TRPA1 channel mediates organophosphate-induced delayed neuropathy

Abstract

The organophosphate-induced delayed neuropathy (OPIDN), often leads to paresthesias, ataxia and paralysis, occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate (OP) insecticides or nerve agents, and may contribute to the Gulf War Syndrome. The acute phase of OP poisoning is often attributed to acetylcholinesterase inhibition. However, the underlying mechanism for the delayed neuropathy remains unknown and no treatment is available. Here we demonstrate that TRPA1 channel (Transient receptor potential cation channel, member A1) mediates OPIDN. A variety of OPs, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels. Malathion increases the intracellular calcium levels and upregulates the excitability of mouse dorsal root ganglion neurons in vitro. Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors, which resembles OPIDN. Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene. In the classic hens OPIDN model, malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate (TOCP), which also activates TRPA1 channel. Treatment with HC030031 reduces the damages caused by malathion or tri-ortho-cresyl phosphate. Duloxetine and Ketotifen, two commercially available drugs exhibiting TRPA1 inhibitory activity, show neuroprotective effects against OPIDN and might be used in emergency situations. The current study suggests TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN.

Pregnancy exposure of titanium dioxide nanoparticles causes intestinal dysbiosis and neurobehavioral impairments that are not significant postnatally but emerge in adulthood of offspring

“…Delayed neurobehavioral impairment is commonly defined as a delayed onset of neurotoxic effects on behaviors resulting from a single or repeated exposure to environmental xenobiotics [ 47 ]. The delayed neurotoxic effects have been reported in some chemicals, such as organophosphates [ 48 ] and PCB126 [ 49 ], with the absence of symptoms associated with acute toxicity. These delayed toxic effects of TiO 2 NPs have not been reported at present, although the neurobehavioral impairments induced by TiO 2 NPs have been extensively studied.…”

Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review)

“…Organophosphate-induced delayed neurotoxicity refers to a series of neurological symptoms that occur within 1-3 weeks after the ingestion of organophosphorus compounds ( 68 ). A study from the Shanghai Institute of Pharmacy, Chinese Academy of Sciences, discovered that TRPA1 is the major mediator of delayed neuropathy ( 69 ). In the same study, verapamil (an L-type Ca 2+ channel blocker that effectively relieves the symptoms of the disease) was indicated to have a neuroprotective role by inhibiting TRPA1-mediated Ca 2+ influx.…”

Catalytic Hydrolysis of Tricresyl Phosphate by Ruthenium (III) Hydroxide and Iron (III) Hydroxide towards Sensing Application

“…Bilateral degeneration of sensory and motor functions follows acute toxic exposure, and the chance of recovering full motor coordination is poor. Long-term exposure to ToCP can induce a delayed neurodegenerative condition recognized as organophosphorous-induced delayed neuropathy (OPIDN) [12][13][14]. The other isomers of TCP have also been found functional on the inhibition of enzymes in human beings [6,[15][16][17][18] and on the formation of axon-like processes, as well as on the disruption of neurofilaments in cultured cells [19].…”