Inhibitors of Advanced Glycation End Product Formation and Neurovascular Dysfunction in Experimental Diabetes

Abstract

Advanced glycation and lipoxidation end products (AGEs/ALEs) have been implicated in the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy, and retinopathy. This article reviews the evidence regarding the peripheral nerve and its vascular supply. Most investigations done to assess the role of AGEs/ALEs in animal models of diabetic neuropathy have used aminoguanidine as a prototypic inhibitor. Preventive or intervention experiments have shown treatment benefits for motor and sensory nerve conduction velocity, autonomic nitrergic neurotransmission, nerve morphometry, and nerve blood flow. The latter depends on improvements in nitric oxide-mediated endothelium-dependent vasodilation and is responsible for conduction velocity improvements. A mechanistic interpretation of aminoguanidine's action in terms of AGE/ALE inhibition is made problematic by the relative lack of specificity. However, other unrelated compounds, such as pyridoxamine and pyridoxamine analogues, have recently been shown to have beneficial effects similar to aminoguanidine, as well as to improve pain-related measures of thermal hyperalgesia and tactile allodynia. These data also stress the importance of redox metal ion-catalyzed AGE/ALE formation. A further approach is to decrease substrate availability by reducing the elevated levels of hexose and triose phosphates found in diabetes. Benfotiamine is a transketolase activator that directs these substrates to the pentose phosphate pathway, thus reducing tissue AGEs. A similar spectrum of improvements in nerve and vascular function were noted when using benfotiamine in diabetic rats. Taken together, the data provide strong support for an important role for AGEs/ALEs in the etiology of diabetic neuropathy.

Cytological and Histochemical Studies in Rat Liver and Pancreas during Progression of Streptozotocin Induced Diabetes and Possible Protection of Certain Natural Antioxidants

“…In many previous morphological studies there were many pathological changes, degenerated hepatocytes with polymorphic nuclei, dilated sinusoids and mononuclear cell infiltrate extending through hepatic tissue. Kupffer cells appeared engulfing debris and hyperplasia of bile duct is also found as pathological finding in diabetic animal [27]. This confirms our finding observed in this work.…”

“…Therefore, monitoring of blood glucose levels solely is not sufficient in retarding diabetes complications. Thus, a suitable drug must have both antioxidant and blood glucose decreasing properties [25][26][27][28][29][30]. In accordance to our results blood glucose level of treated diabetic rat were significantly decreased when compared with diabetic group and nearly normal when compared to normal control.…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…Surprisingly, a number of mechanisms contributing to increased thermal sensitivity in the rat models with relatively short-term duration of diabetes were also implicated in development of thermal hypoalgesia in rats with diabetes of longer duration or diabetic mice. Those include increased AR activity, 19 activation of the AGE/ RAGE axis, 25,45,48 and oxidative-nitrosative stress, 13,14,47,53 as well as activation of ACE 22,61 and PARP. 12,44 Several studies, including one identifying an important role of insulin signaling, 51 implicate neurotrophic factor deficiency in diabetes-induced thermal sensory loss.…”

“…Thermal hyperalgesia has been described in streptozotocin (STZ)-diabetic and Zucker diabetic fatty rats with short-term (2-8 weeks) diabetes, [19][20][21][22] as well as in type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats. 23,24 This phenomenon develops with participation of multiple pathogenetic mechanisms, including (but not limited to) increased aldose reductase (AR), 19 the advanced glycation end product/receptor for advanced glycation end product (AGE/RAGE) axis, 25 protein kinase C (PKC), 26 poly(ADP-ribose) polymerase (PARP), 12 and angiotensin converting enzyme (ACE) activities, 22 oxidative stress, 20,21 and C-peptide deficiency. 27 Thermal hyperalgesia in STZ-diabetic rats was prevented or reversed by the AR inhibitor lidorestat, 19 the AGE formation inhibitor pyridoxamine, 25 the PKC LY333531, 26 several antioxidants (including ␣-lipoic acid, 20 the hydroxyl radical scavenger dimethylthiourea, 21 the xanthine oxidase inhibitor allopurinol, 28 and taurine 29 ), the PARP inhibitors 1,5-isoquinolinediol 12 and nicotinamide, 30 and the neurocytokine interleukin-6, 31 as well as by transgene-mediated expression of enkephalin in dorsal root ganglia neurons.…”

Outcome of Capparis Spinosa Fruit Extracts Treatment on Liver, Kidney, Pancreas and Stomach Tissues in Normal and Diabetic Rats

“…Liver is an organ effective in maintaining normal blood glucose levels and increases blood sugar levels leading to imbalance oxidation reduction reactions in the hepatocytes. Thus, hyperglycemia [via increased production of AGEs (advanced glycation end products)] facilitates the production of free radicals throughout impaired production of endogenous scraper (ROS: reactive oxygen species) such as superoxide dismutase (SOD) and catalase [27].…”