Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs.

Abstract

Status epilepticus (SE) is a medical emergency associated with a high rate of mortality if not treated promptly. Exogenous and endogenous cannabinoids have been shown to possess anticonvulsant properties both in vivo and in vitro. Here we study the influence of endocannabinoid metabolism on the development of kainic acid-induced SE in guinea pigs. For this purpose, the inhibitors of endocannabinoid transport, AM404, and enzymatic (fatty acid amide hydrolase) degradation, URB597, were applied. Cannabinoid CB1 receptor antagonist, AM251, was also tested. Animal behavior as well as local electric field potentials in four structures: medial septum, hippocampus, entorhinal cortex and amygdala were analyzed when AM404 (120nmol), URB597 (4.8nmol) or AM251 (20nmol) were administrated alone or together with 0.4μg of kainic acid. All substances were injected i.c.v. AM404, URB597 or AM251 administered alone did not alter markedly local field potentials of all four studied structures in the long-term compared with their basal activity. AM404 and URB597 significantly alleviated kainic acid-induced SE, decreasing behavioral manifestations, duration of seizure events and SE in general without changing the amplitude of local field potentials. AM251 did not produce distinct effects on SE in terms of our experimental paradigm. There was no apparent change of the seizure initiation pattern when kainic acid was coadministrated with AM404, URB597 or AM251. The present study provides electrophysiologic and behavioral evidences that inhibition of endocannabinoid metabolism plays a protective role against kainic acid-induced SE and may be employed for therapeutic purposes. Further investigations of the influences of cannabinoid-related compounds on SE genesis and especially epileptogenesis are required.

• Authors: Liubov Shubina, Rubin Aliev, Valentina Kitchigina
• Journal: Epilepsy research (Epilepsy Res) Vol. 111 Pg. 33-44 (Mar 2015) ISSN: 1872-6844 [Electronic] Netherlands
• PMID: 25769371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Anticonvulsants
• Arachidonic Acids
• Benzamides
• Cannabinoid Receptor Antagonists
• Carbamates
• Endocannabinoids
• Piperidines
• Pyrazoles
• Receptor, Cannabinoid, CB1
• cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
• AM 251
• Amidohydrolases
• fatty-acid amide hydrolase
• Kainic Acid
• N-(4-hydroxyphenyl)arachidonylamide

Topics

• Amidohydrolases (metabolism)
• Animals
• Anticonvulsants (pharmacology)
• Arachidonic Acids (pharmacology)
• Benzamides (pharmacology)
• Biological Transport (drug effects)
• Brain (drug effects, physiopathology)
• Cannabinoid Receptor Antagonists (pharmacology)
• Carbamates (pharmacology)
• Endocannabinoids (metabolism)
• Guinea Pigs
• Kainic Acid
• Piperidines (pharmacology)
• Pyrazoles (pharmacology)
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
• Seizures (drug therapy, physiopathology)
• Status Epilepticus (drug therapy, physiopathology)