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

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 hip-pocampus 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-alpha, IL-1 beta, IL-18, and IL-6. Furthermore, we verified that the main pyroptosis cell type might be a neuron, indicated by reduced neuronal marker expression. Me-chanically, we also found that knockdown of hippocampal TRPV4 might inhibit phosphorylation of CamkII alpha which results in NF kappa b mediated inflammasome reduction in the hippocampus of LPS-treated mice. More inter-estingly, 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.

Automated summary

This study investigated whether a TRPV4 blocker and knockdown of TRPV4 could improve cognitive behavior affected by pyroptotic processes. The results showed that both the TRPV4 blocker and TRPV4 knockdown inhibited pyroptosis in the hippocampus of mice treated with lipopolysaccharide (LPS) and improved cognitive behavior.