Galantamine modulates nicotinic receptor and blocks Aβ-enhanced glutamate toxicity

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Abstract

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.

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Materials and methods

Experiments were carried out on animals treated in accordance with the guidelines published in the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Materials. The sources of drugs and materials were as follows: Eagle’s minimum essential medium (EMEM) (Nissui Pharmaceutical, Tokyo, Japan); (−)-nicotine, MK801, methyllycaconitine (MLA), and mecamylamine (Sigma-RBI, Natick, MA); α-bungarotoxin (αBTX) (Wako Pure Chemical Industries, Osaka, Japan); galantamine HBr, PI3K

Galantamine protects neurons from Aβ-enhanced glutamate cytotoxicity

Cortical neurons were incubated with both Aβ1–40 (10 nM) and Aβ1–42 (1.0 nM) for 4 days, which did not directly induce cell death. Treatment with a low dose (20.0 μM) of glutamate alone did not significantly induce cell death (Figs. 1A and B), but exposure to the same dose of glutamate for 24 h (20.0 μM) caused a significant reduction in the number of Aβ-treated neuronal cells (Figs. 1A and B). Co-incubating the cultures with galantamine and Aβ significantly reduced Aβ-enhanced glutamate

Discussion

Galantamine allosterically modulates both α7 and α4β2 nAChRs [9], [19], besides its activity as an AChEI [1] which could increase ACh levels via the inhibition of AChE. And both α7 and α4β2 nAChR stimulation protect neurons from Aβ- and glutamate-induced neuronal death [6], [7], [8], [14]. Therefore, it is possible that galantamine exerts a neuroprotective effect.

Aβ accumulation is one of the earliest changes in AD pathology, and this peptide may cause neuronal death in the central nervous

Acknowledgments

This study was supported in part by Grants-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by grants from the Ministry of Health, Labour and Welfare of Japan, and the Smoking Research Foundation.

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