Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat.
OBJECTIVE
Fidarestat, an aldose reductase inhibitor (ARI), has been reported to improve clinical symptoms and nerve conduction deficits in human diabetic neuropathy. We evaluated the dose-dependency and some of the mechanisms of the drug action in experimental diabetic neuropathy (EDN).


METHODS
Control rats and rats with EDN were fed on normal pellets or pellets containing 0.00066% (1 mg/kg) or 0.00263% (4 mg/kg) fidarestat for 10 weeks. We evaluated the effect of fidarestat on nerve blood flow (NBF), electrophysiology, and sorbitol and fructose content in sciatic nerve in control and diabetic rats. For detection of oxidative stress in peripheral nerve, we measured sciatic nerve reduced glutathione (GSH) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunolabelling of dorsal root ganglion (DRG) neurons.


RESULTS
NBF, compound muscle action potential and amplitude of C-potential were significantly improved in diabetic rats fed on the diet supplemented with fidarestat. Fidarestat suppressed the increase in sorbitol and fructose, normalised GSH in sciatic nerve, and reduced the number of 8-OHdG-positive cells in DRG.


CONCLUSIONS
Fidarestat improves neuropathy, presumably via an improvement in oxidative stress. This study supports a role for fidarestat in the treatment of diabetic neuropathy.
Kuzumoto
Y
Y
Department of Neurology, Kinki University, School of Medicine, 377-2 Ohno-Higashi Osaka-Sayama, Osaka, Japan. kuzumoto@neuron.med.kindai.ac.jp
Kusunoki
S
S
Kato
N
N
Kihara
M
M
Low
P A
PA
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005727:Ganglia, Spinal / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D048289:Imidazolidines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000098:blood supply* / Q000503:physiopathology
D048289:Imidazolidines; D000080242:8-Hydroxy-2'-Deoxyguanosine; C077139:fidarestat; D000449:Aldehyde Reductase; D003849:Deoxyguanosine; D005978:Glutathione