Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade.

Abstract

We show here that donepezil, galanathamine and tacrine, therapeutic acetylcholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-beta-erythroidine and methyllycaconitine, antagonists for alpha4-nAChR and alpha7-nAChR, respectively, antagonized the protective effect of donepezil and galanthamine, but not that of tacrine. Previous reports suggest the involvement of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in the nicotine-induced neuroprotection. Inhibitors for a non-receptor type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. Furthermore, LY294002, a PI3K inhibitor, also suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galanthamine treatment, but not with tacrine treatment. These results suggest that donepezil and galanthamine prevent glutamate neurotoxicity through alpha4- and alpha7-nAChRs, followed by the PI3K-Akt pathway, and that tacrine protects neuronal cells through a different pathway.

• Authors: Yuki Takada-Takatori, Toshiaki Kume, Mitsuhiro Sugimoto, Hiroshi Katsuki, Hachiro Sugimoto, Akinori Akaike
• Journal: Neuropharmacology (Neuropharmacology) Vol. 51 Issue 3 Pg. 474-86 (Sep 2006) ISSN: 0028-3908 [Print] England
• PMID: 16762377 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinergic Antagonists
• Cholinesterase Inhibitors
• Enzyme Inhibitors
• Receptors, Nicotinic
• Glutamic Acid
• Phosphatidylinositol 3-Kinases

Topics

• Alzheimer Disease (drug therapy)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Count (methods)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Cholinergic Antagonists (pharmacology)
• Cholinesterase Inhibitors (therapeutic use)
• Dose-Response Relationship, Drug
• Drug Interactions
• Embryo, Mammalian
• Enzyme Inhibitors (pharmacology)
• Glutamic Acid (toxicity)
• Neurons (drug effects)
• Neurotoxicity Syndromes (etiology, pathology, prevention & control)
• Phosphatidylinositol 3-Kinases (physiology)
• Rats
• Rats, Wistar
• Receptors, Nicotinic (physiology)
• Time Factors