Agmatine exerts anticonvulsant effect in mice: modulation by alpha 2-adrenoceptors and nitric oxide.

The effect of agmatine, an endogenous polyamine metabolite, on seizure susceptibility was investigated in mice. Acute intraperitoneal administration of agmatine (5, 10, 20, 40 mg/kg) had a significant and dose-dependent inhibitory effect on pentylenetetrazole (PTZ)-induced seizures. The peak of this anticonvulsant effect was 45 min after agmatine administration. We further investigated the possible involvement of the alpha(2)-adrenoceptors and L-arginine/NO pathway in this effect of agmatine. The alpha(2)-adrenoceptor antagonist, yohimbine (0.5-2 mg/kg), induced a dose-dependent blockade of the anticonvulsant effect of agmatine. The nitric oxide synthase (NOS) substrate, L-arginine (60 mg/kg), inhibited the anticonvulsant property of agmatine and this effect was significantly reversed by NOS inhibitor N(G)-nitro-L-arginine (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for L-arginine effect. We further examined a possible additive effect between agmatine (1 or 5 mg/kg) and L-NAME (10 mg/kg). The combination of L-NAME (10 mg/kg) with agmatine (5 but not 1 mg/kg) induced a significantly higher level of seizure protection as compared with each drug alone. Moreover, a combination of lower doses of yohimbine (0.5 mg/kg) and L-arginine (30 mg/kg) also significantly decreased the anticonvulsant effect of agmatine. In conclusion, the present data suggest that agmatine may be of potential use in seizure treatment.

Lithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway.

Lithium has been reported to inhibit opioid-induced properties. The present study examined the effect of acute and chronic administration of lithium chloride (LiCl) on morphine's biphasic modulation of susceptibility to pentylenetetrazole (PTZ)-induced clonic seizure in mice. We also examined the possible involvement of nitric oxide (NO) pathway in lithium effect. Both acute (0.1 and 1 mg/kg) and chronic (same doses, 21 consecutive days) administration of LiCl completely inhibited the anticonvulsant and proconvulsant effects of morphine (at doses 1 and 30 mg/kg, respectively). A very low and per se noneffective dose of LiCl (0.05 mg/kg) significantly inhibited both phases of morphine effect when administered concomitant with a noneffective low dose of naloxone (0.1 mg/kg). The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) at a per se noneffective dose of 0.3 mg/kg potentiated the inhibitory effects of low doses of LiCl (0.01 and 0.05 mg/kg) on both phases of morphine effect. l-arginine, a NO synthase substrate, at a per se noneffective dose of 30 mg/kg reversed the inhibitory effects of lithium (1 mg/kg). Lithium is capable of antagonizing both modulatory effects of morphine on seizure susceptibility even at relatively low doses. These inhibitory effects of lithium may also involve NO synthesis.