Interplay among platelet-activating factor, oxidative stress, and group I metabotropic glutamate receptors modulates neuronal survival

J Neurosci Res. 2004 Aug 15;77(4):525-31. doi: 10.1002/jnr.20175.

Abstract

Platelet-activating factor (PAF) is a potent phospholipid messenger in the nervous system that participates in synaptic plasticity and in pathologic processes, including neurodegeneration. Oxidative stress plays important roles in neuronal cell death. To define the interaction between PAF and oxidative radicals in neuronal death, we studied the effects of PAF in the presence of oxidative radicals in primary neurons in culture. Exogenous PAF (50 microM) caused PAF receptor-independent injury to neurons. A nonneurotoxic PAF concentration (500 nM) potentiated neuronal death caused by hydrogen peroxide as determined by lactate dehydrogenase (LDH) assay, Hoechst staining, and TUNEL analysis, but it did not potentiate neuronal death caused by menadione, a superoxide donor, or by the nitric oxide donors 3-morpholino-sydnonimine (SIN-1) and sodium nitroprusside (SNP). This potentiation of the hydrogen peroxide effect was selectively blocked by a PAF membrane-receptor antagonist, BN52021 (5 microM). The neurotoxic effect of PAF and hydrogen peroxide was also completely blocked by ebselen and partially decreased by pretreatment with (S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist. This study suggests that PAF-receptor antagonists may be useful for neuroprotection. A similar effect might also be obtained with group I mGluR agonists, probably by way of a different underlying mechanism.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Azoles / pharmacology
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Diterpenes / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Free Radicals / metabolism
  • Ginkgolides
  • Hydrogen Peroxide / pharmacology
  • Isoindoles
  • L-Lactate Dehydrogenase / metabolism
  • Lactones / pharmacology
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Nitric Oxide Donors
  • Organoselenium Compounds / pharmacology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Platelet Activating Factor / antagonists & inhibitors
  • Platelet Activating Factor / metabolism*
  • Platelet Activating Factor / pharmacology
  • Platelet Membrane Glycoproteins / antagonists & inhibitors
  • Platelet Membrane Glycoproteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Vitamin K 3 / pharmacology

Substances

  • Antioxidants
  • Azoles
  • Diterpenes
  • Excitatory Amino Acid Agonists
  • Free Radicals
  • Ginkgolides
  • Isoindoles
  • Lactones
  • Neuroprotective Agents
  • Nitric Oxide Donors
  • Organoselenium Compounds
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • Receptors, Metabotropic Glutamate
  • platelet activating factor receptor
  • ebselen
  • Vitamin K 3
  • Hydrogen Peroxide
  • ginkgolide B
  • L-Lactate Dehydrogenase