title: 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.affiliation: Laboratory of Systemic Organization of Neurons, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation. Electronic address: shubina.lu@gmail.com.
authors.forename: Liubov
authors.initials: L
authors.lastname: Shubina
authors.affiliation: Laboratory of Biophysics of Active Media, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation; Computer Science Department, Moscow Institute of Physics and Technology, Moscow, Russian Federation; Department of Experimental Cardiology, Federal Clinical and Scientific Center for Federal Biomedical Agency of Russia, Moscow, Russian Federation.
authors.forename: Rubin
authors.initials: R
authors.lastname: Aliev
authors.affiliation: Laboratory of Systemic Organization of Neurons, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Pushchino, Moscow Region, Russian Federation; Department of Biophysics and Biomedicine, Pushchino State Life Science Institute, Pushchino, Moscow Region, Russian Federation.
authors.forename: Valentina
authors.initials: V
authors.lastname: Kitchigina
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism*; D006168:Guinea Pigs; D007608:Kainic Acid; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D013226:Status Epilepticus / Q000188:drug therapy* / Q000503:physiopathology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000927:Anticonvulsants; D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; D007608:Kainic Acid; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C107594:N-(4-hydroxyphenyl)arachidonylamide
keywords: AM251; AM404; Endocannabinoids; Local field potentials; Status epilepticus; URB597