Antiepileptogenic and Anticonvulsant Effects of YM90K, a Selective AMPA‐Receptor Antagonist, in the Rat Kindling Model of Epilepsy
Authors: Kodama Masazumi , Kitamura Yoshihiro , Koyama Fumihiko , Sato Toshiki , Sato Keiko , Yamada Norihito , Kuroda Shigetoshi 
Published: August 2009

Purpose: We previously demonstrated that NBQX, a competitive AMPA‐receptor antagonist, significantly retards the development of kindling and suppresses fully kindled seizures. In contrast, however, it has also been reported that NBQX does not retard the development of kindling. In this study, to investigate the role of AMPA receptors in epileptic seizures, we examined the antiepileptogenic and anticonvulsant effects of YM90K [6‐(1H‐imidazol‐1‐yl)‐7‐nitro‐2,3‐(1H,4H)‐quinoxalinedione hydrochloride], a selective and potent AMPA‐receptor antagonist, in the rat amygdala kindling model of epilepsy.

Methods: Experiment 1: Investigation of the antiepileptogenic action of YM90K on the development of kindling. Twenty‐five Sprague‐Dawley rats, each bearing a tripolar electrode implanted into the left amygdala, were used. From days 2 to 9, rats received i.p. injections of either YM90K (7.5, 15, or 30 mg/kg) or saline 30 min before each electrical stimulation. From days 10 to 30, daily kindling stimulations were continued without drug administration. Experiment 2: Investigation of the anticonvulsant action of YM90K on fully kindled amygdaloid seizures. Eight rats previously kindled from the left amygdala were used. To determine whether the effect of YM90K was dose dependent, the rats were subjected to stimulation at the generalized seizure‐triggering threshold (GST) intensity, 30 min after i.p. administration of YM90K (7.5, 15, or 30 mg/kg) or saline. The effects of YM90K (15 mg/kg, i.p.) at various times (15 min‐4 h) between the injection and the stimulation also were examined. Furthermore, to determine the effect on GST, rats received the stimulation at twice the GST intensity, 30 min after i.p. administration of YM90K (15 mg/kg).

Results: Experiment 1: Pretreatment with YM90K markedly retarded the evolution of kindling during drug sessions in a dose‐dependent manner, as assessed in terms of both seizure stage and after discharge (AD) duration. In the YM90K‐treated group, the number of stimulations required to induce the first stage 2 or generalized stage 4 or 5 kindled seizure was greater than that in the saline‐treated group.

Experiment 2: The administration of YM90K significantly and dose‐dependently suppressed fully kindled seizures. None of the rats treated with 15 or 30 mg/kg of YM90K showed generalized seizures. The maximal effects were observed at 15–30 min after the injection, and the effects disappeared 1 h after the injection. At the GST intensity, only one rat showed generalized seizures, and five rats did not show ADS after i.p. administration of YM90K (15 mg/kg). On the other hand, the effects of YM9OK were reversed at twice the GST intensity. Six rats showed generalized seizures, and all rats showed ADS.

Conclusions: The role of AMPA receptors in the development of kindling is not yet fully understood. However, the effects of YM90K suggest that AMPA receptors participate in the development of kindling, as we previously reported with NBQX. It was also shown that YM90K has an anticonvulsant effect as potent as that of NBQX, on previously kindled seizures from the amygdala in rats. It appears that the mechanism underlying the anticonvulsant effect differs between the two AMPA receptor antagonists (i.e., YM90K increases the GST, whereas NBQX does not). These results indicate that AMPA receptors play an important role in the seizure‐expression mechanism and the development of kindling‐induced epileptogenesis.