Besides the receptor-mediated effects of
pioglitazone, the involvement of
nitric oxide (NO) has been previously demonstrated in some
pioglitazone-induced central and peripheral effects. In the present study, the effects of acutely administered
pioglitazone on
pentylenetetrazole (PTZ)-induced
seizures and involvement of NO were evaluated in mice. To determine the threshold for
clonic seizures, PTZ was administered intravenously. A single dose of
pioglitazone (10, 20, 40 and 80 mg/kg, p.o.) was administered either 2 or 4h prior to induction of
seizures. For determination of possible role of
peroxisome proliferator activated receptor gamma (
PPAR-γ) and
nitric oxide pathway in this effect, the effects of a
PPAR-γ antagonist,
GW9662 (2 mg/kg); a non-specific
nitric oxide synthase (NOS) inhibitor,
NG-nitro-L-arginine methyl ester (
L-NAME; 0.3, 1, 3, and 10 mg/kg); a specific iNOS inhibitor,
aminoguanidine (100mg/kg, i.p.) or a
nitric oxide precursor,
L-arginine (30, 60, 100 and 200mg/kg, i.p.); each administered 15 min prior to
pioglitazone, were investigated on the
anticonvulsant effect of this
drug. Administration of
pioglitazone (40 and 80 mg/kg) increased the threshold of PTZ-induced seizure in a dose-dependent, and time-dependent manner.
GW9662 reversed the
anticonvulsant effect of
pioglitazone (40 mg/kg). Acute administration of
L-NAME (1, 3 and 10mg/kg) inhibited the
anticonvulsant effect of
pioglitazone (40 mg/kg), the same result was detected with
aminoguanidine (100mg/kg); whereas
L-arginine, in the noneffective dose (100mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of
pioglitazone (20mg/kg).
CONCLUSION: