TRPA1 channel mediates organophosphate-induced delayed neuropathy

doi:10.1038/celldisc.2017.24

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	TRPA1 channel mediates organophosphate-induced delayed neuropathy
	Ding, Qiang 3,4; Fang, Sui 3,4; Chen, Xueqin 3,4; Wang, Youxin 1; Li, Jian 5; Tian, Fuyun 3,4; Xu, Xiang 3,4; Attali, Bernard 2; Xie, Xin3,4 ; Gao, Zhaobing3,4
刊名	CELL DISCOVERY
	2017-08-01
卷号	3
关键词	organophosphate malathion TOCP OPIDN TRPA1
ISSN号	2056-5968
DOI	10.1038/celldisc.2017.24
文献子类	Article
英文摘要	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.
资助项目	National Key Scientific Instrument & Equipment Development Program of China[2012YQ03026010] ; Joint NSFC-ISF Research Program[8146114802] ; National Natural Science Foundation of China[00000000] ; Israel Science Foundation[00000000] ; State Key Program of Basic Research of China[2013CB910604] ; National Natural Science Foundation of China[61327014] ; National Natural Science Foundation of China[61175103]
WOS关键词	ORTHO-CRESYL PHOSPHATE ; TARGET ESTERASE ; COVALENT MODIFICATION ; TRICRESYL PHOSPHATE ; AQUEOUS-SOLUTION ; NERVOUS-SYSTEM ; ION-CHANNEL ; IN-VITRO ; EXPOSURE ; HENS
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000414918200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272535]
专题	神经药理学研究国际科学家工作站中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Gao, Zhaobing
作者单位	1.Shanghai Leado Pharmatech Co Ltd, Shanghai, Peoples R China; 2.Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, Tel Aviv, Israel 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai, Peoples R China; 4.Univ Chinese Acad Sci, Beijing, Peoples R China; 5.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Ding, Qiang,Fang, Sui,Chen, Xueqin,et al. TRPA1 channel mediates organophosphate-induced delayed neuropathy[J]. CELL DISCOVERY,2017,3.
APA	Ding, Qiang.,Fang, Sui.,Chen, Xueqin.,Wang, Youxin.,Li, Jian.,...&Gao, Zhaobing.(2017).TRPA1 channel mediates organophosphate-induced delayed neuropathy.CELL DISCOVERY,3.
MLA	Ding, Qiang,et al."TRPA1 channel mediates organophosphate-induced delayed neuropathy".CELL DISCOVERY 3(2017).