Ibudilast Reduces Intracellular Calcium Elevation Induced by in Vitro Ischaemia in Gerbil Hippocampal Slices

A microfluorometry was carried out to investigate the effect of 3-isobutyryl-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. When slices, loaded with a calcium ion sensitive dye (rhod-2) were exposed to a glucose-free physiological medium equilibrated with a 95% N2/5% CO2 gas mixture (standard in vitro ischaemia), a large [Ca2+]i elevation was detected approximately 5 min after the beginning of in vitro ischaemia. 3. When slices were perfused with the in vitro ischaemic medium containing 43 mumol/L ibudilast, a [Ca2+]i elevation was still observed; however, the extent of the increase in [Ca2+]i was significantly depressed in all subregions of the hippocampal slices. 4. The extent of this inhibitory effect of ibudilast on the in vitro ischaemia-induced [Ca2+]i elevation was in a similar range as those of Ca2+ blockers, including (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine maleate (MK-801), flunarizine and dantrolene. 5. Similar [Ca2+]i increases in the CA1 field were induced by a Ca(2+)-free in vitro ischaemia, a high concentration of KCl or by specific agonists for glutamate receptor subtypes (N-methyl-D-aspartate (NMDA), (s)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate); these increases were also depressed with 43 mumol/L ibudilast present in the perfusion medium. 6. These results indicate that ibudilast may act by depressing 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.