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Sunday, December 5th, 2021

Lawrence Livermore scientists develop antidote to treat sarin exposure, research other nerve agents

Credit: LLNL

Nerve agent poisoning can result in a quick death, causing the central and peripheral nervous systems to shut down. For those fortunate enough to receive medical care and survive exposure, long-lasting side effects are probable, including seizures, extreme muscle spasms, and diminished mental functioning.

Now, scientists from Lawrence Livermore National Laboratory (LLNL) have announced the development of a new antidote that substantially counteracts the exposure of nerve agent poisoning. Their research appeared this summer in Scientific Reports and was a collaboration between LLNL’s Global Security Directorate, its Forensic Science Center, and the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD).

The antidote, labeled LLNL-02, was first identified by the researchers in 2017 after two years of experimentation, including 120 attempts to design compounds before finding a winning candidate. In subsequent years, the scientists achieved two milestones with LLNL-02: the compound crossed the blood-brain barrier, and it attacked the parts of the brain hijacked by the nerve agent sarin. The researchers described it like finding a needle in a haystack.

“It’s like you have to find a compound that not only was able to cross the blood-brain barrier, but it also needed to reactivate the enzyme,” said Carlos A. Valdez, LLNL lead chemist of the project.

That “enzyme,” acetylcholinesterase (AChE), is a key player in neurotransmission. When a nerve agent enters the body, it attaches itself to AChE, disrupting the enzyme’s ability to break down the neurotransmitter acetylcholine. This results in the buildup of the chemical acetylcholine in the brain. The accumulation causes organs to fail, and exposure becomes lethal when the muscles involved in respiration cease to work. LLNL-02 reverses that process.

The gold-standard antidote 2-PAM is currently used to treat exposure to sarin and provides effective protection of the peripheral nervous system when 2-PAM enters the bloodstream. The peripheral nervous system manages several functions including respiration. However, 2-PAM cannot offer protection to the central nervous system—which controls the brain and spinal cord— because it cannot travel through the blood-brain barrier.

“It’s a very complex protective layer that is composed of very tight cell junctions,” Valdez said. “You have cells that are very close to each other. That’s like a second level of protection the body has for this very special organ.”

This protective layer can make it challenging for many drug makers to create medications that can treat ailments that affect the brain. The LLNL team focused on compounds known as ‘reactivators’ that could reestablish the normal processes of AChE after a person was exposed to sarin. They also relied on powerful computational modeling techniques to narrow down the right compound.

Animal studies showed that 15 to 20 minutes after administering LLNL-02, the animals fully recovered from sarin exposure and their breathing returned to normal. Brain scans demonstrated that the drug crossed the blood-brain barrier. LLNL-02 was also found to be non-toxic to human cell lines.

The use of nerve agents has made the news in recent years. Individuals exposed to sarin gas during the Syrian civil war had less than 10 minutes after the attacks before the nerve agent caused severe injury and death. Beyond sarin, the scientists will investigate whether LLNL-02 works against nerve agents VX and the Novichoks, the latter of which gained attention in the assassination attempt of former Russian military intelligence officer Sergei Skripal and his daughter in 2018. Last year, a Novichok was also used against Russian lawyer and opposition leader Alexei Navalny, who received medical attention at a hospital in Berlin.

“We keep doing the research and we’re trying to find the other compounds that are hopefully more powerful than LLNL-02,” said Valdez of trying to discover drugs to treat a variety of nerve agents. “It’s an extremely challenging process but we have the resources and minds to tackle it.”

LLNL-02 is still in the development phase and will not be available for real-world application for several more years.

The LLNL research was sponsored by the Defense Threat Reduction Agency.