gw9662 and pimagedine

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).. The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.

Topics: Anilides; Animals; Anticonvulsants; Arginine; Convulsants; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanidines; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Pioglitazone; PPAR gamma; Seizures; Signal Transduction; Thiazolidinediones

In this study, the potential antidepressant-like effects of pioglitazone and the possible involvement of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide system in antidepressant effects of pioglitazone were determined using forced swimming test (FST) in mice.. After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses (5, 10, 20 and 30 mg/kg) 2 and 4h before FST. To assess the involvement of PPARγ in the possible antidepressant effect of pioglitazone, GW9662, a PPARγ antagonist (2mg/kg) was administered before pioglitazone (20mg/kg). For determination of possible role of nitric oxide pathway in this effect, a non-specific NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME, 10mg/kg, i.p.), a specific iNOS inhibitor, aminoguanidine (50mg/kg, i.p.), or a NO precursor, L-arginine (750 mg/kg, i.p.) was co-administered with pioglitazone, either 2 or 4h before FST.. The immobility time significantly decreased after pioglitazone administration (20 and 30 mg/kg). GW-9662 significantly reversed antidepressant effect of pioglitazone administered 2 and 4h prior to FST. Co-administration of non-effective doses of pioglitazone and l-NAME revealed antidepressant-like effect in FST; while, co-administration of non-effective doses of aminoguanidine and pioglitazone did not affect the immobility time. l-Arginine also reversed the antidepressant-like effect of pioglitazone.. The antidepressant-like effect of pioglitazone on mice in the FST is mediated at least in part through PPARγ receptors and nitric oxide pathway.

Topics: Anilides; Animals; Antidepressive Agents; Arginine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanidines; Hypoglycemic Agents; Male; Mice; Motor Activity; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Pioglitazone; PPAR gamma; Swimming; Thiazolidinediones