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.
"Neurodegenerative, sensorimotor and psychiatric disorders associated with cognitive decline and decreased attention have been linked to deficits in the expression and function of nicotinic acetylcholine receptors (Freedman et al., 1995; Guan et al., 2000; Leonard et al., 2000; Nordberg and Winblad, 1986; Perry et al., 1995). By contrast, activation of nicotinic receptors by endogenous and exogenous nicotinic agents is generally pro-cognitive and can be therapeutic in patients and animal models of age-, disease-and trauma-related neurocognitive dysfunctions (Arendash et al., 1995; Bencherif et al., 2011; Guseva et al., 2008; Kelso and Oestreich, 2012; Lendvai et al., 2013; Olincy et al., 2006; Thomsen et al., 2011; Verbois et al., 2003; Wallace and Porter, 2011). "
[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; 727(1). DOI:10.1016/j.ejphar.2014.01.072 · 2.53 Impact Factor
"It has been shown that nicotine enhances synaptic transmission, which is critical for new learning to take place  . Post mortem studies have shown that the loss of nAChR activity correlates closely with the severity of impairment at the time of death  . Finally, the formation of amyloid plaques and neurofibrillary tangles appear to be directly associated with nAChRs . "
[Show abstract][Hide abstract] ABSTRACT: Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed.
Mini Reviews in Medicinal Chemistry 08/2012; 13(3). DOI:10.2174/1389557511313030012 · 2.90 Impact Factor
"Although most of the latter studies did not distinguish between the different nAChRs subtypes , they consistently reported a reduction of nAChRs in the striatum of deceased PD patients ( Aubert et al , 1992 ; Court et al , 2000 ; Perry et al , 1995 ; Rinne et al , 1991 ) . In addition , the substantia nigra was examined once ( Perry et al , 1995 ) and a significant decrease of nAChRs was also reported . More recent postmortem studies ( Pimlott et al , 2004 ; Quik et al , 2004 ; Schmaljohann et al , 2006 ) using more specific ligands , confirmed the previous studies showing a significant decrease of 5 - [ 125 I ] iodo - A - 85380 and 2 - [ 18 F ] fluoro - A - 85380 binding in the striatum of PD patients . "
[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 · 5.41 Impact Factor
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