Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

Abstract

Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy.

Keywords: Alpha7; Neuroprotection; Nicotinic receptors; Parkinson's disease; l-dopa-induced dyskinesias.

Fig. 1

Schematic representation of α7 nAChR structure and localization. The α7 nAChR subunit consists of a large extracellular N-terminal region, four transmembrane (TM) domains and an extracellular carboxy-terminal (A). The α7 receptor is membrane bound and composed of 5 identical α subunits, with five agonist binding sites, with (B) depicting a top view and a side view of the receptor in the cell membrane. α7 nAChRs are very widely distributed in numerous brain regions (C). The smaller font size represents a lower density of α7 nAChRs in the various brain areas.

Fig. 2

The α7 nAChR agonist ABT-107 reduces LIDs in parkinsonian monkeys. MPTP-lesioned monkeys were gavaged with L-dopa plus carbidopa twice daily 5 days per week, with the α7 nAChR agonist ABT-107 given orally 30 min before L-dopa. The left panel (A) shows that ABT-107 significantly reduced LIDs by 60%. The middle panel (B) shows that the reduction in LIDs with combined ABT-107 plus ABT-894 treatment was similar to that with ABT-107 or ABT-894 alone. The right panel (C) shows ABT-107 discontinuation leads to a return of LIDs to vehicle-treated levels by 6 wk. Values are the mean ± SEM of 5–6 monkeys. Significance of difference from vehicle, *p < 0.05, **p < 0.01, ***P < 0.001 using two-way ANOVA. Taken in modified form from [149].

Fig. 3

Various intracellular signaling pathways have been linked to α7 nAChR activation as described in the text. These lead to secondary events within the same cell or others, with consequent alterations in synaptic plasticity, development, maintenance, survival, apoptosis, neurotransmitter release, immune responsiveness or others. These subsequently modulate movement, addiction, anxiety, attention, learning, memory, sensory gating, inflammation, and neuroprotection. Bcl, B-cell lymphoma; CaMK, Ca2+/calmodulin-dependent protein kinase; ERK, extracellular signal-regulated kinases; MEK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; p-AKT, phosphorylated AKT.