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Nerve agents: Research could result in new therapies for attack victims

Image: Health Science Center

Research from neuroscientists at the College of Medicine may lead to new drug therapies for victims of nerve agent attacks.

Samba Reddy, professor, Department of Neuroscience and Experimental Therapeutics, recently published two papers showing why current therapies fail to break the chemically induced neuronal circuit that causes seizures and brain cell death—and what type of drug might be better.

Organophosphate (OP) nerve agents, used as chemical warfare weapons in combat or as bioterror agents against civilians, have severe, fast-acting effects on the body. These compounds interfere with brain chemicals that turn neurons and muscles “on” and “off.”

Two major therapeutic drugs are used to reverse the effects of OP nerve agents: diazepam and midazolam, which are benzodiazepine anticonvulsants that can work to prevent OP-induced brain damage and seizures, if given very soon after exposure. Both drugs are very effective antidotes when given within 30 minutes of OP exposure, but do not have much effect after an hour or two after exposure. In the context of chemical warfare and unexpected civilian bioterrorism, this is not a realistic timeline.

“Although soldiers often carry auto-injectors of a drug to use on themselves in case of a nerve agent attack, in civilian populations, the quickest midazolam could be administered after calling 911 and getting to the hospital would likely be at least 40 minutes,” Reddy said. “That is the critical time period, so any anticonvulsant antidote for these OP chemical seizures has to work even after 40 minutes. That is the goal.”

Reddy published two papers in the journals Biochim Biophys Acta and the Journal of Pharmacology and Experimental Therapeutics, co-authored by two members of his research staff, Ramkumar Kuruba and Xin Wu.

In the research reported in these articles, Reddy’s team examined two major points for diazepam and midazolam. First, they examined how efficiently each medication suppressed seizures. Second, they looked at how efficiently each drug protected against brain damage. The results of both studies showed that diazepam and midazolam were very effective when given 10 minutes after exposure. However, both medications were completely ineffective when administered at 60 minutes or 120 minutes after exposure.

“The benzodiazepines don’t control seizures at later time points, but it’s not because they aren’t reaching enough quantities in the brain,” Reddy said. “The three main reasons are the loss of target receptors, the loss of neurons and damage-induced inflammation.”

Reddy and his team are developing innovative injectable neurosteroid products for approval by the Food and Drug Administration, which could be revolutionary for both military members and civilian victims of nerve agent attacks.

“There is an urgent need to develop next-generation anticonvulsants antidotes superior to midazolam for better treatment of OP and nerve agent poisoning,” Reddy said.