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.
AuthorsYoshiki Koriyama, Kenzo Chiba, Tetsuro Mohri
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 458 Issue 3 Pg. 235-41 (Jan 05 2003) ISSN: 0014-2999 [Print] Netherlands
PMID12504778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • Bax protein, rat
  • Enzyme Inhibitors
  • Isoquinolines
  • Neuroprotective Agents
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Xanthines
  • amyloid beta-protein (1-42)
  • bcl-2-Associated X Protein
  • H 85
  • propentofylline
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Amyloid beta-Peptides (toxicity)
  • Animals
  • Apoptosis (drug effects)
  • Caspase 3
  • Caspases (metabolism)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Cyclic AMP (metabolism)
  • Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors)
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Hippocampus (cytology, drug effects, metabolism)
  • Isoquinolines (pharmacology)
  • Neurons (cytology, drug effects, metabolism)
  • Neuroprotective Agents (pharmacology)
  • Peptide Fragments (toxicity)
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Rats
  • Rats, Wistar
  • Sulfonamides
  • Xanthines (pharmacology)
  • bcl-2-Associated X Protein

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