Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents.
Oxygen free radical activity is elevated in diabetes mellitus and has been implicated in the etiology of vascular complications. Recent studies have shown that impaired perfusion of nerve endoneurium is a major cause of nerve fiber dysfunction in experimental diabetes. Free radical scavenger treatment prevents the development of nerve conduction abnormalities in diabetic rats. In vitro experiments suggest that autoxidation reactions of glucose, catalyzed by free transition metal ions, are a potential source of free radicals in diabetes. We investigated whether chronic treatment with deferoxamine and trientine, transition metal chelating agents which can prevent autoxidation, could correct nerve conduction and blood flow changes in streptozotocin-diabetic rats. A 20% reduction in sciatic nerve motor conduction velocity after 2 mo diabetes was 90% ameliorated by 2 wk of treatment with deferoxamine or trientine. Sciatic endoneurial nutritive blood flow was 45% reduced by diabetes, but was completely corrected by treatment. In contrast, transition metal chelation had no effect on blood flow or conduction velocity in nondiabetic rats. Thus, the data support the hypothesis that increased free radical activity by glucose autoxidation as a result of impaired transition metal handling is a major cause of early neurovascular deficits in diabetes.
Cameron
N E
NE
Department of Biomedical Sciences, University of Aberdeen, Scotland, United Kingdom.
Cotter
M A
MA
D000818:Animals; D015687:Cell Hypoxia; D002614:Chelating Agents / Q000627:therapeutic use*; D015913:Chelation Therapy; D003676:Deferoxamine / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005609:Free Radicals; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D007511:Ischemia / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008670:Metals / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000503:physiopathology; D013311:Streptozocin; D014266:Trientine / Q000627:therapeutic use*
D002614:Chelating Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D008670:Metals; D013311:Streptozocin; D005947:Glucose; D003676:Deferoxamine; D014266:Trientine