The Role of Neuronal Nicotinic Acetylcholine Receptors in Acute and Chronic Neurodegeneration

Abstract

In the last five years there has been a rapid explosion of publications reporting that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in neurodegenerative disorders. Furthermore, there is a well-established loss of nAChRs in post-mortem brains from patients with Alzheimer's disease, Parkinson's disease and a range of other disorders. In the present review we discuss the evidence that nicotine and subtype selective nAChR ligands can provide neuroprotection in in vitro cell culture systems and in in vivo studies in animal models of such disorders. Whilst in vitro data pertaining to a protective effect of nicotine against nigral neurotoxins like MPTP is less robust, most studies agree that nicotine is protective against glutamate and beta-amyloid toxicity in various culture systems. This effect appears to be mediated by alpha7 subtype nAChRs since the protection is blocked by alpha-bungarotoxin and is mimicked by alpha7 selective agonists. In vivo studies indicate that alpha7 receptors play a critical role in protection from cholinergic lesions and enhancing cognitive function. The exact subtype involved in the neuroprotectant effects seen in animal models of Parkinson's disease is not clear, but in general broad spectrum nAChR agonists appear to provide protection, while alpha4beta2 receptors appear to mediate symptomatic improvements. Evidence favouring a protectant effect of nicotine against acute degenerative conditions is less strong, though some protection has been observed with nicotine pre-treatment in global ischaemia models. A variety of cellular mechanisms ranging from the production of growth factors through to inactivation of toxins and antioxidant actions of nicotine have been proposed to underlie the nAChR-mediated neuroprotection in vitro and in vivo. In summary, although the lack of subtype selective ligands has hampered progress, it is clear that in the future neuronal nAChR agonists could provide functional improvements and slow or halt the progress of several crippling degenerative diseases.

Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system

“…Involvement in neuroprotection Nicotine and other nAChR agonists are neuroprotective in several models of neuronal death, both in vivo and in vitro [81] . The nAChRmediated neuroprotection against excitotoxicity is calciumdependent [82][83][84] and does not involve blockade of glutamate receptor function [83][84][85] .…”

Nicotinic receptors as CNS targets for Parkinson's disease

“…Extensive evidence using culture systems has shown that nicotine protects against toxicity mediated by β-amyloid, glutamate, ethanol, trophic factor deprivation, arachidonic acid and others [11,[18][19][20]. Of more direct relevance are studies using cultured ventral mesencephalic dopaminergic neurons which show that nicotine pre-treatment attenuates toxicity-induced by MPP + , the metabolite of MPTP that selectively destroys dopaminergic terminals [21].…”

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

“…This may indicate that the loss of receptors in basal ganglia and cortical regions is partly a consequence of deafferentation from midbrain nuclei. Since there is evidence for a neuroprotective role of both the noradrenergic (Martel et al 1998) and the cholinergic (O'Neill et al 2002) system, the loss of receptors might aggravate the damage caused by excitotoxic glutamatergic flow of cortical projection neurones, which in turn is triggered by the high neocortical load of mutant huntingtin (Cepeda et al 2003).…”