The interaction of melatonin and agmatine on pentylenetetrazole-induced seizure threshold in mice

Melatonin, the major hormone produced by the pineal gland, has a number of functions in mammals, for example, its function as an anticonvulsant. Agmatine, a biogenic amine formed by decarboxylation of L-arginine by arginine decarboxylase, also has anticonvulsant effects. This study investigated the effect of the interaction of melatonin and agmatine on seizure susceptibility in the mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Further, the researchers investigated the involvement of melatonin receptors in this interaction using luzindole, a ML1/2 receptor antagonist and prazosin, a ML3 receptor antagonist. Melatonin, at 40 and 80 mg/kg, and agmatine, at 10 and 20 mg/kg, exerted anticonvulsant effects. Luzindole, at 1.25 and 2.5 mg/kg, or prazosin, at 0.5 mg/kg, did not change the seizure threshold as compared with that of vehicle-treated mice. The anticonvulsant effect of melatonin (40 and 80 mg/kg) was prevented by luzindole (2.5 mg/kg) (P < 0.001) but not prazosin (0.5 mg/kg), indicating the possible involvement of ML1/2 receptors in the anticonvulsant effect of melatonin. Agmatine (5 mg/kg) significantly increased the anticonvulsant effect of both the noneffective dose (20 mg/kg) (P < 0.05) and the effective dose (80 mg/kg) (P < 0.001) of melatonin. Luzindole (2.5 mg/kg), but not prazosin (0.5 mg/kg), decreased the anticonvulsant effect of agmatine (20 mg/kg) (P < 0.05). Luzindole (2.5 mg/kg), but not prazosin (0.5 mg/kg), also decreased the seizure threshold when agmatine (5 mg/kg) was administered before melatonin (20 mg/kg); the decrease was significant compared with that of the group that received only agmatine and melatonin (P < 0.001). In conclusion, melatonin and agmatine exhibit an additive effect in decreasing pentylenetetrazole-induced seizure threshold in mice, probably through ML1/2 receptors.

► Melatonin 40 and 80 mg/kg and agmatine 10 and 20 mg/kg had anticonvulsant effects in mice. ► The anticonvulsant effects of melatonin 40 and 80 mg/kg were prevented by luzindole 2.5 mg/kg, a ML1/2 receptor antagonist. ► Agmatine 5 mg/kg increased the anticonvulsant effect of both noneffective and effective doses of melatonin. ► Luzindole 2.5 mg/kg decreased the anticonvulsant effect of agmatine. ► Melatonin and agmatine exhibit an additive effect on decreasing threshold in mice, probably through ML1/2 receptors.