Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity.
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.
Yoshioka
A
A
Department of Neurology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Shimizu
Y
Y
Hirose
G
G
Kitasato
H
H
Pleasure
D
D
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007608:Kainic Acid / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014970:Xanthines / Q000494:pharmacology; D007212:Indolizines; D011720:Pyrazoles
D003994:Bucladesine; D002118:Calcium; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003513:Cycloheximide; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D007770:L-Lactate Dehydrogenase; D010749:Phosphoprotein Phosphatases; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D014970:Xanthines; C032114:propentofylline; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles