title: Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition.
abstract: 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. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic-clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABAA receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA-induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition.
authors.affiliation: F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Neuromodulation Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gersner
authors.affiliation: Department of Neurology, The Agnes Ginges Center of Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Ekstein
authors.affiliation: F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Neuromodulation Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Dhamne
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Schachter
authors.affiliation: F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Neuromodulation Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: alexander.rotenberg@childrens.harvard.edu.
authors.forename: A
authors.initials: A
authors.lastname: Rotenberg
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000470:Alkaloids; D000927:Anticonvulsants; D012717:Sesquiterpenes; C050426:huperzine A; D010433:Pentylenetetrazole
keywords: Cortical inhibition; Huperzine A; PTZ; Paired-pulse TMS; Rat