Current Pharmaceutical Design - Volume 14, Issue 10, 2008

There is a growing body of evidence to show that AGEs, which form and accumulate at an accelerated rate under diabetes and normal aging, are implicated in the pathogenesis of various devastating disorders such as diabetic vascular complications, coronary heart diseases, Alzheimer's disease, cancer growth and metastasis, insulin resistance and nonalcoholic fatty liver disease. In addition, the engagement of the receptor for AGEs, RAGE with the macroprotein derivatives is reported to elicit oxidative stress and vascular inflammation and subsequently activate the downstream signalings, thereby being involved in the development and progression of these devastating disorders. These observations suggest that the AGEs-RAGE axis is a novel therapeutic target for various disorders. In this issue, I would like to reinforce the emerging knowledge regarding AGEs and RAGE as an important mediator in health and disease. I believe that the issue is helpful for most of the researchers and physicians in the field of drug design and clinical pharmacology, especially those who would like to understand the pathophysiological role of the AGEs-RAGE system in health and numerous devastating disorders.

Recent clinical studies have reported an increased risk for various types of cancers in patients with diabetes. Diabetes is characterized by increased oxidative stress conditions. Hyperglycemia induces oxidative stress generation in a variety of cells via various metabolic pathways, thus causing oxidative DNA damage, an initial step of carcinogenesis. There is accumulating evidence that advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate under normal aging process and diabetes, are involved in the development and progression of cancers. AGE stimulate oxidative stress generation through the interaction with a receptor for AGE (RAGE), while oxidative stress generation promotes the formation of AGE and increases the expression of RAGE. These findings suggest that the crosstalk between the AGE-RAGE system and oxidative stress generation may form a positive feedback loop, thus further increasing the risk for cancers in patients with diabetes. This paper reviews current knowledge about the role of AGE-RAGE system in the development of various types of cancers.

Diabetic nephropathy is the most common cause of end-stage renal disease in the world, and accounts for a significant increase in morbidity and mortality in patients with diabetes. Therapeutic options such as strict blood pressure and/or glycemic control are effective for preventing the development and progression of diabetic nephropathy, but the number of diabetic patients on hemodialysis is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. Advanced glycation end products (AGEs) are heterogeneous cross-linked sugar-derived proteins which could accumulate in glomerular basement membrane, mesangial cells, endothelial cells, and podocytes in patients with diabetes and/or end-stage renal failure. AGEs are thought to be involved in the pathogenesis of diabetic nephropathy via multifactorial mechanisms such as oxidative stress generation and overproduction of various growth factors and cytokines. Further, recently, the cross-talk between AGEs and the renin-angiotensin system (RAS) has been proposed to participate in diabetic nephropathy. In addition, activation of the RAS elicits ROS generation and subsequently stimulates growth factor and cytokine production by kidney cells as well. These observations suggest that combination therapy with inhibitors of the RAS and blockers of the AGEs formation and/or their downstream pathway may be a novel therapeutic option for preventing diabetic nephropathy. In this paper, we review the role of AGEs and their receptor system in the pathogenesis of diabetic nephropathy. We further discuss here the cross-talk between AGEs and the RAS in the development and progression of diabetic nephropathy.

Diabetic neuropathy is the commonest form of peripheral neuropathy in the developed countries of the world. In diabetic patients, the presence of peripheral neuropathy increases their risks for developing foot ulceration and subsequent necrosis that necessitates lower limb amputation. Although the precise mechanisms underlying diabetic neuropathy remain unclear, there is evidence that hyperglycemia- induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy; AGE-modified peripheral nerve myelin is susceptible to phagocytosis by macrophages and contributes to segmental demyelination; modification of major axonal cytoskeletal proteins such as tubulin, neurofilament, and actin by AGEs results in axonal atrophy/degeneration and impaired axonal transport; and glycation of extracellular matrix protein laminin leads to impaired regenerative activity in diabetic neuropathy. Recently, the receptor for AGEs (RAGE) has been found to colocalize with AGEs in diabetic peripheral nerves. This suggests that, in diabetic neuropathy, AGEs and AGE/RAGE interactions induce oxidative stress, result in upregulation of nuclear factor (NF)-kappaB and various NF-kappaB-mediated proinflammatory genes, and exaggerate neurological dysfunction, including altered pain sensation. Additionally, AGE/RAGE-induced oxidative stress further accelerates formation of glycoxidation products such as Nepsilon-(carboxymethyl)lysine and pentosidine. Although new drugs that inhibit the formation of AGEs and block the AGE-RAGE interaction are being studied, no effective treatment modalities against AGE-induced nerve injury are currently available clinically. A therapeutic strategy to prevent and ameliorate diabetic neuropathy using anti-AGE agents needs to be established. In this review, the current issues involved in the role of the glycation process and the potential treatment options for diabetic neuropathy are explored.

Diabetic retinopathy is a common and potentially devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. However, current therapeutic options for the treatment of sight-threatening proliferative diabetic retinopathy such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target diabetic retinopathy is actually desired for most of the patients with diabetes. Chronic hyperglycemia is a major initiator of diabetic retinopathy. However, recent clinical study has substantiated the concept of ‘hyperglycemic memory’ in the pathogenesis of diabetic retinopathy. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least several years after the DCCT trial, despite increasing hyperglycemia. These findings suggest a long-term beneficial influence of early metabolic control on clinical outcomes in type 1 diabetic patients. Among various biochemical pathways implicated in the pathogenesis of diabetic retinopathy, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory ‘hyperglycemic memory’. Further, there is a growing body of evidence that AGEs-RAGE (receptor for AGEs) interaction- mediated oxidative stress generation plays an important role in diabetic retinopathy. This article summarizes the role of AGEs and oxidative stress in the development and progression of diabetic retinopathy and the therapeutic interventions that could prevent this devastating disorder. We also discuss here the pathological crosstalk between the AGEs-RAGE and the renin-angiotensin system in diabetic retinopathy and a potential clinical utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-γ-modulating activity.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules, formed in vivo both by non-oxidative and oxidative reactions of sugars and their adducts to proteins and lipids. It is now well established that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being implicated in various types of AGEs-related disorders such as diabetic vascular complications, neurodegenerative diseases and cancers. There is a growing body of evidence that activation of RAGE (receptor for AGEs) system is also implicated in these devastating disorders. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells including hepatocytes and hepatic stellate cells. Liver is not only a target organ, but also an important site for clearance and catabolism of circulating AGEs. Although there are several papers to suggest the involvement of AGEs-RAGE system in various types of liver diseases such as non-alcoholic steatohepatitis, liver cirrhosis and cancers, as far as we know, there are few comprehensive reviews to deal with this issue. Therefore, in this paper, we shortly review the pathological role of AGEs and RAGE in various liver diseases.

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the major constituents of which are amyloid β protein and tau protein, respectively. Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under normal aging, can be identified immunohistochemically in both SPs and NFTs in AD patients. Further, recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of AD. Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of AGEs through the non-enzymatic glycation, thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of AGEs with a receptor for AGEs (RAGE) elicits reactive oxygen species generation and vascular inflammation, and subsequently alters various gene expressions in numerous types of cells, all of which could contribute to the pathological changes of diabetic vascular complications and AD. Indeed, we have recently found that glyceraldehyde-derived AGEs (Glycer-AGE) induce apoptotic cell death in cultured cortical neuronal cells. In addition, we also found that neurotoxic effect of diabetic serum on neuronal cells was blocked by neutralizing antibody raised against Glycer-AGE. In human AD brains, Glycer-AGE are actually detected in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. These observations suggest that Glycer-AGE play a role in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of AD, especially focusing on Glycer-AGE.

Advanced glycation end-products (AGEs) are generated in the diabetic milieu, as a result of chronic hyperglycemia and enhanced oxidative stress. These AGEs, via direct and receptor dependent pathways promote the development and progression of cardiovascular disease. AGEs accumulate at many sites of the body including the heart and large blood vessels in diabetes. These modified proteins interact with receptors such as RAGE to induce oxidative stress, increase inflammation by promoting NFκB activation and enhance extracellular matrix accumulation. These biological effects translate to accelerated plaque formation in diabetes as well as increased cardiac fibrosis with consequent effects on cardiac function. Strategies to reduce the ligation of AGEs to their receptors such as agents which reduce AGE accumulation, soluble RAGE which acts as a competitive antagonist to the binding of AGEs to RAGE and genetic deletions of RAGE appear to attenuate diabetes associated atherosclerosis. Benefits on cardiac dysfunction with these inhibitors of the AGE/RAGE axis are not as well characterised. In conclusion, therapeutic strategies targeting AGEs appear to have significant clinical potential, often in combination with currently used agents such as inhibitors of the renin-angiotensin system, to reduce the major burden of diabetes, its associated cardiovascular complications.

Non-enzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Further, recently, engagement of their receptor, RAGE with AGEs is shown to activate its down-stream signaling and evoke oxidative stress and inflammation in diabetes. Since oxidative stress generation and inflammation are closely associated with insulin resistance as well, it is conceivable that the AGEs-RAGE system could play a role in the pathogenesis of insulin resistance and subsequently the development of diabetes. In this paper, we review the role of the AGEs-RAGE system in insulin resistance, especially focusing on its effects on the insulin-signaling pathways in skeletal muscles and adipocytes.

Cytochrome P450 (CYP) 3A4, one of the most abundant hepatic Phase I enzymes, is able to metabolize more than 50% currently available therapeutic drugs. However, this enzyme is subject to mechanism-based inhibition by a number of xenobiotics and commonly- used drugs, which is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when the parental drugs are converted by CYPs to reactive metabolites. The inactivation of CYP3A4 by drugs may lead to important clinical consequences, because the inhibition frequently causes unfavorable drug-drug interactions and toxicity, depending on many factors associated with the enzyme, drugs and the patients. Some drugs (e.g. mibefradil) have been withdrawn from the market since they are eventually identified as CYP3A4 inactivators that can cause toxicity-related fatal events. Clinical professionals should take proper approaches to avoid such toxicities when using drugs that are mechanism-based CYP3A4 inhibitors, in particular, when in combination with other drugs that are substrates for CYP3A4. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (e.g. safe drug combination regimen, dose adjustment or discontinuation of therapy when toxic drug interactions occur), close therapeutic drug monitoring, and prediction of the risks for potential drug-drug interactions. Clinicians should have sound knowledge on drugs that behave as CYP3A4 inactivators and take cautions for their clinical use. A fifth approach is the design of drugs with minimal potential for behaving as a CYP3A4 inactivator. These new drugs are so called “hard drugs” which are non-metabolizable (thus mechanism- based CYP3A4 inhibition is avoided), and excreted through either the bile or kidney, with predictable pharmacokinetics. Further studies are needed to explore the suitable approaches for minimizing mechanism-based inhibition of CYP3A4 and thus avoiding potential toxicities and unfavorable drug-drug interactions.

Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/ antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoximes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also extensively reviewed.