| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
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| Research Abstract |
Previously, we have found that CaィイD12+ィエD1 accumulation via non-N-methyl-D-aspartate (NMDA) glutamate receptor (GluR) mediates oxygen-glucose deprivation induced oligodendroglial injury. In the present study, we investigated the mechanism of CaィイD12+ィエD1 accumulation when non-NMDA GluR are activated in oligodendroglial cells. Oligodendroglial cells express mRNAs encoding each of the three known NaィイD1+ィエD1-CaィイD12+ィエD1 exchanger isoforms. Kainate-induced oligodendroglial CaィイD12+ィエD1 accumulation is dimished by replacement of extracellular NaィイD1+ィエD1 with N-methyl-D-glucamine, and by the NaィイD1+ィエD1-CaィイD12+ィエD1 exchanger blockers, 3, 4-dichlorobenzamil (DCB) and benzamil. These results indicate that kainate-induced CaィイD12+ィエD1 accumulation results, at least in part, from NaィイD1+ィエD1-CaィイD12+ィエD1-mediated exchange of intracellular NaィイD1+ィエD1 for extracellular CaィイD12+ィエD1. We previously found that agents which elevate intracellular cAMP or cGMP inhibit kainate-induced CaィイD12+ィエD1 accumulation and prevent kainate induced excitotoxicity. To test the hypothesis that cAMP and cGMP inhibit "reverse" mode operation of NaィイD1+ィエD1-CaィイD12+ィエD1 exchangers, we loaded oligodendroglia with NAィイD1+ィエD1 in the absence of quaint by incubation with veratridine and ouabain in an NaィイD1+ィエD1 containing medium. This caused CaィイD12+ィエD1 accumulation, which was inhibited by agents that elevate intracellular cMAP or cGMP prevent oxygen-glucose deprivation-induced oligodendroglial injury by inhibiting "reverse" mode operation of NaィイD1+ィエD1-CaィイD12+ィエD1 exchangers.
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