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(-)-Huperzine A is a natural product that acts as an NMDA receptor antagonist and reversible inhibitor of AChE (acetylcholinesterase), the enzyme primarily responsible for degradation of the neurotransmitter acetylcholine and termination of the acetylcholine synaptic signal. (-)-Huperzine A is the more potent stereoisomer of racemic (±)-Huperzine A (sc-218582) preparations, an approximately 38-fold more potent inhibitor of AChE than (+)-Huperzine A. Both the (-) and (+) stereoisomers also demonstrate NMDA receptor antagonism with similar affinity. Pretreatment of cerebral neuronal cells with (-)-Huperzine A confers protection against glutamate-mediated Ca2+ influx and excitotoxicity, moderated by blockade of NMDA-associated ion channel activity. Disruption of spatial memory induced by scopolamine (sc-203259) and muscimol (sc-200460) was reversed by introduction of (-)-Huperzine A. Excitotoxicity resulting from organophosphorous nerve agent-induced accumulation of acetylcholine, also mediated through NMDA receptor stimulation, is diminished by exposure to the enantiomer (+)-Huperzine A and preparations of (±)-Huperzine A are suggested for use in nerve agent protection. (-)-Huperzine A is demonstrated to suppress cerebral hypoperfusion-related inflammation through its indirect effects upon the nicotinic acetylcholine receptor.
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