Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model.
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 microM significantly attenuated the H(2)O(2)-induced decrease in cell viability. Ibudilast inhibited the H(2)O(2)-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 H(2)O(2)-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 H(2)O(2)-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 D(4) antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H(2)O(2)-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H(2)O(2)-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway.
Takuma
K
K
Department of Analytical Chemistry, Kobe Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe 651-2180 Japan.
Lee
E
E
Enomoto
R
R
Mori
K
K
Baba
A
A
Matsuda
T
T
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002227:Carbazoles; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D015398:Signal Transduction; D013806:Theophylline / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology; D007212:Indolizines; D011720:Pyrazoles
D000470:Alkaloids; D002227:Carbazoles; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D003574:Cytochrome c Group; D004247:DNA; D004176:Dipyridamole; D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D007211:Indoles; D010431:Pentoxifylline; D010447:Peptide Hydrolases; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011725:Pyridines; D013806:Theophylline; D014748:Vinca Alkaloids; C073601:KT 5823; C013983:vinpocetine; C108711:DEVDase; C011145:zaprinast; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles