Aldose reductase in the etiology of diabetic complications 3. Neuropathy

Abstract

Aldose reductase has been shown to be present in both autonomic and somatic nerves. Activation of this enzyme and the polyol pathway has been demonstrated in diabetic animal models to cause a range of biochemical, functional, and structural consequences that include the accumulation of sorbitol and fructose; axoglial dysjunction; paranodal demyelination; abnormalities in axonal transport, blood flow, and vascular permeability; and resistance to ischemic transmission of action potentials. These data provide an insight into the range of processes that if activated may either singly or in combination result in altered patterns of nerve function and structural alterations in diabetic neuropathy. In animal models of diabetes, it has been shown that inhibition of aldose reductase can modify these diabetes-induced changes. It is hoped that the results of large-scale controlled trials will provide clinical evidence to support these data.

Activation of Nrf2 signaling by natural products-can it alleviate diabetes?

“…Diabetic neuropathy is thought to occur both from hyperglycemia-induced damage to nerve cells per se and from neuronal ischemia caused by hyperglycemia-induced decreases in neurovascular flow. The hyperglycemic damage can be assigned to the already mentioned altered metabolic pathways, the uncontrolled redox state and ER stress (Albers and Pop-Busui, 2014; Lupachyk et al, 2013a, 2013b; O’Brien et al, 2014; Obrosova et al, 2004; Shakeel, 2015; Stribling et al, 1989; Sytze Van Dam et al, 2013; Zochodne, 2014). Besides hyperglycemia, concomitant hyperlipidemia, obesity and hypertension often contribute to neuronal dysfunction in type 2 diabetics (Grisold et al, 2017).…”

Tyrosine-48 Is the Proton Donor and Histidine-110 Directs Substrate Stereochemical Selectivity in the Reduction Reaction of Human Aldose Reductase: Enzyme Kinetics and Crystal Structure of the Y48H Mutant Enzyme

“…kidneys (Gabbay, 1973;Kador, 1988). A number of aldose reductase inhibitors (ARIs) have been developed and tested in patients for the treatment of such complications (Gabbay etal., 1979;Judzewitsch et al, 1983;Dvornik, 1987;Stribling et al, 1989;Masson & Boulton, 1990). Presently, none of these drugs are therapeutically effective due to their side effects, nonspecificity, and inhibition of other members of the aldo-keto reductase family (Martyn et al, 1987;O'Brien et al, 1982;Poulsom, 1986).…”

Effects of Ponalrestat, an Aldose Reductase Inhibitor, on Neutrophil Killing of Escherichia Coli and Autonomic Function in Patients With Diabetes Mellitus

“…In addition, many studies in animals support the hypothesis that polyol pathway activation by hyperglycemia might cause nerve damage (7). The aldose reductase inhibitor class of drugs have been shown to prevent nerve damage in diabetic animals (7), but in humans, results of clinical trials with these drugs in diabetic autonomic neuropathy have been disappointing and have produced, at best, only slight treatment effects (8,9) or none at all (10)(11)(12). There have been no reported clinical trials in which the effects of aldose reductase inhibitor drugs on neutrophil function were assessed.…”

“…Aldose reductase, the rate-limiting enzyme in the polyol pathway, has been demonstrated in neutrophils (3), and some limited evidence suggests that increased polyol pathway activity inhibits neutrophil function in vitro (3)(4)(5)(6). In addition, many studies in animals support the hypothesis that polyol pathway activation by hyperglycemia might cause nerve damage (7). The aldose reductase inhibitor class of drugs have been shown to prevent nerve damage in diabetic animals (7), but in humans, results of clinical trials with these drugs in diabetic autonomic neuropathy have been disappointing and have produced, at best, only slight treatment effects (8,9) or none at all (10)(11)(12).…”