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

Shuai Wang1, Huanhuan He2, Yu Chen1

  • 1College of Medicine, Xinyang Normal University, Xinyang, China.

Brain Injury
|May 7, 2024
PubMed
Abstract

Insights

TRPV4 ion channel antagonism protects against organophosphorus pesticide poisoning brain injury by reducing excitotoxicity and inflammation. This finding offers new therapeutic targets for pesticide-induced neurotoxicity.

Area of Science:

  • Neuroscience
  • Toxicology
  • Pharmacology

Background:

  • Organophosphorus pesticide poisoning causes severe brain damage via poorly understood mechanisms.
  • The role of the TRPV4 ion channel in paraoxon (POX)-induced brain injury requires elucidation.

Purpose of the Study:

  • To investigate the function of the TRPV4 ion channel in POX-induced brain injury.
  • To evaluate the therapeutic potential of a TRPV4 antagonist (GSK2193874) in POX poisoning.

Main Methods:

  • In vivo studies assessed survival, seizures, neuropathology, NMDA receptor phosphorylation, and NLRP3 inflammasome activation in a POX model treated with GSK2193874.
  • In vitro experiments examined GSK2193874's effects on NMDA-induced currents, neuronal viability, cell death, and calcium influx in primary hippocampal neurons.

Main Results:

  • TRPV4 antagonist treatment improved survival, reduced seizures and neuropathology, and decreased NMDA receptor phosphorylation post-POX exposure.
  • GSK2193874 inhibited NLRP3 inflammasome and inflammatory cytokine upregulation following POX exposure.
  • In vitro, the TRPV4 antagonist normalized NMDA-induced currents, improved cell viability, and reduced cell death and calcium accumulation.

Conclusions:

  • TRPV4 plays a significant role in POX-induced brain injury.
  • TRPV4 mediates neurotoxicity through NMDA receptor-dependent excitotoxicity and NLRP3 inflammasome-driven inflammation.
  • Targeting TRPV4 offers a potential therapeutic strategy for organophosphorus pesticide poisoning.
Keywords:
NLRP3NMDAOrganophosphorus pesticideTRPV4brain injury

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