439: 114223-114223 被引量:5
标识
DOI:10.1016/j.bbr.2022.114223
摘要

Pyroptosis, a newly discovered proinflammatory programmed cell death, is involved in the regulation of cognitive dysfunction, such as Alzheimer's disease. Exploring potential drug targets that prevent pyroptotic procedures might benefit the development of a cure for these diseases. In the present study, we explored whether the transient receptor potential vanilloid 4 (TRPV4) blocker HC067047 and knockdown of TRPV4 in the hippocampus could improve cognitive behavior through the inhibition of pyroptosis in a mouse model developed using systemic administration of lipopolysaccharide (LPS). We found that systemic administration of HC067047 or knockdown of hippocampal TRPV4 prevented the activation of canonical and noncanonical pyroptosis in the hippocampus of LPS-treated mice. Consistent with the inhibition of the hippocampal pyroptosis pathway, a knockdown of hippocampal TRPV4 lowered expression of TNF-α, IL-1β, IL-18, and IL-6. Furthermore, we verified that the main pyroptosis cell type might be a neuron, indicated by reduced neuronal marker expression. Mechanically, we also found that knockdown of hippocampal TRPV4 might inhibit phosphorylation of CamkⅡα which results in NFκb mediated inflammasome reduction in the hippocampus of LPS-treated mice. More interestingly, mice intraperitoneally injected with HC067047 or the hippocampus injected with TRPV4 shRNA showed improved cognitive behavior, as indicated by the enhanced discrimination ratio in the NORT, NOPT, and SNPT. Collectively, we consider that HC067047 might be a small molecular drug that prevents pyroptosis, and TRPV4 could be an effective therapeutic target for preventing pyroptosis-induced cognitive dysfunction.
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