Background: An important range of Alzheimer’s disease (AD) symptoms are thought to be caused by a decrease in the neurotransmitter acetylcholine and a loss of cholinergic functions. Therefore current therapeutic interventions mainly focus on compensating the acetylcholine deficit and to restore the synaptic cholinergic neurotransmission. Galantamine inhibits the breakdown of acetylcholine and has a specific potentiating effect at the nicotinic receptors, thus enhancing the cholinergic neurotransmission and facilitating the release of other neurotransmitters. These unique nicotinic receptor-modulating properties of galantamine come on top of the acetylcholinesterase inhibition and may explain the substantial improvement of cognitive and behavioral symptoms in AD. To date, it is not yet clear whether cholinesterase inhibitors are able to modify the underlying pathology of AD or whether the clinical benefits are purely related to symptom relief. Recently, neuroprotective effects of galantamine have been shown in a transgenic mouse model of cholinergic deficiency as a result of NGF (Nerve Growth Factor) depletion. In this animal model galantamine, in contrast to potent ChEIs such as tacrine and physostigmine, could restore the cholinergic functions almost to normal and prevented the expression of vascular APP deposits (Capsoni PNAS 99, 12432, 2002). Here we present more evidence to suggest that the nicotinic receptor stimulation may result in neuroprotection.
Objective: To test the hypothesis that the potentiating effect of galantamine at the nicotinic receptors (nAChRs) results in neuroprotection in conditions relevant for AD.
Materials and Methods: Bovine chromaffin and human neuroblastoma cells do express a7-nAChRs. Cells were exposed to either thapsigargin or beta-amyloid peptide to induce apoptosis. Galantamine was incubated at submicromolecular concentrations (300nM), which are documented to have a potent allosteric potentiating ligand effect at the a7-nAchR. Finally, a-Bungarotoxin, a specific toxin at a7-nAChRs was added to study whether the potential anti-apoptotic effects of galantamine were mediated by its effects at nAchRs. Results: Thapsigargin increased the amount of apoptotic cell threefold, beta-amyloid almost twofold. Galantamine at 300nM reversed both effects and reduced the apoptotic cells almost to control levels. a-Bungarotoxin (a-BTX) suppressed the anti-apoptotic effects of galantamine, which strongly supports the hypothesis of an action at the a7-nAChR. Galantamine induced the expression of bcl-2, a key anti-apoptotic protein; the induction of this protein was reverted by a-bungarotoxin.
Conclusion: In both models, galantamine has shown to prevent apoptosis and reverse induced cell death at non-therapeutic (ACh blocking) concentrations. The fact that a-BTX suppressed galantamine’s antiapoptotic effect strongly suggests that its neuroprotective effect is mediated by a modulation at the nicotinic receptors causing the opening of the receptor and generating a mild and sustained Ca2+ signal. This can improve survival by up-regulating bcl-2 levels in addition to augmenting the expression of new a7-nAChRs. By decreasing these apoptotic effects, induced by the beta-amyloid peptide, galantamine may furthermore decrease neuronal loss and thereby modify the course of AD.
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