Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model

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Abstract
We examined the effect of 3‐isobutyryl‐2‐isopropylpyrazolo[1,5‐a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 – 100 μM significantly attenuated the H2O2‐induced decrease in cell viability. Ibudilast inhibited the H2O2‐induced cytochrome c release, caspase‐3 activation, DNA ladder formation and nuclear condensation, suggesting its anti‐apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine‐3′,5′‐cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H2O2‐induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP‐dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H2O2‐induced decrease in cell viability, while the cyclic AMP‐dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp‐cyclic AMPS, the mitogen‐activated protein/extracellular signal‐regulated kinase inhibitor PD98059 and the leukotriene D4 antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H2O2‐induced cytochrome c release and caspase‐3‐like protease activation. These findings suggest that ibudilast prevents the H2O2‐induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway. British Journal of Pharmacology (2001) 133, 841–848; doi:10.1038/sj.bjp.0704146