Binding of adenosine receptor ligands to brain of adenosine receptor knock-out mice: evidence that CGS 21680 binds to A 1 receptors in hippocampus

The adenosine receptor agonist 2-[ p-(2-carboxyethyl)phenylethylamino]-5'- N-ethylcarboxamidoadenosine (CGS 21680) is generally considered to be a selective adenosine A 2A receptor ligand. However, the compound has previously been shown to exhibit binding characteristics that are not compatible with adenosine A 2A receptor binding, at least in brain regions other than the striatum. We have examined binding of [ 3H]CGS 21680 and of antagonist radioligands with high selectivity for adenosine A 1 or A 2A receptors to hippocampus and striatum of mice lacking either adenosine A 1 (A1R (-/-)) or A 2A (A2AR (-/-)) receptors. Both receptor autoradiography and membrane binding techniques were used for this purpose and gave similar results. There were no significant changes in the binding of the A 1 receptor antagonist [ 3H]DPCPX in mice lacking A 2A receptors, or in the binding of the A 2A receptor antagonists [ 3H]SCH 58261 and [ 3H]ZM 241385 in mice lacking A 1 receptors. Furthermore, [ 3H]CGS 21680 binding in striatum was abolished in the A2AR (-/-), and essentially unaffected in striatum from mice lacking A 1 receptors. In hippocampus, however, binding of [ 3H]CGS 21680 remained in the A2AR (-/-), whereas binding was virtually abolished in the A1R (-/-). There were no adaptive alterations in A 2A receptor expression in this region in A1R (-/-) mice. Thus, most of the [ 3H]CGS 21680 binding in hippocampus is dependent on the presence of adenosine A 1 receptors, but not on A 2A receptors, indicating a novel binding site or novel binding mode

A genome-wide association study in progressive multiple sclerosis

Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established.Objective: We aimed to identify genetic variants associated with progressive MS (PrMS).Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10-4) in two independent sets of primary progressive MS cases and controls.Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934T, pcombined=6.7\uc3\u9710-16, OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343G, pcombined=2.4\uc3\u9710-5, OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02).Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role