■有机磷农药中毒可导致严重的脑损伤,但是所涉及的具体机制还没有完全理解。我们的研究旨在阐明TRPV4离子通道在对氧磷(POX)引起的脑损伤发展中的功能。
■体内,我们检查了存活率,行为癫痫,组织病理学改变,NMDA受体磷酸化,以及TRPV4拮抗剂GSK2193874干预后POX中毒模型中NLRP3-ASC-caspase-1复合物和下游炎症因子的表达。体外,我们研究了GSK2193874对NMDA诱导的内向电流的影响,细胞活力,细胞死亡率,和原代海马神经元中的Ca2积累。
■用TRPV4拮抗剂治疗可提高生存率,抑制了癫痫持续状态,改善病理损伤,并降低POX暴露后NMDA受体的磷酸化水平。此外,它抑制POX暴露后NLRP3炎症小体和炎症细胞因子的表达上调。此外,TRPV4拮抗剂纠正了NMDA诱导的内向电流和细胞死亡率的增加,细胞活力降低,和Ca2+积累。
■TRPV4通过NMDA介导的兴奋性毒性和NLRP3介导的炎症反应参与POX暴露所致脑损伤的机制。
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: TRPV4 participates in the mechanisms of brain injury induced by POX exposure through
NMDA-mediated excitotoxicity and NLRP3-mediated inflammatory response.