Galantamine modulates nicotinic receptor and blocks Aβ-enhanced glutamate toxicity

Galantamine is a plant alkaloid that is used in the treatment of Alzheimer’s disease. We have studied the effects of galantamine on β-amyloid-enhanced glutamate toxicity using primary rat cultured cortical neurons. Nicotine and galantamine alone, and in combination, protected neurons against this neurotoxicity. The protection was not blocked by α4β2 nicotinic acetylcholine receptor (nAChR) antagonists, but was partially blocked by α7 nAChR antagonists. Galantamine induced phosphorylation of Akt, an effector of phosphatidylinositol 3-kinase (PI3K), while PI3K inhibitors blocked the protective effect and Akt phosphorylation. The antibody FK1, which selectively blocks the allosterically potentiating ligand site on nAChR, significantly reduced the galantamine-induced protection and Akt phosphorylation. Furthermore, suppression of α7 nAChR using an RNA interference technique reduced Akt phosphorylation induced by galantamine. Our data suggest that neuroprotection by galantamine is mediated, at least in part, by α7 nAChR-PI3K cascade.