Epilepsy is a chronic neurological
disorder, characterized by recurrent,
spontaneous, and transient seizures, and affects more than 70 million
people worldwide. Although two dozen antiepileptic drugs (AEDs) are
approved and available in the market, seizures remain poorly controlled
in one-third of epileptic patients who are suffering from drug resistance
or various adverse effects. Recently, the xanthone skeleton has been
regarded as an attractive scaffold for the discovery and development
of emerging anticonvulsants. We had isolated several dihydroxanthone
derivatives previously, including oliganthin H, oliganthin I, and
oliganthin N, whose structures were similar and delicately elucidated
by spectrum analysis or X-ray crystallographic data, from extracts
of leaves of Garcinia oligantha. These xanthone analogues
were evaluated for anticonvulsant activity, and a novel xanthone,
oliganthin H, has been identified as a sound and effective natural
inhibitor of convulsions in zebrafish in vivo. A
preliminary structure–activity relationship analysis on the
relationship between structures of the xanthone analogues and their
activities was also conducted. Oliganthin H significantly suppressed
convulsant behavior and reduced to about 25% and 50% of PTZ-induced
activity, in 12.5 and 25 μM treatment groups (P < 0.01 and 0.001), respectively. Meanwhile, it reduced seizure
activity, velocity, seizure duration, and number of bursts in zebrafish
larvae (P < 0.05). Pretreatment of oliganthin
H significantly restored aberrant induction of gene expressions including npas4a, c-fos, pyya, and bdnf, as well as gabra1, gad1, glsa, and glula, upon PTZ treatment.
In addition, in silico analysis revealed the stability
of the oliganthin H–GABAA receptor complex and their detailed
binding pattern. Therefore, direct interactions with the GABAA receptor
and involvement of downstream GABA–glutamate pathways were
possible mechanisms of the anticonvulsant action of oliganthin H.
Our findings present the anticonvulsant activity of oliganthin H,
provide a novel scaffold for further modifications, and highlight
the xanthone skeleton as an attractive and reliable resource for the
development of emerging AEDs.