AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24 h

Eur J Pharmacol. 1993 Jun 4;236(3):347-53. doi: 10.1016/0014-2999(93)90470-3.

Abstract

The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) and the selective N-methyl-D-aspartate (NMDA) receptor antagonists MK 801 and ifenprodil were administered to Mongolian gerbils following a 5 min period of bilateral carotid artery occlusion. NBQX when given 4, 6 or 24 h after ischaemia gave a reduced loss of hippocampal CA1 neurones compared to control animals receiving vehicle only. Dizocilipine (MK 801) (1-10 mg/kg i.p.) and ifenprodil (a total of 45 mg/kg i.p.) gave no protection. The peak levels of NBQX obtained in the cerebrospinal fluid of gerbils receiving the neuroprotective dose (3 x 30 mg/kg i.p.) was 1 microM. In gerbil cortex slices, this concentration had no effect on NMDA-evoked depolarization, but had a moderate effect on kainate and gave a total blockade of AMPA depolarizations. It is concluded that antagonists of non-NMDA glutamate receptor subtypes, possibly AMPA, may be a useful therapeutic approach for cerebral ischaemia-related brain damage following global ischaemia.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Dizocilpine Maleate / administration & dosage
  • Dizocilpine Maleate / cerebrospinal fluid
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists*
  • Female
  • Gerbillinae
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Ibotenic Acid / analogs & derivatives
  • Ibotenic Acid / metabolism
  • Ischemic Attack, Transient / drug therapy*
  • Ischemic Attack, Transient / metabolism
  • Ischemic Attack, Transient / pathology
  • Kinetics
  • Male
  • Neurons / drug effects
  • Piperidines / administration & dosage
  • Piperidines / cerebrospinal fluid
  • Piperidines / pharmacology
  • Quinoxalines / administration & dosage
  • Quinoxalines / cerebrospinal fluid
  • Quinoxalines / pharmacology*
  • Receptors, AMPA
  • Receptors, Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Substances

  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Ibotenic Acid
  • Dizocilpine Maleate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • ifenprodil