Propentofylline protects beta-amyloid protein-induced apoptosis in cultured rat hippocampal neurons.
beta-Amyloid protein 1-42 (beta42) can induce apoptosis in the cultured hippocampal neurons, suggesting that it plays an important role in causing neurodegeneration in Alzheimer's disease. Recently, propentofylline, a synthetic xanthine derivative, has been reported to depress ischemic degeneration of hippocampal neurons in gerbils. The present study investigated whether or not propentofylline affected the beta42-induced apoptosis of hippocampal neurons, and if so, which type of signaling machinery works in the neuroprotective action of propentofylline. Addition of propentofylline markedly attenuated the beta42-induced cell death of rat hippocampal neurons. The amyloid protein certainly induced apoptosis in the cultured hippocampal cells revealed by nuclear condensation, caspase-3 activation and an increase of Bax. Intriguingly, propentofylline blocked both the apoptotic features induced by beta42 and further induced an anti-apoptotic protein, Bcl-2, during a short time of incubation. The neuroprotective action of propentofylline was comparably replaced with dibutyryl cAMP (dbcAMP) and was completely suppressed by a low concentration of specific protein kinase A (PKA) inhibitor. Taken altogether, the data strongly suggest that the protection of propentofylline on the beta42-induced neurotoxicity is caused by enhancing anti-apoptotic action through cAMP-PKA system. Propentofylline as a therapeutic agent to Alzheimer's disease is discussed.
Koriyama
Yoshiki
Y
Department of Biodynamics, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan. koriyama@med.kanazawa-u.ac.jp
Chiba
Kenzo
K
Mohri
Tetsuro
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides; D014970:Xanthines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D016229:Amyloid beta-Peptides; C494828:Bax protein, rat; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014970:Xanthines; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; C071449:H 85; C032114:propentofylline; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide