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Effect of Antioxidant Treatment of Streptozotocin-Induced Diabetic Rats on Endoneurial Blood Flow, Motor Nerve Conduction Velocity, and Vascular Reactivity of Epineurial Arterioles of the Sciatic Nerve
Open accessAbstract
We have shown that diabetes-induced reduction in endoneurial blood flow (EBF) and impaired endothelium-dependent vascular relaxation precede slowing of motor nerve conduction velocity (MNCV) and decreased sciatic nerve Na+/K+ ATPase activity. Furthermore, vascular dysfunction was accompanied by an accumulation of superoxide in arterioles that provide circulation to the sciatic nerve. In the present study, we examined the effect that treatment of streptozotocin-induced diabetic rats with antioxidants has on vascular and neural function. Diabetic rats were treated with 0.5% α-lipoic acid as a diet supplement or with hydroxyethyl starch deferoxamine (HES-DFO) by weekly intravenous injections at a dose of 75 mg/kg. The treatments significantly improved diabetes-induced decrease in EBF, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and MNCV. The treatments also reduced the production of superoxide by the aorta and superoxide and peroxynitrite by arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with α-lipoic acid prevented the diabetes-induced increase in thiobarbituric acid–reactive substances in serum and significantly improved lens glutathione levels. In contrast, treating diabetic rats with HES-DFO did not prevent diabetes-induced changes of either of these markers of oxidative stress. Diabetes-induced increase in sciatic nerve conjugated diene levels was not improved by treatment with either α-lipoic acid or HES-DFO. Treating diabetic rats with α-lipoic acid but not HES-DFO partially improved sciatic nerve Na+/K+ ATPase activity and myo-inositol content. The increase in sciatic nerve sorbitol levels in diabetic rats was unchanged by either treatment. These studies suggest that diabetes-induced oxidative stress and the generation of superoxide may be partially responsible for the development of diabetic vascular and neural complications.
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“Further, treating diabetic rats with three different types of antioxidants prevented the diabetes-induced increase in superoxide and peroxynitrite formation in aorta and epineurial arterioles of the sciatic nerve and diabetes-induced vascular and neural dysfunction, thereby providing evidence that increased oxidative stress contributes to diabetes-induced vascular and neural disease (67–69).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [68]
Experimental — accuracy not yet measuredIn the citing paper
“Further, treating diabetic rats with three different types of antioxidants prevented the diabetes-induced increase in superoxide and peroxynitrite formation in aorta and epineurial arterioles of the sciatic nerve and diabetes-induced vascular and neural dysfunction, thereby providing evidence that increased oxidative stress contributes to diabetes-induced vascular and neural disease (67–69).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [68]
In the citing paper
“Studies in our laboratory of epineural arterioles of the sciatic nerve derived from diabetic rats have provided evidence that the generation of oxidative stress through the production of superoxide and peroxynitrite impairs vascular function and endothelium-dependent vascular relaxation (67–69, 342).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [68]
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Citations
Cites
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S.-I., Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates, P. J., Hammes, H.-P., et al. (2000) · Nature · doi:10.1038/35008121 · Cited by 4,277
Self-citationRole of oxidative stress in diabetic complications: a new perspective on an old paradigm.
Baynes, J. W., & Thorpe, S. R. (1999) · Diabetes · doi:10.2337/diabetes.48.1.1 · Cited by 2,441
Oxidative Stress and Diabetic Vascular Complications
Giugliano, D., Ceriello, A., & Paolisso, G. (1996) · Diabetes Care · doi:10.2337/diacare.19.3.257 · Cited by 1,921
The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide
Pryor, W. A., & Squadrito, G. L. (1995) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1995.268.5.l699 · Cited by 1,511 · cited 1×
“Peroxynitrite is a highly reactive intermediate known to nitrate protein tyrosine residues and cause cellular oxidative damage (39,40).”
BackgroundBetteridge, D. J. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80077-3 · Cited by 1,475
Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus
Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., Skatchkov, M. P., Thaiss, F., Stahl, R. A. K., Warnholtz, A., et al. (2001) · Circulation Research · doi:10.1161/01.res.88.2.e14 · Cited by 1,191
Endothelial dysfunction in diabetes
De Vriese, A. S., Verbeuren, T. J., Van de Voorde, J., Lameire, N. H., & Vanhoutte, P. M. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703393 · Cited by 1,165
Cellular and molecular mechanisms of endothelial cell dysfunction.
Harrison, D. G. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119751 · Cited by 1,059
Oxidative Damage and Tyrosine Nitration from Peroxynitrite
Beckman, J. S. (1996) · Chemical Research in Toxicology · doi:10.1021/tx9501445 · Cited by 993
Radicals and oxidative stress in diabetes
West, I. C. (2000) · Diabetic Medicine · doi:10.1046/j.1464-5491.2000.00259.x · Cited by 913
Cited by
Sorted by citations
Nitric Oxide and Peroxynitrite in Health and Disease
Pacher, P., Beckman, J. S., & Liaudet, L. (2007) · Physiological Reviews · doi:10.1152/physrev.00029.2006 · Cited by 6,390
Feldman, E. L., Callaghan, B. C., Pop-Busui, R., Zochodne, D. W., Wright, D. E., Bennett, D. L., Bril, V., Russell, J. W., & Viswanathan, V. (2019) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0092-1 · Cited by 1,697
Oxidative Stress in the Pathogenesis of Diabetic Neuropathy
Vincent, A. M., Russell, J. W., Low, P. A., & Feldman, E. L. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0019 · Cited by 1,001
Sivitz, W. I., & Yorek, M. A. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2531 · Cited by 742
Self-citationCeriello, A. (2003) · Diabetes Care · doi:10.2337/diacare.26.5.1589 · Cited by 734
Metadata
- Authors
- Coppey, L. J., Gellett, J. S., Davidson, E. P., Dunlap, J. A., Lund, D. D., & Yorek, M. A.
- Affiliations
- University of Iowa (US)
- ORCID
- Yorek, Mark A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2001-08-01
- Volume
- 50
- Issue
- 8
- Pages
- 1927-1937
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2147294760
- Cited by
- 300
- References
- 63
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 9 · 2018: 7 · 2017: 16 · 2016: 8 · 2015: 13 · 2014: 10 · 2013: 17 · 2012: 18
- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- U.S. Department of Veterans Affairs (DK-25295)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-25295, DK-58005, P30DK025295)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- streptozotocin-induced diabetes, antioxidant treatment, alpha-lipoic acid, motor nerve conduction velocity, sciatic nerve, superoxide, peroxynitrite, oxidative stress, Na+/K+-ATPase, myo-inositol, sorbitol, diabetic vascular complications, diabetic neuropathy, glutathione, lipid peroxidation
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Animals, Antioxidants, Aorta, Arterioles, Diabetes Mellitus, Experimental, Inositol, Thioctic Acid, Male, Motor Neurons, Muscle, Smooth, Vascular, Neural Conduction, Nitrates, Reference Values, Regional Blood Flow, Sciatic Nerve, Sorbitol, Superoxides, Vasodilation, Rats, Sprague-Dawley, Microscopy, Video, Dietary Supplements, Rats
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