An aldose reductase inhibitor reverses early diabetes‐induced changes in peripheral nerve function, metabolism, and antioxidative defense

Abstract

Aldose reductase inhibitors (ARIs) prevent peripheral nerve dysfunction and morphological abnormalities in diabetic animal models. However, some experimental intervention studies and clinical trials of ARIs on diabetic neuropathy appeared disappointing because of either 1) their inadequate design and, in particular, insufficient correction of the sorbitol pathway activity or 2) the inability to reverse established functional and metabolic deficits of diabetic neuropathy by AR inhibition in general. We evaluated whether diabetes-induced changes in nerve function, metabolism, and antioxidative defense are corrected by the dose of ARI (sorbinil, 65 mg/kg/d in the diet), resulting in complete inhibition of increased sorbitol pathway activity. The groups included control rats and streptozotocin-diabetic rats treated with/without ARI for 2 weeks after 4 weeks of untreated diabetes. ARI treatment corrected diabetes-induced nerve functional changes; that is, decrease in endoneurial nutritive blood flow, motor and sensory nerve conduction velocities, and metabolic abnormalities (i.e., mitochondrial and cytosolic NAD+/NADH redox imbalances and energy deficiency). ARI restored nerve concentrations of two major non-enzymatic antioxidants, reduced glutathione (GSH) and ascorbate, and completely arrested diabetes-induced lipid peroxidation. In conclusion, treatment with adequate doses of ARIs (that is, doses that completely inhibit increased sorbitol pathway activity) is an effective approach for reversal of, at least, early diabetic neuropathy.

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

“…The latter is quite understandable in light of recent findings suggesting the dependence of inner mitochondrial membrane potential on insulin-dependent neurotrophic support [40], which is likely to be unrelated to the state of perfusion, but which is affected by intracellular oxidative stress [26,41]. Our present findings demonstrate that inhibition of diabetes-induced PARP activation, which is known to be responsible for NAD depletion [1,3] and downregulation of glyceraldehyde 3-phosphate dehydrogenase (or insufficient up-regulation as in the peripheral nerve) [7], as well as for decreased rates of glycolysis and mitochondrial oxidation [1], restores normal nerve energy state, the metabolic variable that correlates best with nerve conduction [5,17,18,20]. Unfortunately, the specific mechanisms by which diabetes disrupts electric impulse transmission in the peripheral nerve are not understood, which impedes the investigation of the role of any neuronal or Schwann cell factor, e.g.…”

“…Activation of PARP is a response to increased free radical and oxidant (peroxynitrite) generation [1] present in neural elements and vasa nervorum of the peripheral nervous system [5,25]. A number of studies, including those from our group, provide evidence of increased lipid peroxidation [17,18,19,26], impaired oxidative defence [17,18,19,20,26], and superoxide formation [27,28] in the peripheral nerve. Furthermore, recent findings [27,29] indicate increased formation of peroxynitrite, a product of the reaction between superoxide anion radicals and nitric oxide, in experimental models and human subjects with PDN.…”

“…The role of PARP in diabetes-induced sorbitol pathway hyperactivity has never been explored. At the same time, growing evidence generated in studies with aldose reductase inhibitors [18,45,46] and antioxidants [20], as well as AR-overexpressing [36,47] and AR-knockout mice [48], indicates that AR activation precedes and is largely responsible for enhanced oxidative stress in tissue sites for diabetic complications. Furthermore, a recent study of endothelial cells exposed to high glucose concentrations [46], and the studies of our group on the peripheral nerve, retina and kidneys of diabetic rats (I. G. Obrosova and P. Pacher, unpublished) suggest that AR is also a key player in peroxynitrite-induced nitrosative stress, which is a major contributor to PARP activation.…”

“…The steady-state concentrations of glutamate, α-ketoglutarate, ammonia, pyruvate, lactate, ATP, phosphocreatine (PCr), creatine (Cr), glucose, sorbitol and fructose were assayed spectrofluorometrically by enzymatic procedures as already described [17,18,19,20]. Free mitochondrial and cytosolic NAD + :NADH ratios were calculated from the steadystate metabolite concentrations and equilibrium constants of the glutamate dehydrogenase and lactate dehydrogenase systems [17,19].…”

“…Male Wistar rats (Charles River, Wilmington, Mass., USA), with body weights of 250 to 300 g, were fed a standard rat chow (PMI Nutrition, Brentwood, Mo., USA) and had free access to drinking water. STZ-diabetes was induced as described previously [5,17,18]. Blood samples for measurements of glucose were taken from the tail vein approximately 48 h after the STZ injection, and the day before the animals were killed.…”