Protective action of isoquinolinesulfonamides in in vitro models of neuronal apoptosis.
We have previously reported that a group of isoquinolinesulfonamide kinase inhibitors (H7, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine; H8, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide; and H9, N-2-(aminoethyl)-5-isoquinolinesulfonamide) prevents apoptosis triggered in neurons by an inhibition of phosphatases 1 and 2A with okadaic acid, and by inhibition of protein kinase C with staurosporine and chelerythrine. In the present study we assessed the capability of isoquinolinesulfonamides (IQS) to prevent different types of apoptosis in primary cultures of cerebellar granule neurons. We induced apoptosis by: a) serum removal, b) potassium deficiency, c) serum removal + potassium deficiency, and d) beta-amyloid peptide (beta AP). The IQS prevented apoptosis in all the above models. Thus, it appears that the IQS-sensitive pathway is a common mechanism in different types of neuronal apoptosis, and that it might be used as a target in the development of novel neuroprotective drugs.
Cagnoli
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Neurosciences Research Center, Allegheny-Singer Research Institute, Medical College of Pennsylvania, Pittsburgh 15212, USA.
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010879:Piperazines; D013449:Sulfonamides; C044388:N-(2-aminoethyl)-5-isoquinolinesulfonamide; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D011493:Protein Kinase C