Propentofylline protects beta-amyloid protein-induced apoptosis in cultured rat hippocampal neurons.

Abstract

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.

• Authors: Yoshiki Koriyama, Kenzo Chiba, Tetsuro Mohri
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 458 Issue 3 Pg. 235-41 (Jan 05 2003) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12504778 (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

Topics

• 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