Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy.

Abstract

Experimental diabetic peripheral neuropathy (DPN) is marked by impaired nerve conduction velocity (NCV), reduced nerve blood flow (NBF), and a variety of metabolic abnormalities in peripheral nerve that have been variously ascribed to hyperglycemia, abnormal fatty acid metabolism, ischemic hypoxia, and/or oxidative stress. Some investigators propose that NCV slowing in experimental DPN can be explained entirely on the basis of nerve energy depletion secondary to reduced NBF. This article reports highly selective effects of administration of the antioxidant DL-␣-lipoic acid (LA) to streptozotocin-injected diabetic rats. LA improved digital sensory but not sciatic-tibial motor NCV, corrected endoneurial nutritive but not composite NBF, increased the mitochondrial oxidative state without correcting nerve energy depletion, and enhanced the accumulation of polyol pathway intermediates without worsening myo-inositol or taurine depletion. These studies implicate oxidative stress as an important pathophysiological factor in experimental DPN. They reveal complex interrelationships among nerve perfusion, energy metabolism, osmolyte content, conduction velocity, and oxidative stress that may reflect the heterogeneous and compartmentalized composition of peripheral nerve.

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].…”

“…We have previously reported [19,20] that a number of anaesthetics distort the profile of peripheral nerve metabolites, whereas sedation by a short exposure to CO 2 (approximately 15-20 s) with immediate cervical dislocation preserves high-energy phosphate levels in the range of those obtained after decapitation without any narcosis. For this reason, two different sets of animals were used for functional and metabolic studies.…”