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

• AM404, URB597 and AM251 administered alone did not alter LFPs in the long-term.
• Unilateral i.c.v. injection of KA induced long-lasting convulsive SE in guinea pigs.
• AM404 and URB597 alleviated motor and electrographic seizures during the SE.
• AM251 did not change seizure manifestations in terms of our experimental paradigm.

SummaryStatus 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 (120 nmol), URB597 (4.8 nmol) or AM251 (20 nmol) were administrated alone or together with 0.4 μg 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.