The anti-inflammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from β-amyloid neurotoxicity by acting on Wnt signaling components

• Published in: Neurobiology of disease Vol. 18; no. 1; pp. 176 - 183
• Main Authors: Farías, Ginny G., Godoy, Juan A., Vázquez, Mary C., Adani, Rellie, Meshulam, Haim, Avila, Jesús, Amitai, Gabi, Inestrosa, Nibaldo C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2005; Elsevier
• Subjects: Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - drug effects; Amyloid beta-Protein Precursor - metabolism; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Anti-inflammatory ibuprofen; Aβ neurotoxicity; beta Catenin; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Cells, Cultured; ChE inhibitor pyridostigmine; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cytoskeletal Proteins - drug effects; Cytoskeletal Proteins - metabolism; Disease Models, Animal; Down-Regulation - drug effects; Down-Regulation - physiology; Drug Compounding; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β overexpression; Ibuprofen - pharmacology; Ibuprofen - therapeutic use; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Transgenic; Neuroprotective Agents - pharmacology; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - metabolism; Pyridinium Compounds - pharmacology; Pyridinium Compounds - therapeutic use; Pyridostigmine Bromide - pharmacology; Pyridostigmine Bromide - therapeutic use; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Trans-Activators - drug effects; Trans-Activators - metabolism; Wnt Proteins; Wnt signaling; Anti-inflammatory ibuprofen; GSK-3β overexpression; Aβ neurotoxicity; Wnt signaling; ChE inhibitor pyridostigmine; Alzheimer disease
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2004.09.012

Changes in signal transduction are implicated in neuronal responses to the Alzheimer's amyloid-β-peptide (Aβ), which include neurotransmitter systems and pathways involved in the maintenance of the nervous system. We report here that a new bifunctional compound IBU-PO, which combines a non-steroidal anti-inflammatory drug (NSAID) (Ibuprofen) and a cholinesterase (ChE) inhibitor (Octyl-Pyridostigmine), is neuroprotective against Aβ-neurotoxicity, and its activity is associated to Wnt signaling components in rat hippocampal and mouse cortical neurons. IBU-PO (0.01–1 μM) inhibits glycogen-synthase-kinase-3β (GSK-3β) and stabilizes cytoplasmic β-catenin reverting the silencing of the Wnt pathway caused by Aβ-toxicity and GSK-3β overexpression. In addition, IBU-PO enhances, dose-dependently, the non-amyloidogenic amyloid precursor protein (APP) cleavage by increasing secreted APP and decreasing endogenous Aβ1–40 in rat hippocampal neurons.