Galantamine modulates nicotinic receptor and blocks Abeta-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 beta-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 alpha4beta2 nicotinic acetylcholine receptor (nAChR) antagonists, but was partially blocked by alpha7 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 alpha7 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 alpha7 nAChR-PI3K cascade.
Kihara
Takeshi
T
Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.
Sawada
Hideyuki
H
Nakamizo
Tomoki
T
Kanki
Rie
R
Yamashita
Hirofumi
H
Maelicke
Alfred
A
Shimohama
Shun
S
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005702:Galantamine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D011978:Receptors, Nicotinic; D005702:Galantamine; D018698:Glutamic Acid