Allosteric Modulation of Nicotinic Receptors as a Treatment Strategy for Alzheimer’s Disease

Abstract

Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer’s disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common approaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhib- its AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients’ level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine’s modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine’s sustained efficacy.

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

“…Interestingly, galanthamine was reported to interact with nAChRs directly and sensitize nAChRs by increasing the probability of channel opening and by slowing down receptor desensitization (Coyle and Kershaw, 2001;Maelicke et al, 2001). These allosterically potentiating ligand actions of galanthamine were observed in both ␣4␤2-and ␣7-nAChRs (Maelicke, 2000;Samochocki et al, 2000). Nevertheless, a recent study showed that galanthamine, but not donepezil, acting primarily as an allosteric potentiating ligand at presynaptically located nAChRs, potentiated glutamatergic transmission in rat hippocampal slice (Santos et al, 2002).…”

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

“…309 Presynaptic nAChRs are capable of modulating the release of Ach, and other neurotransmitters, such as glutamate, serotonin, and GABA, which may contribute to the symptoms of schizophrenia. 310 Galantamine has been shown to improve cognitive and global function in placebocontrolled trials in Alzheimer's disease patients (for a review, see Coyle and Kershaw 311 ). Results from case reports suggest that adjuvant galantamine administration improves negative symptoms in patients with treatment-refractory schizophrenia.…”

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…Therefore, cholinergic agents may ameliorate cerebral ischemia injury via their anti-inflammatory activity. Cholinergic agents include ACh precursors, which increase the synthesis of ACh; nicotinic or M1 muscarinic agonists, which directly stimulate cholinergic receptors or allosterically modulate nAChR [41] ; and synaptic AChE inhibitors, which prevent the degradation of ACh. Recent preclinical and clinical evidence indicates that treatment with cholinergic agents has beneficial effects on dementia of vascular origin [42][43][44][45][46][47][48] .…”