A team of scientists from Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences has identified a potential new therapy for the currently untreatable delayed neuropathy caused by organophosphate（OP) that attack the nervous system.

OPs are the active ingredient of many insecticides, herbicides, and nerve agents such as sarin and are also widely used as solvents, plasticizers, and additives in industry. The study reveals a new biological mechanism underlying the neuropathy, as well as the potential drugs to treat it. The finding has been published online in the open access journal Cell Discovery.

In this study, scientists from SIMM found that organophosphates damage sensory neurons by activating TRPA1, a Ca²⁺ permeable non-selective cation channel, in the neuron cell membrane. Activation of TRPA1 caused hyperactivation of the neuron, which is known to cause neuronal damage and symptoms including burning pains on the skin, loss of muscle control and paralysis. Mice that were genetically engineered not to express TRPA1 in neuronal cells did not suffer the effects of OP poisoning that were seen in normal mice and their nerves showed no signs of damage.

TRPA1 mediates the translocation of Ca²⁺into neurons, which is an important process that leads to activation of a neuron and the physiological processes such as smell, taste, vision and temperature sensation. In addition, TRPA1 is also involved in various pathological processes, such as noxious cold sensation, coughing, itching and pain.Using several organophosphates commonly used in insecticides and industrial additives, the scientists found that the organophosphates activated TRPA1, causing an influx of Ca²⁺ into the neuron. They also showed that neurons stimulated by the organophosphates produced a current and showed signs of electrical activation commonly seen in active neurons.

Although acute organophosphate poisoning can be fatal, the initial symptoms are treatable. However, delayed neuropathy often occurs one to five weeks after exposure and at this stage no effective treatments are available.

Prof. GAO Zhaobing, lead author from SIMM, said: "In our study we have begun to unravel the biological mechanism which causes organophosphate-induced delayed neuropathy. Using our expertise in drug discovery we were also able to screen a Federal Drugs Administration approved drug library of around 2,000 drugs and identify two potent drugs, duloxetine and ketotifen, which alleviated the signs of neuropathy in an animal model."

Prof. Gao added: "Our study provides compelling evidence that TRPA1 mediates organophosphate-induced neuropathy and further research will need to be conducted to assess the applicability of our findings to humans."

This study is limited by the fact that all experiments were carried out in vitro or in animal models. However, the findings reveal a biological mechanism by which organophosphates interact with sensory neurons and present a novel explanation for how exposure to organophosphates leads to symptoms of neuropathy and nerve damage.

Full text links: https://www.nature.com/articles/celldisc201724

Figure: The schematic diagram of the nerve injuries induced by organophosphates and the neuroprotective effects of TRPA1 inhibitors (Image by Ding Qiang)

Contact：
GAO Zhaobing
Shanghai Institute of Materia Medica，
Chinese Academy of Sciences
Email: zbgao@simm.ac.cn

(Credit: GAO Zhaobing)