Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity

J Neurochem. 1998 Jun;70(6):2416-23. doi: 10.1046/j.1471-4159.1998.70062416.x.

Abstract

Previously, we have demonstrated that cells of the oligodendroglial lineage express non-NMDA glutamate receptor genes and are damaged by kainate-induced Ca2+ influx via non-NMDA glutamate receptor channels, representing oligodendroglial excitotoxicity. We find in the present study that agents that elevate intracellular cyclic AMP prevent oligodendroglial excitotoxicity. After oligodendrocyte-like cells, differentiated from the CG-4 cell line established from rat oligodendrocyte type-2 astrocyte progenitor cells, were exposed to 2 mM kainate for 24 h, cell death was evaluated by measuring activity of lactate dehydrogenase released into the culture medium. Released lactate dehydrogenase increased about threefold when exposed to 2 mM kainate. Kainate-induced cell death was prevented by one of the following agents: adenylate cyclase activator (forskolin), cyclic AMP analogues (dibutyryl cyclic AMP and 8-bromo-cyclic AMP), and cyclic AMP phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, pentoxifylline, propentofylline, and ibudilast). Simultaneous addition of both forskolin and phosphodiesterase inhibitors prevented the kainate-induced cell death in an additive manner. A remarkable increase in Ca2+ influx (approximately 5.5-fold) also was induced by kainate. The cyclic AMP-elevating agents caused a partial suppression of the kainate-induced increase in Ca2+ influx, leading to a less prominent response of intracellular Ca2+ concentration to kainate. The suppressing effect of forskolin on the kainate-induced Ca2+ influx was partially reversed by H-89, an inhibitor of cyclic AMP-dependent protein kinase. In contrast to this, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, brought about a decrease in the kainate-induced Ca2+ influx. We therefore concluded that cyclic AMP-elevating agents prevented oligodendroglial excitotoxicity by cyclic AMP-dependent protein kinase-dependent protein phosphorylation, resulting in decreased kainate-induced Ca2+ influx.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bucladesine / pharmacology
  • Calcium / antagonists & inhibitors
  • Cell Death / drug effects
  • Cell Line
  • Colforsin / pharmacology
  • Cyclic AMP / biosynthesis*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cycloheximide / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / toxicity*
  • Kainic Acid / toxicity*
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects*
  • Oligodendroglia / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Protein Synthesis Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Xanthines / pharmacology

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Protein Synthesis Inhibitors
  • Pyridines
  • Xanthines
  • Colforsin
  • propentofylline
  • Bucladesine
  • Cycloheximide
  • Cyclic AMP
  • L-Lactate Dehydrogenase
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • ibudilast
  • Kainic Acid
  • Calcium