A POTENT SORBITOL DEHYDROGENASE INHIBITOR EXACERBATES SYMPATHETIC AUTONOMIC

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。一种有效的山梨醇脱氢酶抑制剂加重链脲佐菌素诱导的糖尿病大鼠的交感自主神经病变：我们在慢性链脲佐菌素(STZ)糖尿病大鼠中建立了一种以神经轴索营养不良(NAD)为特征的交感神经自主神经病变的动物模型。糖尿病引起的山梨醇途径的改变发生在交感神经节，抑制醛糖还原酶或山梨醇脱氢酶的治疗剂分别改善或加重糖尿病诱导的NAD。山梨醇脱氢酶抑制剂SDI-711(CP-470711，辉瑞)的效力大约是我们早期研究中使用的结构相关化合物SDI-158(CP 166,572)的50倍。SDI-711(5 mg/kg/d)治疗3个月后，对照组和糖尿病大鼠神经节细胞山梨醇含量增加(26-40倍)，果糖含量降低(20-75%)。与未经治疗的糖尿病患者相比，SDI-711治疗的糖尿病大鼠的SMG和回肠系膜神经中的NAD分别增加了2.5倍和4-5倍。尽管SDI-711治疗的非糖尿病对照组大鼠神经节中神经节苷脂山梨醇增加了40倍(这一数值比未治疗的糖尿病患者高8倍)，但NAD的发生频率保持在对照组水平。STZ糖尿病大鼠(1型糖尿病模型)和Zucker糖尿病肥胖大鼠(ZDF，2型糖尿病的遗传模型)的神经节细胞山梨醇途径中间产物水平相似，尽管STZ糖尿病大鼠和ZDF糖尿病大鼠不发生NAD。SDI未能使糖尿病相关神经节细胞神经生长因子高于未经治疗的糖尿病患者的水平。在9个月的糖尿病病程的最后4个月开始索比尼治疗，在不影响糖尿病的代谢严重程度的情况下，显著逆转了糖尿病大鼠SMG中已建立的NAD的频率。这些发现表明，山梨醇途径相关的代谢改变在NAD的发生发展中起着重要作用，但山梨醇途径的活性，而不是山梨醇或果糖本身的绝对水平，可能是其发病机制中最关键的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes: We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.