Abstracts

Rationale: Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata. While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Previous work shows HupA anticonvulsant activity in the 6-Hz maximal electroshock mouse model. However, HupA has not been tested in other rodent epilepsy models, and the mechanism of its anticonvulsant efficacy remains unknown. Methods: We tested the antiepileptic capacity of systemic HupA in the rat pentylenetetrazole (PTZ) acute seizure model. We also applied paired-pulse transcranial magnetic stimulation (ppTMS) coupled with electromyography (EMG) to test whether HupA augments paired-pulse motor evoked potential inhibition in rats. We tested whether the HupA effect on the magnitude of paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA and the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic cholinergic receptors or GABA-A receptors by separate ppTMS measures that followed co-administration of HupA with atropine and PTZ, respectively. Results: HupA decreased the number of epileptic spikes on EEG (p=0.046) and increased the time to first myoclonus after PTZ injection (p<0.001). In addition, fast Fourier transformation analysis of the EEG revealed significantly enhanced power in the delta (p=0.012) and gamma (p<0.001) band frequencies, and decreased theta power (p=0.018) in the HupA-treated group. We also found that HupA increased paired-pulse cortical inhibition (p=0.033) and blocked PTZ-induced cortical excitation (p=0.036). The enhanced cortical inhibition was centrally-mediated and persisted (p=0.028) despite muscarinic acetylcholine receptor blockade. Conclusions: Our data support further development of HupA as an anticonvulsant and suggest that its antiepileptic potential may be via enhanced GABAergic cortical inhibition. We propose that HupA might be particularly useful in acquired epilepsies where the pathophysiology is characterized by loss of cortical inhibition.