CYCLIC AMP-ELEVATING AGENTS PREVENT OLIGODENDROGLIAL EXCITOTOXICITY

Previously, we have demonstrated that cells of the oligodendroglial li neage express non-NMDA glutamate receptor genes and are damaged by kai nate-induced Ca2+ influx via non-NMDA glutamate receptor channels, rep resenting oligodendroglial excitotoxicity. We find in the present stud y that agents that elevate intracellular cyclic AMP prevent oligodendr oglial excitotoxicity. After oligodendrocyte-like cells, differentiate d from the CG-4 cell line established from rat oligodendrocyte type-2 astrocyte progenitor cells, were exposed to 2 mM kainate for 24 h, cel l death was evaluated by measuring activity of lactate dehydrogenase r eleased into the culture medium. Released lactate dehydrogenase increa sed 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-i sobutyl-1-methylxanthine, pentoxifylline, propentofylline, and ibudila st). Simultaneous addition of both forskolin and phosphodiesterase inh ibitors prevented the kainate-induced cell death in an additive manner . A remarkable increase in Ca2+ influx(similar to 5.5-fold) also was i nduced by kainate. The cyclic AMP-elevating agents caused a partial su ppression of the kainate-induced increase in Ca2+ influx, leading to a less prominent response of intracellular Ca2+ concentration to kainat e. The suppressing effect of forskolin on the kainate-induced Ca2+ inf lux was partially reversed by H-89, an inhibitor of cyclic AMP-depende nt 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-depend ent protein kinase-dependent protein phosphorylation, resulting in dec reased kainate-induced Ca2+ influx.