Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer’s disease and Parkinson’s disease

Abstract

Nicotinic systems play an important role in the neural basis of working memory and attention. Recent progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents. In this paper, we review the theoretical justification and the experimental evidence supporting these developments. We focus on the applications of nicotinic agonists in CNS disorders that are degenerative in nature, namely Parkinson’s disease and Alzheimer’s disease. We suggest that there is considerable potential for therapeutic applications in the near future. Clinically, two major issues remain: (a) the selectivity of effects, that is, developing compounds which are selective in producing improvement in cognition, motor function, attention, or pain without significant side-effects; and (b) the realistic likelihood of long-term improvements in everyday functioning in people who have degenerative diseases.

Introduction

Progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents [3], [55]. This paper reviews the theoretical justification for such an exploration, and offers comment on some of the key issues, which may influence the success of such a strategy.

Nicotinic mechanisms are implicated in the pathophysiology of AD [20]. Patients suffering from AD have a marked reduction in cortical nicotinic cholinergic receptor binding, over and above the normal age-related decline [4], [13], [89]. Warpman and Nordberg [86] used epibatidine and ABT-418 to show selective losses of α4β2 nicotinic receptors in the brains of patients with AD. Perry et al. [62] showed that the entorhinal cortex (important in memory formation) rich in nicotinic binding, appears particularly vulnerable to amyloid plaque-induced loss of receptors. More generally, Perry et al. [63] have shown that nicotine receptor loss seems tightly linked to the primary pathology in the dementias, e.g. linked to dopaminergic cell loss in PD and Lewy Body dementia, and linked to amyloid plaques and tangles in hippocampal and parahippocampal areas in AD. These investigators also theorize that down-regulation of these nicotinic receptors in entorhinal cortex that gate Ca²⁺ may play a specific role in AD-type cognitive pathology.

Evidence from studies of cerebral blood flow (CBF) also suggests an important nicotinic component to AD. AD is associated with a marked perfusion deficit in parietotemporal cortex in addition to the global decrease in cerebral perfusion. This focal deficit is seen even in early stages of the disease and appears to be specific to AD [67]. Although the pathophysiology of this deficit is incompletely understood, attempts have been made to model these changes with pharmacologic agents. It is of interest that the nicotinic antagonist mecamylamine reliably reproduces this abnormal cerebral blood flow pattern (in normal volunteers), while the muscarinic antagonist scopolamine does not [16]. Studies in animals suggest that CBF may be in part controlled by basal forebrain cholinergic neurons [45] and nicotine reliably augments the enhancement in CBF produced by electrically stimulating this region [2] suggesting an underlying nicotinic mechanism. As the basal forebrain cholinergic neurons are heavily damaged in AD, changes in observed CBF may be secondary to damage to nicotinic systems.

Neuroimaging studies clearly support the involvement of nicotinic cholinergic systems in AD. Nordberg [58] showed a significant correlation change between the change in temporal cortex labelling of ¹¹C-nicotine and cognitive function scores in AD patients using positron emission tomography (PET). This result was bolstered by further work from these investigators [59] in which a kinetic model was developed to quantify the loss of nicotinic receptor binding in-vivo in AD patients. Significant correlations were shown between cognitive dysfunction and the loss of nicotinic receptor binding in temporal and frontal cortices and hippocampus in these patients using PET. Critically, this decrease in binding appears amenable to drug therapy: treatment of AD patients with the anticholinesterase tetrahydroaminoacridine (THA) produced an increase in ¹¹C-nicotine receptor binding along with increased cerebral blood flow after 3 weeks of chronic administration [58], and increases in nicotinic receptor binding, induced by either chronic THA treatment or by chronic infusion of nerve growth factor [10], [60] correlate with cognitive improvements on tests of attention and memory.

Epidemiological studies offer another route connecting nicotinic systems with AD. A meta-analysis of studies on smoking and AD completed by Lee [24] indicated that a history of smoking decreased the likelihood of an individual developing AD, although the reliability of this inverse relationship between smoking and AD has been questioned by subsequent work incorporating prospective components [84]. It is not untenable, however, that chronic self-administration of nicotine might produce changes in nicotinic binding similar to those observed in the laboratory based studies described above, and some evidence does exist for upregulation of nicotine binding in brains of long-term smokers [5].

In addition to AD, changes in CNS cholinergic systems have also been shown to occur in the brains of patients with PD. In particular, a loss of cholinergic cells in the basal forebrain nuclei similar to that seen in AD has been described in PD [88]. The loss of cholinergic markers in the cortex [63] that occur in PD may be related to lesions in these nuclei and other cholinergic projections to the cortex [90]. In demented PD patients, the loss of cortical cholinergic markers has been shown to be of greater magnitude and more extensive than that of non-demented PD patients [61]. Studies have shown that, as with AD, a roughly linear relationship exists between the loss of cortical (particularly temporal) cholinergic markers (choline acetyltransferase and acetylcholinesterase) and the degree of cognitive impairment before death [71]. PD patients have also been shown to have an exaggerated sensitivity to the cognitive-impairing effects of scopolamine, similar to AD [8]. Studies have shown a marked reduction in cortical nicotinic receptor binding that parallels the degree of dementia in PD and increasing age [4], [90], and similarities between these sites and between the other cholinergic markers in PD and AD.

Studies of the cognitive deficits seen in PD suggest that cholinergic mechanisms may play a substantial role, particularly in producing so-called subcorticofrontal deficits [9], [69]. Although the anatomy of the deficits is incompletely understood, this shared damage to cholinergic systems observed in PD and AD may be responsible for qualitatively similar attentional deficits.

Taken together, these results suggest that loss of nicotinic receptors and their associated source and/or target cells may play an important role in the cognitive deficits seen in both of these disorders.