Effects of an extracellular metal chelator on neurovascular function in diabetic rats
Open accessAbstract
Aims/hypothesis Increased oxidative stress has been causally linked to diabetic neurovascular complications, which are attenuated by antioxidants. There are several possible sources of reactive oxygen species in diabetes. Our aim was to assess the contribution of free radicals, produced by transition metal catalysed reactions, to early neuropathic changes. To this end, we examined, firstly, the effects of an extracellular high molecular weight chelator, hydroxyethyl starch-deferoxamine, which is expected to be confined to vascular space, on nerve perfusion and conduction deficits in diabetic rats and, secondly, the action of a single chelator dose.Methods Diabetes was induced by streptozotocin. In vivo measurements comprised sciatic nerve motor conduction velocity and endoneurial perfusion, monitored by hydrogen clearance microelectrode polarography.Results We found that 8 weeks of diabetes reduced sciatic blood flow and conduction velocity by 48.3 % and 19.9% respectively. Two weeks of intravenous treatment corrected these deficits. Starch vehicle was ineffective. The time-course of action of a single hydroxyethyl starch-deferoxamine injection was examined in diabetic rats. There was a rapid increase in nerve blood flow on day 1, which remained within the non-diabetic range for 9 days before declining to the diabetic level at day 27. In contrast, conduction velocity changes were slower, reaching the non-diabetic range at day 6 and declining to the diabetic level at day 27.Conclusion/interpretation Extracellular transition metal catalysed reactions play a major role in the neurovascular deficits of experimental diabetes. Given the long-lasting effect of a single treatment, extracellular metal chelator therapy could be suitable for further assessment in clinical trials.
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Treating diabetic rats with α-lipoic acid or the metal chelators hydroxyethyl starch deferoxamine or trientine prevented the diabetes-induced impairment in vascular relaxation associated with hyperalgesia and neurovascular deficits.
“Cameron and colleagues (46, 48–50, 145) demonstrated that treating diabetic rats with α-lipoic acid or the metal chelators, hydroxyethyl starch deferoxamine or trientine, prevented the diabetes-induced impairment in vascular relaxation associated with hyperalgesia and neurovascular deficits.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [46]
Formation of hydroxyl radicals also contributes to impairment of vascular reactivity and nerve function in diabetes.
“Because metal chelators and hydroxyl radical scavengers have also been demonstrated to be effective in preventing diabetes-induced vascular and neural dysfunction, it is likely that the formation of hydroxyl radicals also contributes to impairment of vascular reactivity and nerve function in diabetes (46–51, 145).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [46]
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Cites
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- Pieper GM (1998) Review of alterations in endothelial ni- tric oxide production in diabetes: protective role of argin- ine on endothelial dysfunction. Hypertension 31: 1047±1060
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Cross-Talk Between Iron Metabolism and Diabetes
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Self-citation
- Authors
- Cameron, N. E., & Cotter, M. A.
- Affiliations
- University of Aberdeen (GB)
- Venue
- Diabetologia
- Published
- 2001-04-25
- Volume
- 44
- Issue
- 5
- Pages
- 621-628
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1994895968
- Cited by
- 54
- References
- 17
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 3 · 2014: 3 · 2013: 3
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- diabetic neuropathy, neurovascular dysfunction, transition metal catalysis, free radicals, oxidative stress, metal chelation, deferoxamine, hydroxyethyl starch, nerve blood flow, sciatic nerve, motor nerve conduction velocity, streptozotocin-induced diabetes, antioxidant therapy
- MeSH terms
- Animals, Blood Glucose, Deferoxamine, Diabetes Mellitus, Experimental, Hydroxyethyl Starch Derivatives, Iron Chelating Agents, Male, Motor Neurons, Neural Conduction, Reference Values, Regional Blood Flow, Sciatic Nerve, Time Factors, Rats, Sprague-Dawley, Rats
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