The Role of Neuronal Nicotinic Acetylcholine Receptors in Acute and Chronic Neurodegeneration
M. J. O'Neill, T. K. Murray, V. Lakics, N. P. Visanji and S. Duty
Affiliation: Eli Lilly&Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH,U.K.
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 Alzheimers disease, Parkinsons 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 β-amyloid toxicity in various culture systems. This effect appears to be mediated by α7 subtype nAChRs since the protection is blocked by α-bungarotoxin and is mimicked by α7 selective agonists. In vivo studies indicate that α7 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 Parkinsons disease is not clear, but in general broad spectrum nAChR agonists appear to provide protection, while α4β2 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.
Keywords: Nicotinic receptors, Parkinsons disease, Alzheimers disease, neuroprotection, Ab toxicity, cognition, stroke, nicotine
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