4-hydroxy-2-nonenal and Diabetic-Neuropathies

Since the landmark discovery of α,β-unsaturated 4-hydroxyalkenals by Esterbauer and colleagues most studies have addressed the consequences of the tendency of these lipid peroxidation products to form covalent adducts with macromolecules and modify cellular functions. Many studies describe detrimental and cytotoxic effects of 4-hydroxy-2E-nonenal (4-HNE) in myriad tissues and organs and many pathologies. Other studies similarly assigned unfavorable effects to 4-hydroxy-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE). Nutrient overload (e.g., hyperglycemia, hyperlipidemia) modifies lipid metabolism in cells and promotes lipid peroxidation and the generation of α,β-unsaturated 4-hydroxyalkenals. Advances glycation- and lipoxidation end products (AGEs and ALEs) have been associated with the development of insulin resistance and pancreatic beta cell dysfunction and the etiology of type 2 diabetes and its peripheral complications. Less acknowledged are genuine signaling properties of 4-hydroxyalkenals in hormetic processes that provide defense against the consequences of nutrient overload. This review addresses recent findings on such lipohormetic mechanisms that are associated with lipid peroxidation in pancreatic beta cells. This article is part of a Special Issue entitled SI: LIPID OXIDATION PRODUCTS, edited by Giuseppe Poli.

Topics: Aldehydes; Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Glycation End Products, Advanced; Hormesis; Humans; Hyperglycemia; Hyperlipidemias; Insulin Resistance; Insulin-Secreting Cells; Lipid Peroxidation; Oxidative Stress; Phospholipases A2

We determined the impact diet-induced obesity (DIO) and types 1 and 2 diabetes have on peripheral neuropathy with emphasis on corneal nerve structural changes in C57Bl/6J mice. Endpoints examined included nerve conduction velocity, response to thermal and mechanical stimuli and innervation of the skin and cornea. DIO mice and to a greater extent type 2 diabetic mice were insulin resistant. DIO and both types 1 and 2 diabetic mice developed motor and sensory nerve conduction deficits. In the cornea of DIO and type 2 diabetic mice there was a decrease in sub-epithelial corneal nerves, innervation of the corneal epithelium, and corneal sensitivity. Type 1 diabetic mice did not present with any significant changes in corneal nerve structure until after 20 weeks of hyperglycemia. DIO and type 2 diabetic mice developed corneal structural damage more rapidly than type 1 diabetic mice although hemoglobin A1 C values were significantly higher in type 1 diabetic mice. This suggests that DIO with or without hyperglycemia contributes to development and progression of peripheral neuropathy and nerve structural damage in the cornea.

Topics: Aldehydes; Animals; Cornea; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diet; Ganglia, Spinal; Glucose Tolerance Test; Mice; Mice, Inbred C57BL; Neural Conduction; Obesity; Tyrosine

Evidence for an important role for Na(+)/H(+) exchangers in diabetic complications is emerging. The aim of this study was to evaluate whether Na(+)/H(+) exchanger 1 inhibition reverses experimental peripheral diabetic neuropathy. Control and streptozotocin-diabetic rats were treated with the specific Na(+)/H(+) exchanger 1 inhibitor cariporide for 4 wk after 12 wk without treatment. Neuropathy end points included sciatic motor and sensory nerve conduction velocities, endoneurial nutritive blood flow, vascular reactivity of epineurial arterioles, thermal nociception, tactile allodynia, and intraepidermal nerve fiber density. Advanced glycation end product and markers of oxidative stress, including nitrated protein levels in sciatic nerve, were evaluated by Western blot. Rats with 12-wk duration of diabetes developed motor and sensory nerve conduction deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. All these changes, including impairment of nerve blood flow and vascular reactivity of epineurial arterioles, were partially reversed by 4 wk of cariporide treatment. Na(+)/H(+) exchanger 1 inhibition was also associated with reduction of diabetes-induced accumulation of advanced glycation endproduct, oxidative stress, and nitrated proteins in sciatic nerve. In conclusion, these findings support an important role for Na(+)/H(+) exchanger 1 in functional, structural, and biochemical manifestations of peripheral diabetic neuropathy and provide the rationale for development of Na(+)/H(+) exchanger 1 inhibitors for treatment of diabetic vascular and neural complications.

Topics: Aldehydes; Animals; Arterioles; Behavior, Animal; Blood Glucose; Blotting, Western; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Glycation End Products, Advanced; Guanidines; Male; Nerve Fibers; Nitrates; Pain Measurement; Pyruvaldehyde; Rats; Rats, Wistar; Reduced Folate Carrier Protein; Sciatic Nerve; Skin; Sulfones; Superoxides; Tyrosine

Previous results indicate that intaperitoneal administration of a TRPA1 channel antagonist attenuates diabetic hypersensitivity. We studied whether the antihypersensitivity effect induced by a TRPA1 channel antagonist in diabetic animals is explained by action on the TRPA1 channel in the skin, the spinal cord, or both. For comparison, we determined the contribution of cutaneous and spinal TRPA1 channels to development of hypersensitivity induced by topical administration of mustard oil in healthy controls. Diabetes mellitus was induced by streptozotocin in the rat. Hypersensitivity was assessed by the monofilament- and paw pressure-induced limb withdrawal response. Intrathecal (i.t.) administration of Chembridge-5861528 (CHEM, a TRPA1 channel antagonist) at doses 2.5-5.0 microg/rat markedly attenuated diabetic hypersensitivity, whereas 20 microg of CHEM was needed to produce a weak attenuation of diabetic hypersensitivity with intraplantar (i.pl.) administrations. In controls, i.pl. administration of CHEM (20 microg) produced a weak antihypersensitivity effect at the mustard oil-treated site. I.t. administration of CHEM (10 microg) in controls produced a strong antihypersensitivity effect adjacent to the mustard oil-treated area (site of secondary hyperalgesia), while it failed to influence hypersensitivity at the mustard oil-treated area (site of primary hyperalgesia). A reversible antagonism of the rat TRPA1 channel by CHEM was verified using in vitro patch clamp recordings. The results suggest that while cutaneous TRPA1 channels contribute to mechanical hypersensitivity induced by diabetes or topical mustard oil, spinal TRPA1 channels, probably on central terminals of primary afferent nerve fibers, play an important role in maintenance of mechanical hypersensitivity in these conditions.

Topics: Aldehydes; Analysis of Variance; Animals; Ankyrins; Antihypertensive Agents; Calcium Channels; Cell Line, Transformed; Cysteine Proteinase Inhibitors; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Humans; Hyperalgesia; Male; Membrane Potentials; Mustard Plant; Pain Measurement; Pain Threshold; Patch-Clamp Techniques; Plant Oils; Rats; Rats, Wistar; Skin; Spinal Cord; Time Factors; Transfection; TRPA1 Cation Channel; TRPC Cation Channels

There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

Topics: Aldehydes; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Formaldehyde; Hyperalgesia; Malondialdehyde; Neural Conduction; Rats; Rats, Sprague-Dawley; Streptozocin; Touch; Vitamin B Complex

Oxidative stress has a key role in the pathogenesis of diabetic complications. We have previously reported that taurine (T), which is known to counteract oxidative stress in tissues (lens, kidney, retina) of diabetic rats, attenuates nerve blood flow and conduction deficits in early experimental diabetic neuropathy (EDN). The purpose of this study was to evaluate whether dietary T supplementation counteracts oxidative stress and the nerve growth factor (NGF) deficit in the diabetic peripheral nerve. The experiments were performed in control rats and streptozotocin-diabetic rats fed standard or 1% T-supplemented diets for 6 weeks. All measurements were performed in the sciatic nerve. Malondialdehyde (MDA) plus 4-hydroxyalkenals (4-HA) were quantified with N-methyl-2-phenylindole. GSH, GSSG, dehydroascorbate (DHAA), and ascorbate (AA) were assayed spectrofluorometrically, T by reverse-phase HPLC, and NGF by ELISA. MDA plus 4-HA concentration (mean +/- SEM) was increased in diabetic rats (0.127 +/- 0.006 vs 0.053 +/- 0.003 micromol/g in controls, P < 0.01), and this increase was partially prevented by T (0.096 +/- 0.004, P < 0.01 vs untreated diabetic group). GSH levels were similarly decreased in diabetic rats treated with or without taurine vs controls. GSSG levels were similar in control and diabetic rats but were lower in diabetic rats treated with T (P < 0.05 vs controls). AA levels were decreased in diabetic rats (0.133 +/- 0.015 vs 0.219 +/- 0.023 micromol/g in controls, P < 0.05), and this deficit was prevented by T. DHAA/AA ratio was increased in diabetic rats vs controls (P < 0.05), and this increase was prevented by T. T levels were decreased in diabetic rats (2.7 +/- 0.16 vs 3.8 +/- 0.1 micromol/g in controls, P < 0.05) and were repleted by T supplementation (4.2 +/- 0.3). NGF levels were decreased in diabetic rats (2.35 +/- 0.20 vs 3.57 +/- 0.20 ng/g in controls, P < 0.01), and this decrease was attenuated by T treatment (3.16 +/- 0.28, P < 0.05 vs diabetic group). In conclusion, T counteracts oxidative stress and the NGF deficit in early EDN. Antioxidant effects of T in peripheral nerve are, at least in part, mediated through the ascorbate system of antioxidative defense. The findings are consistent with the important role for oxidative stress in impaired neurotrophic support in EDN.

Topics: Aldehydes; Animals; Ascorbic Acid; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Supplements; Disease Models, Animal; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Nerve Growth Factor; Oxidative Stress; Rats; Rats, Wistar; Sciatic Nerve; Streptozocin; Taurine