Rat Anti Chicken acetylcholine nicotinic Receptors, neuronal Heterohybridoma [mAB 381]

PurposeIn patients with Alzheimer's disease (AD), the loss of cerebral nicotinic acetylcholine receptors (nAChRs) that are implicated in higher brain functions has been reported. However, it is unclear if nAChR deficits occur in association with cognitive impairments. The purpose of this study was to assess the relationship between nAChR deficits and cognitive impairments in a mouse model of AD (APP/PS2 mice).ProceduresThe cognitive abilities of APP/PS2 and wild-type mice (aged 2-16months) were evaluated using the novel object recognition test. Double-tracer autoradiography analyses with 5-[I-125]iodo-A-85380 ([I-125]5IA: 42 nAChR imaging probe) and 2-deoxy-2-[F-18]fluoro-D-glucose were performed in both mice of different ages. [I-123]5IA-single-photon emission tomography (SPECT) imaging was also performed in both mice at 12months of age. Furthermore, each age cohort was investigated for changes in cognitive ability and expression levels of 7 nAChRs and N-methyl-D-aspartate receptors (NMDARs).ResultsNo significant difference was found between the APP/PS2 and wild-type mice at 2-6months of age in terms of novel object recognition memory; subsequently, however, APP/PS2 mice showed a clear cognitive deficit at 12months of age. [I-125]5IA accumulation decreased in the brains of 12-month-old APP/PS2 mice, i.e., at the age at which cognitive impairments were first observed; this result was supported by a reduction in the protein levels of 4 nAChRs using Western blotting. nAChR deficits could be noninvasively detected by [I-123]5IA-SPECT in vivo. In contrast, no significant changes in glycometabolism, expression levels of 7 nAChRs, or NMDARs were associated with cognitive impairments in APP/PS2 mice.ConclusionA decrease in cerebral 42 nAChR density could act as a biomarker reflecting cognitive impairments associated with AD pathology.

Alpha7 nicotinic acetylcholine receptor is emerging as a central regulator in inflammatory processes, as documented by increasing studies reported in the literature. For instance, the activation of this nicotinic receptor subtype in resident macrophages inhibits the production of pro-inflammatory cytokines, thereby attenuating local inflammatory responses, and may open a new window in the treatment of chronic inflammatory disease, such as Crohn's disease, rheumatoid arthritis, psoriasis, and asthma. In continuation of our ongoing research for the development of new cholinergic drug candidates, we selected the nicotine derivative CAP55, which was previously shown to exert anti-inflammatory effects via nicotinic stimulation, as a suitable compound for lead optimization. Through the isosteric replacement of its 3,5-disubstituted 4,5-dihydroisoxazole core with a 1,4-disubstituted 1,2,3-triazole ring, we could rapidly generate a small library of CAP55-related analogs via a one-pot copper(I)-catalyzed azide-alkyne cycloaddition. Receptor binding assays at nAChRs led to the identification of two promising derivatives, compounds 4 and 10, worthy of further pharmacological studies.