Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat
Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat
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DOI：
10.1007/s00125-006-0400-7
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发表时间：
2006-12-01
期刊：
影响因子：
8.2
通讯作者：
Low, P. A.
中科院分区：
文献类型：
--
作者：
Kuzumoto, Y.;Kusunoki, S.;Low, P. A.
目的/假设非达司他是一种醛糖还原酶抑制剂（ARI），据报道可改善人类糖尿病神经病变的临床症状和神经传导缺陷。方法对照组和实验性糖尿病神经病变（EDN）组大鼠分别给予正常微丸和含0.00066%（1 mg/kg）或0.00263%（4 mg/kg）非达司他的微丸10周。我们评估了非达司他对对照组和糖尿病大鼠坐骨神经中神经血流量（NBF）、电生理学以及山梨醇和果糖含量的影响。结果非达司他能显著改善糖尿病大鼠的NBF、复合肌肉动作电位和C电位波幅，并能显著改善糖尿病大鼠的神经功能。非达司他抑制山梨醇和果糖的增加，正常的GSH在坐骨神经，并减少了8-OHdG阳性细胞的DRG的数量。结论/解释非达司他改善神经病变，大概是通过改善氧化应激。本研究支持非达司他在治疗糖尿病神经病变中的作用。
Aims/hypothesis 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/interpretation Fidarestat improves neuropathy, presumably via an improvement in oxidative stress. This study supports a role for fidarestat in the treatment of diabetic neuropathy.