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Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice.

AbstractUNLABELLED:
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:
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.
AuthorsRazieh Adabi Mohazab, Mehrak Javadi-Paydar, Bahram Delfan, Ahmad Reza Dehpour
JournalEpilepsy research (Epilepsy Res) Vol. 101 Issue 1-2 Pg. 28-35 (Aug 2012) ISSN: 1872-6844 [Electronic] Netherlands
PMID22436324 (Publication Type: Journal Article)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Anticonvulsants
  • Convulsants
  • Enzyme Inhibitors
  • Guanidines
  • PPAR gamma
  • Thiazolidinediones
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase
  • pimagedine
  • NG-Nitroarginine Methyl Ester
  • Pentylenetetrazole
  • Pioglitazone
Topics
  • Anilides (pharmacology)
  • Animals
  • Anticonvulsants
  • Arginine (pharmacology)
  • Convulsants
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (pharmacology)
  • Guanidines (pharmacology)
  • Male
  • Mice
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide (physiology)
  • Nitric Oxide Synthase (antagonists & inhibitors)
  • PPAR gamma (antagonists & inhibitors, drug effects)
  • Pentylenetetrazole
  • Pioglitazone
  • Seizures (chemically induced, drug therapy, physiopathology)
  • Signal Transduction (drug effects, physiology)
  • Thiazolidinediones (antagonists & inhibitors, pharmacology)

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