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.