Involvement of Endogenous Prostaglandin F2alpha on Kainic Acid-Induced Seizure Activity Through FP Receptor: The Mechanism of Proconvulsant Effects of COX-2 Inhibitors

Brain Res. 2008 Feb 8;1193:153-61. doi: 10.1016/j.brainres.2007.12.017. Epub 2007 Dec 15.

Abstract

COX-2 and prostaglandins (PGs) might play important roles in epilepsy. In kainic acid-induced seizures, the brain largely increases PGD(2), first from COX-1 and later COX-2-induced PGF(2alpha). Pre-treatment with COX-2 inhibitors such as indomethacin, nimesulide, and celecoxib is known to aggravate kainic acid (KA)-induced seizure activity. However it is not known whether the proconvulsant effect of those non-steroidal anti-inflammatory drugs (NSAIDs) is due to changes in endogenous prostaglandins (PGs), or what types of PGs are involved. The purpose of this study was to determine the effect of intracisternally administered PGs on KA-induced seizures aggravated by pre- or post-treatment with COX-2 inhibitors. Systemic KA injection (10 mg/kg i.p.) in mice evoked mild seizure activity within 15 min. PGs were administrated intracisternally 20 min prior to KA administration. COX inhibitors (indomethacin, nimesulide, and ketoprofen, 10 mg/kg i.p.) were injected 1 h before or 15 min after KA. An additional COX-2 inhibitor, celecoxib, was administered orally. Intracisternally administered PGF(2alpha) (700 ng), but not PGD(2) (700 ng) or PGE(2) (700 ng) completely alleviated KA-induced seizures potentiated by COX-2 inhibitors, and also reduced KA-induced hippocampal neuronal death aggravated by indomethacin. PGF(2alpha) alone did not affect KA-induced seizures. However, an FP receptor antagonist, AL 8810 (10 or 50 ng) which is an 11beta-fluoro analogue of PGF(2alpha) potentiated KA-induced seizure activity dose-dependently. In summary, pre- or post-treatment with COX-2 inhibitors aggravates KA-induced seizures, which suggests to change the endogenous PGF(2alpha). Seizure-induced PGF(2alpha) might act as an endogenous anticonvulsant through FP receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cell Survival / drug effects
  • Cyclooxygenase Inhibitors / administration & dosage*
  • Dinoprost / administration & dosage
  • Dinoprost / analogs & derivatives
  • Dinoprost / metabolism*
  • Dinoprost / therapeutic use*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electroencephalography / methods
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred ICR
  • Receptors, Prostaglandin / antagonists & inhibitors
  • Receptors, Prostaglandin / metabolism*
  • Seizures / chemically induced
  • Seizures / metabolism*
  • Seizures / pathology
  • Seizures / prevention & control*

Substances

  • Cyclooxygenase Inhibitors
  • Receptors, Prostaglandin
  • prostaglandin F2alpha receptor
  • AL 8810
  • Dinoprost
  • Kainic Acid