title: Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Razieh
authors.initials: R
authors.lastname: Adabi Mohazab
authors.forename: Mehrak
authors.initials: M
authors.lastname: Javadi-Paydar
authors.forename: Bahram
authors.initials: B
authors.lastname: Delfan
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants; D001120:Arginine / Q000494:pharmacology; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000187:drug effects*; D010433:Pentylenetetrazole; D000077205:Pioglitazone; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D006146:Guanidines; D047495:PPAR gamma; D045162:Thiazolidinediones; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D010433:Pentylenetetrazole; D000077205:Pioglitazone