Comments for:
Abstract
Authors
Eva L. Feldman
DIABETIC NEUROPATHY AND OXIDATIVE STRESS
Submitter: Anders A.F. Sima | asima@med.wayne.edu
Wayne State University School of Medicine
Published August 12, 2003
We read with interest the commentary by Dr. Eva Feldman in the February 2003 issue of the Journal entitled “Oxidative stress and diabetic neuropathy: a new understanding of an old problem.” In her article, Dr. Feldman discussed the four main pathways leading to overproduction of reactive oxygen species (ROS) in diabetes; the polyol pathway, advanced glycation end-products (AGE’s), the activation of PKC and hexosamine flux, and suggested that these pathways converge to perturb mitochondrial function and ROS formation. While ROS represents one of a number of possible pathogenetically relevant mechanisms, it is not likely to be the unifying or the only common culprit underlying microvascular complications in diabetes, including diabetic polyneuropathy (DPN). The studies underpinning Dr. Feldman’s construct have largely been performed in the acutely steptozotocin-diabetic rat, which is not an optimal model of the human disease. To this end it should be pointed out that distinct differences exist in underlying metabolic, molecular, functional and structural changes in diabetic neuropathy accompanying type 1 and type 2 diabetes. In this sense the streptozotocin-diabetic rat is best characterized as type 1.5. When these mechanisms are explored in models that more closely resemble the human conditions, it is becoming increasingly clear that deficiencies of insulin itself and insulinomimetic C-peptide in type 1 diabetes account for substantial pathogenetic components. These relate in particular to the effects of C-peptide replacement on Na+/K+-ATPase, vascular NO, and neurotrophic factor expression without any effects on oxidative stress per se, oxidative stress defense mechanisms or on the polyol pathway.3-6 These effects by C-peptide translate into corrections of axonal atrophy, degeneration, and nodal degenerative changes and increased regenerative capacities in chronically diabetic animals.7 Similarly, in experimental diabetes, acetyl-L-carnitine administration corrects increased PKC activity, Na+/K+-ATPase, endoneurial blood flow, expression of IGF-I, NGF levels, nerve function and structural abnormalities without affecting the polyol pathway or non- enzymatic glycation.8-10 On the other hand, acetyl-L-carnitine does decrease lipid peroxidation in rat cardiac muscle and that occurring following ischemia-reperfusion injury in a variety of models, also showing anti-oxidant activities by modulating the expression of critical genes in the maintenance of cellular redox homoeostasis.11-15
Clinically, acetyl-L-carnitine improved sensory and motor nerve conduction velocities in two randomized, placebo-controlled trials: the first involved 426 patients with polyneuropathy of various origins16, while the second one in which 333 patients with DPN were enrolled also showed improvement in neuropathic pain17. Recently, the results from two further randomized, placebo- controlled studies involving 1346 patients with DPN showed significant improvements in neuropathic pain and other clinical symptoms, paralleled by an increased number of regenerating fibers in a subgroup of biopsied patients.18 Hence, there is both pre-clinical and clinical data reporting beneficial effects of acetyl-L- carnitine without necessarily invoking oxidative stress. Further examples of effects on specific pathogenetic mechanisms, without effects on oxidative stress, are demonstrated by the acetylcholin- induced vasodilation and improvement of endoneurial blood flow and nerve conduction velocity with myo-inositol or aminoguanidine.19-21
It is therefore evident that blocking multiple pathogenetic pathways or those mentioned by Dr. Feldman representing causes of ROS overproduction do not necessarily lead to a decrease in oxidative stress. Instead, as shown in several studies, blockage of one or several of the pathways under discussion prevents and improves long-term experimental diabetic neuropathy, without invoking oxidative stress. Having said this, we do whole-heartedly agree with Dr. Feldman that a combination therapy targeting the various pathogenetic components is a rational, although challenging approach, since the mechanisms to be targeted vary with the type of diabetes and differ in the same type of diabetes at different stages of DPN.
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