Effects of 15-month aldose reductase inhibition with fidarestat on the experimental diabetic neuropathy in rats.
We examined the effects of long-term treatment with an aldose reductase inhibitor (ARI) fidarestat on functional, morphological and metabolic changes in the peripheral nerve of 15-month diabetic rats induced by streptozotocin (STZ). Slowed F-wave, motor nerve and sensory nerve conduction velocities were corrected dose-dependently in fidarestat-treated diabetic rats. Morphometric analysis of myelinated fibers demonstrated that frequencies of abnormal fibers such as paranodal demyelination and axonal degeneration were reduced to the extent of normal levels by fidarestat-treatment. Axonal atrophy, distorted axon circularity and reduction of myelin sheath thickness were also inhibited. These effects were associated with normalization of increased levels of sorbitol and fructose and decreased level of myo-inositol in the peripheral nerve by fidarestat. Thus, the results demonstrated that long-term treatment with fidarestat substantially inhibited the functional and structural progression of diabetic neuropathy with inhibition of increased polyol pathway flux in diabetic rats.
Kato
N
N
Research and Development Department, Sanwa Kagaku Kenkyusho Co. Ltd., 363 Shiosaki, Hokusei, Inabe, 511 0406, Mie, Japan.
Mizuno
K
K
Makino
M
M
Suzuki
T
T
Yagihashi
S
S
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005632:Fructose / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013497:Sural Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013979:Tibial Nerve / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors
D000449:Aldehyde Reductase; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005632:Fructose; D006442:Glycated Hemoglobin; D007093:Imidazoles; D048289:Imidazolidines; D007294:Inositol; D013012:Sorbitol; C077139:fidarestat