After nearly 60years,
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 (30mg/kg ip) increased seizure threshold, whereas pretreatment with a low and independently noneffective dose of
agmatine (3mg/kg) potentiated a subeffective dose of
lithium (10mg/kg). N(G)-
L-arginine methyl ester (
L-NAME, nonspecific
nitric oxide synthase inhibitor) at 1 and 5mg/kg and
7-nitroindazole (7-NI, preferential
neuronal nitric oxide synthase inhibitor) at 15 and 30mg/kg augmented the
anticonvulsant effect of the noneffective combination of
lithium (10mg/kg ip) and
agmatine (1mg/kg), whereas several doses (20 and 40mg/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 60mg/kg) of
L-arginine (substrate for
nitric oxide synthase) inhibited the potentiating effect of
agmatine (3mg/kg) on
lithium (10mg/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.