Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat.
To test the hypothesis that aldose reductase inhibition may prevent or delay the development of functional and structural neuropathy in the insulin-deficient diabetic Bio-Breeding rat (BB-rat), hyperglycemic rats were begun on the aldose reductase inhibitor (ARI) ponalrestat 25 mg/kg body wt soon after the onset of diabetes and followed for 4 or 6 mo. Ponalrestat treatment completely prevented the characteristic nerve conduction slowing and structural abnormalities of the node of Ranvier for 4 mo despite only partial preservation of axonal integrity. Ponalrestat treatment for 6 mo achieved a partial but significant prevention of nerve conduction slowing, axoglial dysjunction, and axonal degenerative changes. This incomplete but significant prevention of neuropathy by ponalrestat suggests that additional mechanisms besides polyol-pathway activation may be of importance in the pathogenesis of diabetic neuropathy. Alternatively, the dosage used in the present study may not have been sufficient to achieve a complete prevention. Despite the only partial protective effect of ARI treatment on degenerative peripheral nerve changes in hyperglycemic BB-rats, 6 mo of treatment resulted in a more than threefold increase in regenerating nerve fibers. These data suggest that prophylactic ARI treatment may be efficacious in delaying the development of diabetic neuropathy.
Sima
A A
AA
Department of Pathology, University of Manitoba, Winnipeg, Canada.
Prashar
A
A
Zhang
W X
WX
Chakrabarti
S
S
Greene
D A
DA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006442:Glycated Hemoglobin / Q000032:analysis; D008297:Male; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000648:ultrastructure; D009431:Neural Conduction / Q000187:drug effects*; D010793:Phthalazines / Q000627:therapeutic use*; D011236:Prediabetic State / Q000188:drug therapy* / Q000503:physiopathology; D011724:Pyridazines / Q000627:therapeutic use*; D011901:Ranvier's Nodes / Q000473:pathology / Q000502:physiology; D051381:Rats; D011913:Rats, Inbred BB; D012016:Reference Values; D013127:Spinal Nerves / Q000503:physiopathology*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013497:Sural Nerve / Q000187:drug effects / Q000503:physiopathology*
D000449:Aldehyde Reductase; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D010793:Phthalazines; D011724:Pyridazines; D013401:Sugar Alcohol Dehydrogenases; C042829:ponalrestat