Agmatine enhances the anticonvulsant effect of lithium chloride on pentylenetetrazole-induced seizures in mice: Involvement of L-arginine/nitric oxide pathway

After nearly 60 years, lithium is still the mainstay in the treatment of mood disorders. In addition to its antimanic and antidepressant effects, lithium also has anticonvulsant properties. Similar to lithium, agmatine plays a protective role in the central nervous system against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on the L-arginine/nitric oxide pathway. This study was designed to investigate: (1) whether agmatine and lithium exert a synergistic effect against clonic seizures induced by pentylenetetrazole and (2) whether or not this synergistic effect is mediated through inhibition of the L-arginine/nitric oxide pathway. In our study, acute administration of a single potent dose of lithium chloride (30 mg/kg ip) increased seizure threshold, whereas pretreatment with a low and independently noneffective dose of agmatine (3 mg/kg) potentiated a subeffective dose of lithium (10 mg/kg). NG-L-arginine methyl ester (L-NAME, nonspecific nitric oxide synthase inhibitor) at 1 and 5 mg/kg and 7-nitroindazole (7-NI, preferential neuronal nitric oxide synthase inhibitor) at 15 and 30 mg/kg augmented the anticonvulsant effect of the noneffective combination of lithium (10 mg/kg ip) and agmatine (1 mg/kg), whereas several doses (20 and 40 mg/kg) of aminoguanidine (inducible nitric oxide synthase inhibitor) failed to alter the seizure threshold of the same combination. Furthermore, pretreatment with independently noneffective doses (30 and 60 mg/kg) of L-arginine (substrate for nitric oxide synthase) inhibited the potentiating effect of agmatine (3 mg/kg) on lithium (10 mg/kg). Our findings demonstrate that agmatine and lithium chloride have synergistic anticonvulsant properties that may be mediated through the L-arginine/nitric oxide pathway. In addition, the role of constitutive nitric oxide synthase versus inducible nitric oxide synthase is prominent in this phenomenon.