Insights from zebrafish and mouse models on the activity and safety of ar-turmerone as a potential drug candidate for the treatment of epilepsy

PLoS One. 2013 Dec 13;8(12):e81634. doi: 10.1371/journal.pone.0081634. eCollection 2013.

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.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / pharmacology
  • Behavior, Animal / drug effects
  • Blood-Brain Barrier*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Injections, Intraperitoneal
  • Ketones / pharmacokinetics*
  • Ketones / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Pentylenetetrazole
  • Postural Balance / drug effects
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / metabolism
  • Seizures / physiopathology
  • Sesquiterpenes / pharmacokinetics*
  • Sesquiterpenes / pharmacology
  • Zebrafish

Substances

  • Anticonvulsants
  • Brain-Derived Neurotrophic Factor
  • Ketones
  • Proto-Oncogene Proteins c-fos
  • Sesquiterpenes
  • ar-turmerone
  • Pentylenetetrazole

Grant support

AMOP was partially funded through a fellowship from the Vlaamse Interuniversitaire Raad (VLIR) "Pharmacological Characterization of Medicinal Plants from the South of Ecuador" Project. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.