title: Insights from zebrafish and mouse models on the activity and safety of ar-turmerone as a potential drug candidate for the treatment of epilepsy.
abstract: In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, β-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium ; Facultad de Ciencias Químicas, Escuela de Bioquímica y Farmacia, Universidad de Cuenca, Cuenca, Ecuador.
authors.forename: Adriana Monserrath
authors.initials: AM
authors.lastname: Orellana-Paucar
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Afrikanova
authors.affiliation: Laboratory for Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Leuven, Belgium.
authors.forename: Joice
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Laboratory for Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Leuven, Belgium.
authors.forename: Yelaman K
authors.initials: YK
authors.lastname: Aibuldinov
authors.affiliation: Laboratory for Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Peter A M
authors.initials: PA
authors.lastname: de Witte
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Camila V
authors.initials: CV
authors.lastname: Esguerra
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D004856:Postural Balance / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012717:Sesquiterpenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D007659:Ketones; D016760:Proto-Oncogene Proteins c-fos; D012717:Sesquiterpenes; C078098:ar-turmerone; D010433:Pentylenetetrazole