Scientists in China have uncovered a potential therapy for delayed brain injury caused by acute exposure to insecticides or chemical weapons. The study is published in the journal Cell Discovery.
Organophosphates (OP) are chemical compounds found in insecticides, herbicides, and nerve agents such as sarin. Although acute OP poisoning can be fatal, the initial symptoms are treatable. However, delayed neuropathy often occurs one to five weeks after exposure. At this stage, no effective treatments are available.
OPs are known to damage sensory neurons by activating a channel, called TRPA1, in the neuron cell membrane. TRPA1 mediates the movement of calcium ions into neurons which leads to their activation and the physiological effects of smell, taste, vision and temperature.
TRPA1 is normally activated in response to cold temperatures of environmental stimuli and is associated with producing cold sensation, coughing, itching and pain. Hyperactivation of the neuron is known to cause neuronal damage and symptoms that include burning pains on the skin, loss of muscle control and paralysis.
In this study, scientists found that the OP activated TRPA1, causing an influx of calcium ions into the neuron. They also showed that neurons stimulated by the OP produced a current and showed signs of electrical activation commonly seen in active neurons, which could lead to nerve damage if prolonged.
Importantly, 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. This suggested that OPs specifically target TRPA1 to damage neurons.
"In our study we have begun to unravel the biological mechanism which causes OP-induced delayed neuropathy," said Dr. Gao Zhaobing, lead author from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
"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. Further research will need to be conducted to assess the applicability of our findings to humans," he added.
