Abstracts

Huperzine A (HupA), a sesquiterpene alkaloid derived from Chinese club moss (Huperzia serrata), has traditionally been used in China for swelling, fever and inflammation. HupA crosses the blood-brain barrier and is a potent and reversible inhibitor of acetylcholinesterase. HupA also has been shown to reduce glutamate-induced neuronal death and act as an NMDA receptor antagonist. We therefore screened HupA for evidence of efficacy and toxicity in two animal seizure models. HupA was evaluated in the mouse maximal electroshock (MES) and s.c. Metrazol (pentylenetetrazol; s.c. Met) models of generalized tonic-clonic and myoclonic seizures, respectively following p.o. administration to Swiss-Webster mice. Minimal motor impairment was evaluated in the rotarod test. HupA was found to be active against s.c. Met- but not MES-induced seizures. Peak anticonvulsant activity was observed one-hour after p.o. administration of 1 mg/kg. At the doses tested (i.e., 1, 2, and 4 mg/kg), a maximum of 62.5% protection was observed at a non-toxic dose of 1 mg/kg. Behavioral motor impairment in 75 and 100% of mice tested was observed at doses of 2 and 4 mg/kg, respectively. HupA was found to display potent, but incomplete protection against clonic seizures induced by s.c. Met. These results demonstrated that HupA is orally bioavailable and reaches effective brain concentrations. Given that HupA is an NMDA receptor antagonist, it may also be effective as neuroprotective therapy for the prevention of epileptogenesis and seizure-induced neuronal toxicity. On-going studies are currently evaluating this hypothesis. (Supported by NINDS Contract NO1-NS-4-2359 (HSW) and a grant from The Epilepsy Project (S.S.).)