Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity

Akira Yoshioka, Yuko Shimizu, Genjiro Hirose, Hiroshi Kitasato, David E Pleasure

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 (~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.

Original languageEnglish (US)
Pages (from-to)2416-2423
Number of pages8
JournalJournal of Neurochemistry
Issue number6
StatePublished - Jun 1998
Externally publishedYes


  • Ca influx
  • Cyclic AMP
  • Cyclic AMP-dependent protein kinase
  • Non-NMDA glutamate receptors
  • Oligodendroglia
  • Protein phosphatase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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