Thalidomide is an old
glutamic acid derivative which was initially used as a
sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including
neurodegenerative disorders. Other than the
antiemetic and
hypnotic aspects,
thalidomide exerts some
anticonvulsant properties in experimental settings. However, the underlying mechanisms of
thalidomide actions are not fully realized yet. Some investigations revealed that
thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including
cytokines (such as TNF α),
neurotransmitters, and
nitric oxide (NO). In this regard, we used a model of clonic seizure induced by
pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the
anticonvulsant effect of
thalidomide is affected through modulation of the
l-arginine-
nitric oxide pathway or not. Injection of a single effective dose of
thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of
l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the
anticonvulsant effect of
thalidomide. On the other hand, NOS inhibitors [
l-NAME and 7-NI] augmented the
anticonvulsant effect of a subeffective dose of
thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of
aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the
anticonvulsant effect of
thalidomide significantly. In summary, our findings demonstrated that the
l-arginine-
nitric oxide pathway can be involved in the
anticonvulsant properties of
thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.