Effect of Treatment with Salsalate, Menhaden Oil, Combination of Salsalate and Menhaden Oil, or Resolvin D1 of C57Bl/6J Type 1 Diabetic Mouse on Neuropathic Endpoints

Aims. In this study a streptozotocin induced type 1 diabetes mouse model was used to assess the effectiveness of salsalate, menhaden oil, the combination of salsalate and menhaden oil, or resolvin D1 on neuropathic endpoints. Materials and Methods. Changes in body weight, blood glucose, serum markers for triglycerides, free fatty acids, cholesterol, and resolvin D1, motor and sensory nerve conduction velocities and thermal sensitivity were assessed, as well as performing in vivo confocal microscopy of subepithelial corneal nerves and immunohistochemistry of nerves in the cornea and foot pad. Results. Diabetic animals failed to gain weight and had elevated blood glucose levels. Diabetic mice had slowed nerve conduction velocity, reduced innervation of the foot pad and cornea subepithelial and epithelial layers, and reduced thermal sensitivity. Monotherapy treatment with salsalate, menhaden oil, and resolvin D1 reduced the pathological signs of diabetic neuropathy. The combination of salsalate and menhaden oil also reduced signs of pathology and generated elevated plasma levels of resolvin D1 compared to other groups. Conclusions. Additional studies are needed to determine whether the combination of salsalate and menhaden oil may be more efficacious than monotherapy alone for the treatment of diabetic peripheral neuropathy

Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats

The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD∶NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I–IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor

Effect of dietary oils on peripheral neuropathy-related endpoints in dietary obese rats

Lawrence Coppey,1 Eric Davidson,1 Hanna Shevalye,1 Michael E Torres,1 Mark A Yorek1–4 1Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; 2Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA, USA; 3Department of Veterans Affairs, Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA, USA; 4Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USA Purpose: This study aimed to determine the effect of dietary oils (olive, safflower, evening primrose, flaxseed, or menhaden) enriched in different mono unsaturated fatty acids or polyunsaturated fatty acids on peripheral neuropathies in diet-induced obese Sprague-Dawley rats.Materials and methods: Rats at 12 weeks of age were fed a high-fat diet (45% kcal) for 16 weeks. Afterward, the rats were fed diets with 50% of the kilocalories of fat derived from lard replaced by the different dietary oils. In addition, a control group fed a standard diet (4% kcal fat) and a high fat fed group (45% kcal) were maintained. The treatment period was 32 weeks. The endpoints evaluated included motor and sensory nerve conduction velocity, thermal sensitivity, innervation of sensory nerves in the cornea and skin, and vascular relaxation by epineurial arterioles.Results: Menhaden oil provided the greatest benefit for improving peripheral nerve damage caused by dietary obesity. Similar results were obtained when we examined acetylcholine-mediated vascular relaxation of epineurial arterioles of the sciatic nerve. Enriching the diets with fatty acids derived from the other oils provided minimal to partial improvements.Conclusion: These studies suggest that omega-3 polyunsaturated fatty acids derived from fish oil could be an effective treatment for neural and vascular complications associated with obesity. Keywords: peripheral neuropathy, fish oil, omega-3 polyunsaturated fatty acids, omega-6 polyunsaturated fatty acids, vascular reactivity, nerve conduction velocit

Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies

This study evaluated the role for 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, in nitrosative stress in peripheral nervous system and peripheral prediabetic and diabetic neuropathies. The experiments were performed in C57Bl6/J mice made diabetic with streptozotocin or fed high-fat diet, and human Schwann cells cultured in 5.5 mM or 30 mM glucose. 12/15-lipoxygenase overexpression and activation were present in sciatic nerve and spinal cord of diabetic and high fat diet-fed mice, as well as in human Schwann cells cultured in high concentrations of D-, but not L-glucose. 12/15-lipoxygenase inhibition with cinnamyl-3,4-dihydroxy-α-cyanocinnamate (8 mgkg(-1)d(-1) s.c., for 4 weeks after 12 weeks without treatment) alleviated accumulation of nitrated proteins in sciatic nerve and spinal cord, and large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss. 12/15-lipoxygenase gene deficiency alleviated nitrosative stress and nerve conduction deficit, but not small sensory fiber neuropathy, in high-fat diet fed mice. In conclusion, 12/15-lipoxygenase is implicated in nitrosative stress and peripheral neuropathy in mouse models of Type 1 and early Type 2 diabetes. Its presence in human Schwann cells and upregulation by high glucose suggest a potential involvement in human disease

A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus

10.1007/s00125-011-2339-6Diabetologia552499-508DBTG

PARP inhibition ameliorates nephropathy in an animal model of type 2 diabetes: focus on oxidative stress, inflammation, and fibrosis

Poly(ADP-ribose) polymerase (PARP) enzyme contributes to nephropathy, a serious diabetic complication which may lead to end-stage renal disease. The study aims to investigate the effect of PARP over-activation on kidney functions in a type 2 diabetic rat model. The study also tests the therapeutic use of PARP inhibitors in diabetic nephropathy. Type 2 diabetes was induced in adult male rats by highfructose/high-fat diet and low streptozotocin dose. Then, the PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for 10 weeks. At the end, urine samples were collected to measure urine creatinine, albumin, and total proteins. PARP activity, superoxide dismutase (SOD) activity, and nitrite content were measured in kidney tissue homogenate. Glucose, fructosamine, insulin, and tumor necrosis factor-alpha (TNF-α) were measured in serum. Furthermore, histological studies, collagen deposition, and immunofluorescence of nuclear factor kappa B (NFκB) and transforming growth factor beta1 (TGF-β1) were carried out. PARP enzyme activity was significantly higher in the diabetic group and was significantly reduced by 4-AB administration. Diabetic animals had clear nephropathy indicated by proteinuria and increased albumin excretion rate (AER) which were significantly decreased by PARP inhibition. In addition, PARP inhibition increased creatinine clearance in diabetic animals and reduced renal TGF-β1 and glomerular fibrosis. Moreover, PARP inhibition alleviated the elevated serum TNF-α level, renal NFκB, nitrite, and the decrease in SOD activity in diabetic animals. However, PARP inhibition did not significantly affect neither hyperglycemia nor insulin sensitivity. PARP enzyme inhibition alleviates diabetic nephropathy through decreasing inflammation, oxidative stress, and renal fibrosi