Protection of PMS777, a new AChE inhibitor with PAF antagonism, against amyloid-beta-induced neuronal apoptosis and neuroinflammation.

Abstract

Amyloid-beta (Abeta) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer's disease, and thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Abeta-induced neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1-100 microM) was found to inhibit Abeta-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Abeta. In vivo experimental study demonstrated that PMS777 could attenuate Abeta-induced microglial and astrocytic activation in the rat hippocampus after systemic administration. These results suggest that PMS777 potently protects against Abeta-induced neuronal apoptosis and neuroinflammation, and warrants further investigations in connection with its potential value in the treatment of Alzheimer's disease.

• Authors: Juan Li, Jinjia Hu, Biyun Shao, Wei Zhou, Yongyao Cui, Changzhi Dong, Jean-Marc Miezan Ezoulin, Xu Zhu, Wenlong Ding, Françoise Heymans, Hongzhuan Chen
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 29 Issue 4 Pg. 589-95 (Jun 2009) ISSN: 1573-6830 [Electronic] United States
• PMID: 19194797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• Furans
• PMS 777
• Platelet Activating Factor
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Caspase 3

Topics

• Amyloid beta-Peptides (pharmacology)
• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (pharmacology)
• Furans (pharmacology)
• Humans
• Inflammation (metabolism)
• Neurons (cytology, drug effects, physiology)
• Platelet Activating Factor (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• bcl-2-Associated X Protein (genetics, metabolism)