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[Ibudilast prevents oligodendroglial excitotoxicity]
A Yoshioka1, Y Shimizu, G Hirose
1Department of Neurology, Kanazawa Medical University, Japan.
No to Shinkei = Brain and Nerve
|December 13, 1997
Summary
Ibudilast protects oligodendroglia from excitotoxicity by reducing kainate-induced calcium influx. This neuroprotective effect involves a protein kinase A (PKA)-dependent pathway, offering potential therapeutic strategies for neurological disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Oligodendrocytes express non-N-methyl-D-aspartate (NMDA) glutamate receptors.
- Kainate-induced calcium influx via alpha-amino-3-hydroxy-5-methyl 4-isoxazole propionate (AMPA) type receptors causes oligodendroglial excitotoxicity.
Purpose of the Study:
- To investigate the neuroprotective effect of ibudilast on oligodendroglial excitotoxicity.
- To elucidate the molecular mechanisms underlying ibudilast's protective action.
Main Methods:
- Oligodendrocyte-like cells (OLC) were exposed to kainate to induce excitotoxicity.
- Cell death was assessed by measuring lactate dehydrogenase (LDH) release.
- Intracellular cAMP levels and 45Ca2+ influx were measured.
- The role of protein kinase A (PKA) and phosphatases was examined using inhibitors.
Main Results:
- Ibudilast (10-100 microM) significantly reduced kainate-induced cell death in OLC.
- Ibudilast treatment increased intracellular cAMP levels.
- Ibudilast attenuated kainate-induced Ca2+ influx.
- The inhibitory effect of ibudilast on Ca2+ influx was dependent on PKA activity and phosphatase activity.
Conclusions:
- Ibudilast effectively prevents oligodendroglial excitotoxicity.
- The mechanism involves a PKA-dependent phosphorylation process that decreases kainate-induced Ca2+ influx.
- Ibudilast shows potential as a therapeutic agent for conditions involving oligodendroglial damage.