Schmidt R E, Dorsey D A, Beaudet L N, Plurad S B, Williamson J R, Ido Y
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neuropathol Exp Neurol. 1998 Dec;57(12):1175-89. doi: 10.1097/00005072-199812000-00010.
The polyol pathway and its dependent biochemical pathways are thought to play a role in the pathogenesis of diabetic neuropathy. We have developed an animal model of diabetic autonomic neuropathy characterized by neuroaxonal dystrophy involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozocin-diabetic rats. Our previous studies have shown a salutary effect of aldose reductase inhibitors on experimental autonomic neuropathy, suggesting a role for the polyol pathway in its pathogenesis. In the current studies we have examined the effect of the sorbitol dehydrogenase inhibitor (SDI) CP-166,572, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the polyol pathway) resulting in markedly increased levels of sorbitol in peripheral nerve. Fourteen weeks of treatment with CP-166,572 resulted in a dramatically increased frequency of neuroaxonal dystrophy in ileal mesenteric nerves and SMG. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics than untreated diabetics did, their anatomic distribution and ultrastructural appearance were identical to that previously reported in long-term untreated diabetics. CP-166,572 treatment did not produce neuroaxonal dystrophy in control animals despite the fact that sciatic nerve sorbitol levels were markedly increased, reaching the same levels as untreated diabetic animals. Treatment of diabetic rats for 14 weeks with the aldose reductase inhibitor zopolrestat resulted in a significant decrease in the frequency of neuroaxonal dystrophy compared with untreated diabetics.
多元醇途径及其相关的生化途径被认为在糖尿病性神经病变的发病机制中起作用。我们已经建立了一种糖尿病自主神经病变的动物模型，其特征为慢性链脲佐菌素诱导的糖尿病大鼠的回肠系膜神经和椎前交感神经肠系膜上神经节（SMG）出现神经轴突营养不良。我们之前的研究表明醛糖还原酶抑制剂对实验性自主神经病变有有益作用，提示多元醇途径在其发病机制中发挥作用。在当前的研究中，我们检测了山梨醇脱氢酶抑制剂（SDI）CP-166,572的作用，该抑制剂可阻断山梨醇向果糖的转化（以及依赖多元醇途径第二步的反应），导致外周神经中山梨醇水平显著升高。用CP-166,572治疗14周导致回肠系膜神经和SMG中神经轴突营养不良的频率显著增加。尽管与未治疗的糖尿病大鼠相比，接受SDI治疗的糖尿病大鼠病变出现得更早且数量更多，但其解剖分布和超微结构外观与长期未治疗的糖尿病大鼠先前报道的相同。尽管坐骨神经中山梨醇水平显著升高，达到与未治疗的糖尿病动物相同的水平，但CP-166,572治疗在对照动物中并未产生神经轴突营养不良。与未治疗的糖尿病大鼠相比，用醛糖还原酶抑制剂唑泊司他治疗糖尿病大鼠为期14周可使神经轴突营养不良的频率显著降低。
