Effects of a new aldose reductase inhibitor, (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamid e (SNK-860), on the slowing of motor nerve conduction velocity and metabolic abnormalities in the peripheral nerve in acute streptozotocin-induced diabetic rats.
The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
Mizuno
K
K
Department of Pharmacology, Mie Research Laboratory, Japan.
Kato
N
N
Matsubara
A
A
Nakano
K
K
Kurono
M
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D048289:Imidazolidines; D007294:Inositol / Q000032:analysis / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism / Q000502:physiology; D013012:Sorbitol / Q000032:analysis / Q000378:metabolism; D013311:Streptozocin
D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D007294:Inositol; D013012:Sorbitol; D013311:Streptozocin; C077139:fidarestat; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase