IBUDILAST REDUCES INTRACELLULAR CALCIUM ELEVATION INDUCED BY IN-VITROISCHEMIA IN GERBIL HIPPOCAMPAL SLICES

1. A microfluorometry was carried out to investigate the effect of 3-i sobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast) on changes in levels of intracellular calcium concentration ([Ca2+](i)) induced by in vitro ischaemia in the CA1 field of gerbil hippocampal slices. 2. W hen slices, loaded with a calcium ion sensitive dye (rhod-2) were expo sed to a glucose-free physiological medium equilibrated with a 95% N-2 /5% CO2 gas mixture (standard in vitro ischaemia), a large [Ca2+](i) e levation was detected approximately 5 min after the beginning of in vi tro ischaemia. 3. When slices were perfused with the in vitro ischaemi c medium containing 43 mu mol/L ibudilast, a [Ca2+](i) elevation was s till observed; however, the extent of the increase in [Ca2+](i) was si gnificantly depressed in all subregions of the hippocampal slices. 4. The extent of this inhibitory effect of ibudilast on the in vitro isch aemia-induced [Ca2+](i) elevation was in a similar range as those of C a2+ blockers, including 0,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-i mine maleate (MK-801), flunarizine and dantrolene. 5. Similar [Ca2+](i ) increases in the CA1 field were induced by a Ca2+-free in vitro isch aemia, a high concentration of KCl or by specific agonists for glutama te receptor subtypes (N-methyl-D-aspartate (NMDA), pha-amino-3-hydroxy -5-methyl-4-isoxazolepropionate (AMPA) and kainate); these increases w ere also depressed with 43 mu mol/L ibudilast present in the perfusion medium. 6. These results indicate that ibudilast may act by depressin g the Ca2+ accumulation during and shortly after ischaemia, a possible pharmacological action of ibudilast that leads to the amelioration of ischaemic injury in the central nervous system.