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 reversibly inhibits acetylcholinesterase and reduces glutamate-induced neuronal death as an NMDA receptor antagonist. We previously reported that huperzine potently protects mice against clonic seizures induced by s.c. pentylenetetrazol at 1 mg/kg (White, 2005) with a TD[sub]50[/sub] of 0.83 mg/kg. We now report results from the 6-Hz model of psychomotor seizures., Anesthetic/electrolyte solution (0.5% tetracaine hydrochloride in 0.9% saline) was applied to the eyes of male, 18-25 g CF1 mice (Charles River Laboratories, Wilmington, MA) prior to placement of corneal electrodes. Seizures induced by 6-Hz corneal stimulation (Barton, 2001) using three levels of stimulation [ndash] 22, 32 and 44 mA [ndash] (3 sec duration) were assessed at various times after i.p. administration of 0.09 [ndash] 1.1 mg/kg HupA. Median effective doses (ED[sub]50[/sub]) and 95% confidence intervals were calculated for each the three current stimulations evaluated., ED[sub]50 [/sub]values for i.p. HupA were 0.28, 0.34 and 0.78 mg/kg for 22, 32, and 44 mA, respectively. The following results were observed at the highest doses tested at each stimulation level: at 22 mA, 7/8 animals were protected with a dosage of 0.7 mg/kg; at 32 mA, 8/8 animals were protected with 0.83 mg/kg; and at 44 mA, 6/8 animals were protected with 1.1 mg/kg., HupA produced a potent anticonvulsant effect in the 6-Hz model of psychomotor seizures at all stimulation levels tested and with ED[sub]50 [/sub]values less than the TD[sub]50[/sub], suggesting a possible advantage over phenytoin, carbamazepine, lamotrigine and topiramate, each of which display limited efficacy in this model at doses devoid of behavioral toxicity. Further, the less than 2-fold ratio of dosages effective across the range of stimulations suggests a possible advantage over other drugs active in this model such as levetiracetam. These findings and the known action of huperzine as an NMDA receptor antagonist warrant further pre-clinical and clinical evaluation.

Barton ME et al. Epilepsy Res 2001;47:217-27.
White HS et al. Epilepsia 2005;46(suppl 8):220., (Supported by: The investigators gratefully acknowledge the support of the NINDS Anticonvulsant Screening Project and a grant from The Epilepsy Project (S.S.).)