TRPV4 modulation participates in paraoxon-induced brain injury via NMDA and NLRP3 regulation

ABSTRACT

Background

Organophosphorus pesticide poisoning can lead to severe brain damage, but the specific mechanisms involved are not fully understood. Our research aims to elucidate the function of the TRPV4 ion channel in the development of brain injury induced by paraoxon (POX).

Methods

In vivo, we examined the survival rate, behavioral seizures, histopathological alterations, NMDA receptor phosphorylation, as well as the expression of the NLRP3-ASC-caspase-1 complex and downstream inflammatory factors in the POX poisoning model following intervention with the TRPV4 antagonist GSK2193874. In vitro, we investigated the effects of GSK2193874 on NMDA-induced inward current, cell viability, cell death rate, and Ca²⁺ accumulation in primary hippocampal neurons.

Results

The treatment with the TRPV4 antagonist increased the survival rate, suppressed the status epilepticus, improved pathological damage, and reduced the phosphorylation level of NMDA receptors after POX exposure. Additionally, it inhibited the upregulation of NLRP3 inflammasome and inflammatory cytokines expression after POX exposure. Moreover, the TRPV4 antagonist corrected the NMDA-induced increase in inward current and cell death rate, decrease in cell viability, and Ca²⁺ accumulation.

Conclusion

TRPV4 participates in the mechanisms of brain injury induced by POX exposure through NMDA-mediated excitotoxicity and NLRP3-mediated inflammatory response.

KEYWORDS:

• Organophosphorus pesticide
• brain injury
• TRPV4
• NMDA
• NLRP3

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval

All of the animal experiments were approved by the Animal Ethics Committee of Xinyang Normal University.

Additional information

Funding

This work was supported by the Key Scientific Research Project of Colleges and Universities in Henan Province [No. 24A330004].