Greene D A, Arezzo J C, Brown M B
Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Neurology. 1999 Aug 11;53(3):580-91. doi: 10.1212/wnl.53.3.580.
To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN).
A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies.
Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers.
Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.
确定醛糖还原酶抑制剂（ARI）泽那司他是否能改善糖尿病性周围多发性神经病（DPN）患者的神经传导速度（NCV）和神经形态。
对轻度至中度DPN患者进行了一项为期52周的随机、安慰剂对照、双盲、多剂量临床试验，使用ARI泽那司他。在基线和研究结束时测量NCV。在6周和研究结束时获取对侧腓肠神经活检样本，用于测量神经山梨醇含量，并通过计算机辅助光学形态测量法确定双侧腓肠神经活检样本中髓鞘神经纤维密度（每平方毫米横截面积的纤维数量）。
腓肠神经泽那司他水平和山梨醇抑制呈剂量依赖性增加，同时NCV有显著改善。在一项次要分析中，山梨醇抑制率>80%的泽那司他剂量与小直径（<5微米）腓肠神经髓鞘纤维密度的显著增加相关。
醛糖还原酶途径抑制可改善人类DPN患者的NCV减慢和小髓鞘神经纤维丢失，但需要神经山梨醇含量抑制>80%。因此，即使醛糖还原酶活性的残余水平较低，在糖尿病中也可能具有神经毒性，可能需要如泽那司他这样强效的ARI来阻止或逆转DPN的进展。
