The neuropathologic mechanisms after exposure to lethal doses of nerve agent are complex and involve multiple biochemical pathways. Effective treatment requires drugs that can simultaneously protect by reversible binding to the acetylcholinesterase (AChE) and blocking cascades of seizure related brain damage, inflammation, neuronal degeneration as well as promoting induction of neuroregeneration. (-)-Huperzine A ([-]-Hup A), is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier. It also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor.
METHODS AND RESULTS:
Toxicities at higher doses restrict the neuroporotective ability of (-)-Huperzine A for treatment. The synthetic stereoisomer, [+]-Hup A, is less toxic due to poor AChE inhibition and is suitable for both pre-/post-exposure treatments of nerve agent toxicity. [+]-Hup A block the N-methyl-D-aspartate (NMDA)-induced seizure in rats, reduce excitatory amino acid induced neurotoxicity and also prevent soman induced toxicity with minimum performance decrement. Unique combinations of two stereo-isomers of Hup A may provide an excellent pre/post-treatment drug for the nerve agent induced seizure/status epilepticus. We investigated a combination of [+]-Hup A with a small dose of (-)-Huperzine A ([+] and (-)-Huperzine A) against soman toxicity. Our data showed that pretreatment with a combination [+] and (-)-Huperzine A significantly increased the survival rate and reduced behavioral abnormalities after exposure to 1.2 × LD(50) soman compared to [+]-Hup A in guinea pigs. In addition, [+] and (-)-Huperzine A pretreatment inhibited the development of high power of EEG better than [+]-Hup A pretreatment alone.
CONCLUSIONS:
These data suggest that a combination of [+] and (-)-Huperzine A offers better protection than [+]-Hup A and serves as a potent medical countermeasure against lethal dose nerve agent toxicity in guinea pigs. |
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