Document Detail

Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor.
MedLine Citation:
PMID:  11701599     Owner:  NLM     Status:  MEDLINE    
The present study was designed to examine the effect of aldose reductase (AR) overexpression on the development of diabetic neuropathy by using mice transgenic for human AR. At 8 weeks of age, transgenic mice (Tg) and non-transgenic littermates (Lm) were made diabetic with streptozotocin. After 8 weeks of untreated diabetes, plasma glucose levels and the reduction in body weight were similar between the groups of diabetic animals. Despite the comparable levels of hyperglycaemia, levels of sorbitol and fructose were significantly greater in the peripheral nerve of diabetic Tg than in diabetic Lm (both P < 0.01). Ouabain sensitive Na(+),K(+)-ATPase activity was similarly decreased in both diabetic Tg and Lm. Protein kinase C activity in the sciatic nerve membrane fraction was unaffected by diabetes in Lm, but was reduced by nearly 40% in the diabetic Tg. Although both groups of diabetic animals exhibited a significant decrease in tibial nerve motor nerve conduction velocity (MNCV), this decrease was significantly more severe (P < 0.01) in diabetic Tg than in diabetic Lm. Consistent with these findings, nerve fibre atrophy was significantly more severe in diabetic Tg than in diabetic Lm (P < 0.01). These findings implicate increased polyol pathway activity in the pathogenesis of diabetic neuropathy. In support of this hypothesis, treating diabetic Tg with an aldose reductase inhibitor (WAY121-509, 4 mg/kg/day) for 8 weeks significantly prevented the accumulation of sorbitol, the decrease in MNCV and the increased myelinated fibre atrophy in diabetic Tg.
S Yagihashi; S I Yamagishi; R Wada Ri; M Baba; T C Hohman; C Yabe-Nishimura; Y Kokai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Brain : a journal of neurology     Volume:  124     ISSN:  0006-8950     ISO Abbreviation:  Brain     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-11-09     Completed Date:  2002-01-03     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0372537     Medline TA:  Brain     Country:  England    
Other Details:
Languages:  eng     Pagination:  2448-58     Citation Subset:  AIM; IM    
Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan.
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MeSH Terms
Aldehyde Reductase / antagonists & inhibitors*,  genetics*,  pharmacology*
Diabetes Mellitus, Experimental / genetics,  metabolism*,  pathology
Diabetic Neuropathies / genetics,  metabolism*,  pathology
Enzyme Inhibitors / pharmacology*
Enzyme-Linked Immunosorbent Assay
Glucose / metabolism
Hyperglycemia / metabolism
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Motor Neurons / enzymology
Neural Conduction
Protein Kinase C / metabolism
Sciatic Nerve / enzymology,  pathology
Sodium-Potassium-Exchanging ATPase / metabolism
Reg. No./Substance:
0/Enzyme Inhibitors; 0/WAY 121-509; 50-99-7/Glucose; EC Reductase; EC Kinase C; EC ATPase

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