In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions

Abstract

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.

Early-Stage High-Concentration Thiacloprid Exposure Induced Persistent Behavioral Alterations in Zebrafish

“…GABA-mediated neurotransmission starts at the early stage of fish development, which begins after the patterning of the spinal cord and hindbrain, regulating the circuitry underlying locomotor behaviors (e.g., rhythmic swimming response) [ 50 ]. Gad1b encodes glutamic acid decarboxylase, converting glutamate into GABA [ 51 ]. Abat encodes the key rate-limiting enzyme for GABA degradation [ 52 ].…”

“…No significant alteration of glsa expression was observed, indicating that THCP may not affect the synthesis of the raw material of GABA. GABA A receptor (encoded by gabra1 ) is universally found in mature neurons, taking part in mediating majority of fast inhibitory transmission [ 51 ]. It was reported that the up-regulation of gabra1 can suppress stress- or anxiety-related behavior of zebrafish [ 55 ].…”

6-Gingerol, a Major Constituent of Zingiber officinale Rhizoma, Exerts Anticonvulsant Activity in the Pentylenetetrazole-Induced Seizure Model in Larval Zebrafish

“…Compounds with antiseizure activity diminish PTZ-induced hyperlocomotion and decrease the number of LFP based epileptiform-discharges [ 7 , 14 ]. Using this model, the antiseizure activity of various plant-derived constituents have been identified, e.g., oliganthin H from Garcinia oligantha [ 15 ], palmatine from Berberis sibirica [ 13 ], indirubin from Indigofera arrecta [ 16 ], or bisabolene sesquiterpenoids from Curcuma longa [ 17 ].…”

Cytotoxic and Antiangiogenetic Xanthones Inhibiting Tumor Proliferation and Metastasis from Garcinia xipshuanbannaensis

“…According to the literature, ,,− cytotoxicity is one of the most frequently reported biological effects of xanthones, with cancer being a severe and enormous threat to human health. Thus, these isolates were subjected to cytotoxic evaluation using an MTT assay.…”