Abstract. The advanced glycosylation end products (AGE) participate in the pathogenesis of nephropathy and other diabetic complications through several mechanisms, including their binding to cell surface receptors. The AGE receptors include RAGE, the macrophage scavenger receptors, OST-48 (AGE-R1), 80K-H (AGE-R2), and galectin-3 (AGE-R3). Galectin-3 interacts with the ␤-galactoside residues of cell surface and matrix glycoproteins via the carbohydrate recognition domain and with intracellular proteins via peptide-peptide associations mediated by its N-terminus domain. These structural properties enable galectin-3 to exert multiple functions, including the mRNA splicing activity, the control of cell cycle, the regulation of cell adhesion, the modulation of allergic reactions, and the binding of AGE. The lack of transmembrane anchor sequence or signal peptide suggests that it is associated with other AGE receptors, possibly AGE-R1and AGE-R2, to form an AGE-receptor complex, rather than playing an independent role. In target tissues of diabetic vascular complications, such as the endothelium and mesangium, galectin-3 is weakly expressed under basal conditions and is markedly upregulated by the diabetic milieu (and to a lesser extent by aging). Galectin-3-deficient mice were found to develop accelerated diabetic glomerulopathy versus the wild-type animals, as evidenced by the more pronounced increase in proteinuria, mesangial expansion, and matrix gene expression. This was associated with a more marked renal/glomerular AGE accumulation, suggesting that it was attributable to the lack of galectin-3 AGEreceptor function. These data indicate that galectin-3 is upregulated under diabetic conditions and is operating in vivo to provide protection toward AGE-induced tissue injury, as opposed to RAGE.Diabetic nephropathy is a major cause of morbidity and mortality in patients with both type 1 and type 2 diabetes. It is characterized by predominant glomerular involvement with expansion of the mesangial region and glomerular basement membrane (GBM) thickening, associated with ialinosis of the afferent and efferent arterioles and tubulointerstitial sclerosis. The enlargement of the mesangium seems to play a major role in the progression of glomerulopathy, for it is initially accommodated by an overall growth of the glomerulus but later impinges on the glomerular capillary lumen and diminishes the filtration surface. The increase in mesangial volume is linked predominantly to increased deposition of the extracellular matrix (ECM) and possibly to an expansion of the cell compartment (1).Hyperglycemia plays a central role in the pathogenesis of diabetic nephropathy, as shown by its prevention by strict metabolic control (2,3). The injurious effects of hyperglycemia have been attributed to its biochemical and metabolic consequences, including the increased glucose flux through the polyol and hexosamine pathways, activation of protein kinase C, enhanced nonenzymatic glycation, and oxidative stress (1).

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Migraine is a common type of headache and its most severe attacks are usually treated with triptans, the efficacy of which is extremely variable. Several SNPs in genes involved in metabolism and target mechanisms of triptans have been described. To define an association between genetic profile and triptan response, we classified a migrainous population on the basis of triptan response and characterized it for polymorphisms in the genes coding for monoamine oxidase A, G protein β3 and the cytochrome CYP1A2. Analysis of the association between genotypic and allelic frequencies of the analyzed SNPs and the grade of response to triptan administration showed a significant correlation for MAOA uVNTR polymorphism. Further stratification of patients in abuser and non-abuser groups revealed a significant association with triptan overuse and, within the abusers, with drug response to the CYP1A2*1F variant.

Migraine is a complex, neurovascular disorder in which genetic and environmental factors interact. At present, frontline therapies in the acute treatment of migraine include the use of non-steroidal anti-inflammatory drugs and triptans. Evidence indicates that calcitonin gene-related peptide (CGRP) plays a fundamental role in the mechanism of migraine. CGRP is a strong vasodilatatory neuropeptide that is released from activated trigeminal sensory nerves. The development of CGRP antagonists has also been driven by the fact that triptans are vasoconstrictive and cannot be safely used in patients with cardiovascular risk factors. Olcegepant (BIBN4096) is the first CGRP antagonist for the treatment of migraine that has been tested in clinical trials, but because of its poor oral bioavailability, only the intravenous formulation has been tested. The first oral non-peptide CGRP antagonist, telcagepant, has been shown recently to be highly effective in the treatment of migraine attacks. This development can be considered as the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are also of importance, since they support an interesting pathophysiological hypothesis of migraine. The pipeline of future compounds for the treatment of acute migraine headaches include TPRV1 antagonists, prostaglandin E receptor 4 (EP(4)) receptor antagonists, serotonin 5HT1(F) receptor agonists and nitric oxide synthase inhibitors. The immediate future of a preventative treatment for migraine headaches is well represented by botulinum toxin type-A, glutamate NMDA receptor antagonists, gap-junction blocker tonabersat and an angiotensin type 1 blocker candesartan.

Pharmacogenomic studies of triptans suggest that some genetic determinants influence drug response, but the complexity of the field calls for application of a systematic approach to genetic association studies, allowing identification of a therapy response prediction panel with adequate predictive power.