Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology.

MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, U.K.
Neuroscience (Impact Factor: 3.33). 02/1995; 64(2):385-95. DOI: 10.1016/0306-4522(94)00410-7
Source: PubMed

ABSTRACT High-affinity nicotine binding, considered to primarily reflect the presence of CNS alpha 4 beta 2 nicotinic receptor subunits, was examined autoradiographically in brain regions most severely affected by Alzheimer and Parkinson types of pathology. In the midbrain, the high density of binding associated with the pars compacta of the substantia nigra was extensively reduced (65-75%, particularly in the lateral portion) in both Lewy body dementia and Parkinson's disease. Since loss of dopaminergic neurons in Lewy body dementia was only moderate (40%), loss or down-regulation of the nicotinic receptor may precede degeneration of dopaminergic neurons in this region. In the dorsolateral tegmentum, where diffuse cholinergic perikarya are located, nicotine binding was highly significantly decreased in both Lewy body dementia and Parkinson's disease with almost no overlap between the normal and disease groups, indicative of a major pathological involvement in or around the pedunculopontine cholinergic neurons. In the hippocampus, binding was decreased around the granular layer in Lewy body dementia and Alzheimer's disease, although unchanged in the stratum lacunosum moleculare, where binding was relatively higher. Dense bands of receptor binding in the presubiculum and parahippocampal gyrus--areas of highest binding in human cortex--were diminished in Alzheimer's disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimer's disease throughout the cortical layers but in Lewy body dementia only in lower layers, in which Lewy bodies are concentrated. Abnormalities of the nicotinic receptor in the diseases examined appear to be closely associated with primary histopathological changes: dopaminergic cell loss in Parkinson's disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimer's disease. Loss or down-regulation of the receptor may precede neurodegeneration.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, the nicotinic-PAM-based treatments are expected to be highly efficacious with fewer side effects as compared to a more indiscriminate action of exogenous orthosteric agonists. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.
    European journal of pharmacology 03/2014; DOI:10.1016/j.ejphar.2014.01.072 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[(18)F]fluoro-3,4-dihydroxy-L-phenylalanine (6-[(18)F]fluoro-L-DOPA) to measure the dopaminergic function and another with 2-[(18)F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[(18)F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[(18)F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P <0.05) decrease of 2-[(18)F]fluoro-A-85380 DV in the striatum (-10%) and substantia nigra (-14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2009; 29(9):1601-8. DOI:10.1038/jcbfm.2009.74 · 5.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The nicotinic acetylcholine receptor (nAChR) system plays a regulatory role in a number of cognitive processes. Cholinesterase inhibitors (i.e., galantamine) that potentiate cholinergic neurotransmission improve cognitive function in Alzheimer's disease (AD); however, the relationship between these effects and associated changes in nAChRs are yet to be established in vivo. 2-[18F]Fluoro-A-85380 (2-FA) binds to nAChRs and with positron emission tomography (PET) imaging provides a composite measure of receptor density and ligand affinity. This study aimed to: (1) quantify nAChRs in vivo in 15 drug-naïve patients with mild AD before and after chronic treatment with galantamine, using 2-FA and PET, and (2) examine the relationship between treatment-induced changes in nAChRs and improvements in cognitive function. Participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of approximately 200 MBq of 2-FA on two occasions (before and after 12 weeks, galantamine treatment). A 3-day washout period preceded the second scan. Brain regional 2-FA binding was assessed through a simplified estimation of distribution volume (DV(S)). Performance on global measures of cognition significantly improved following galantamine treatment (p < 0.05). This improvement extended to specific cognitive measures of language and verbal learning. No significant differences in nAChR DV(S) before and after galantamine treatment were found. The treatment-induced improvement in cognition was not correlated with regional or global nAChR DV(S), suggesting that changes in nAChRs may not be responsible for the improvements in cognition following galantamine in patients with mild AD.
    Psychopharmacology 10/2008; 202(1-3):79-91. DOI:10.1007/s00213-008-1347-9 · 3.99 Impact Factor