Thursday, 21 August 2003
This presentation is part of : Thursday Poster Sessions

PD-024 Galantamine Use in Alzheimer's Disease: A Novel Antiapoptotic Mechanism Linked to Up-Regulation of Bcl-2 and a7 Receptors

Manuela Garcia-Lopez, Departamento de Farmacoligia y Terapeutica, Departamento de Farmacoligia y Terapeutica, Instituto Teofilo Hernando, Universidad Autonoma, Madrid, Spain

Background: Galantamine has shown consistent clinical efficacy and safety in the treatment of Alzheimer’s disease (AD). This drug has been described as a selective acetylcholinesterase inhibitor and a nicotinic acetylcholine receptor modulator, and this could explain the positive cognitive and behavioral effects observed in clinical trials. In addition, nicotinic receptor stimulation has been documented to provide neuroprotection.

Objective: This study focused on further exploring the neuroprotective properties of galantamine.

Design: In vitro comparison of bovine chromaffin cells and human neuroblastoma SH-SY5Y cells and the effects of galantamine on the prevention of apoptosis, induced by the sarcoplasmatic/endoplasmic reticulum (ER) Ca(2+)ATPase (SERCA) inhibitor thapsigargin and by b-amyloid, the component of the amyloid plaques typical of AD pathology.

Materials and Methods: We used primary cultures of bovine chromaffin cells and human neuroblastoma SH-SY5Y cells, Hoechst/PI and annexin V-FITC/PI fluorescent dyes to determine the percentage of apoptotic cells; LDH activity as measurement of cell death; and immunofluorescent and Western blot analysis to determine expression of the antiapoptotic protein Bcl-2 and a7 nicotinic receptors. Inhibition of SERCA by thapsigargin promotes calcium release from the ER and activates the caspase cascade, which in turn activates an apoptotic cell death program.

Results: Galantamine presented concentration-dependent neuroprotection against thapsigargin-induced apoptosis; maximal effect was obtained at 300 nmol/L. The antiapoptotic effect of galantamine was reversed by the a7 nicotinic antagonist a-bungarotoxin, indicating that its neuroprotective mechanism is related to nicotinic receptor activation. At 300 nmol/L, the point at which maximum neuroprotection was observed, galantamine induced a mild increase in the cytosolic levels of calcium. Incubation with galantamine for 48 hours induced the expression of the antiapoptotic protein Bcl-2 and up-regulation of a- nicotinic receptors.

Conclusion: Galantamine can prevent apoptotic cell death by 2 mechanisms: (1) increasing the [Ca2+]c to levels having neurotrophic and plastic influences on neurons and (2) inducing the antiapoptotic protein Bcl-2.

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