Characterization of a novel aldose reductase inhibitor, TAT, and its effects on streptozotocin-induced diabetic neuropathy in rats.
Characterization of a novel aldose reductase inhibitor, TAT, and its effects on streptozotocin-induced diabetic neuropathy in rats.
复制标题
新型醛糖还原酶抑制剂 TAT 的表征及其对链脲佐菌素诱导的大鼠糖尿病神经病变的影响。
DOI：
10.1254/jjp.61.221
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
M. Goto
中科院分区：
文献类型：
--
作者：
S. Inukai;M. Agata;M. Sato;A. Naitou;H. Matsukawa;M. Goto
TAT ([5-(3-噻吩基)四唑-1-基]乙酸) 是一种新型醛糖还原酶 (AR) 抑制剂。它对来自大鼠晶状体（IC50 = 2.1 x 10(-8) M）、兔晶状体（IC50 = 2.3 x 10(-8) M）和人胎盘（IC50 = 2.8 x 10(-8) M）的部分纯化的AR表现出高效抑制作用。另一方面，TAT对小鼠肝醛还原酶(ALR)的抑制活性较弱(IC50 = 2.4 x 10(-6) M)，对几种需要腺嘌呤核苷酸的酶的抑制活性较差。 TAT在1.0×10(-8)M浓度下对大鼠晶状体AR表现出非竞争性抑制，在更高浓度下表现出混合型抑制。 TAT抑制山梨醇在高浓度葡萄糖培养的离体大鼠坐骨神经(IC50 = 1.0 x 10(-6) M)、大鼠晶状体(IC50 = 5.7 x 10(-6) M)、人红细胞(IC50 = 2.5 x 10(-7) M)和兔红细胞(IC50 = 2.1 x 10(-7) M)中的积累。在5天的治疗期间，对链脲佐菌素（STZ）诱导的糖尿病大鼠口服TAT（5-100mg/kg/天）可降低坐骨神经中的山梨醇含量，呈剂量依赖性（ED50：预防时为8.8mg/kg/天，逆转时为9.0mg/kg/天）。此外，TAT（2.5-40 mg/kg/天）在14天的治疗期后改善了运动神经传导速度（MNCV）的下降。 MNCV与坐骨神经山梨醇含量之间存在显着相关性。从这些结果来看，TAT有望用于糖尿病并发症的临床治疗。
TAT ([5-(3-thienyl)tetrazol-1-yl]acetic acid) is a novel aldose reductase (AR) inhibitor. It exhibited highly potent inhibition of partially purified AR from rat lens (IC50 = 2.1 x 10(-8) M), rabbit lens (IC50 = 2.3 x 10(-8) M) and human placenta (IC50 = 2.8 x 10(-8) M). On the other hand, TAT had a weak inhibitory activity against mouse liver aldehyde reductase (ALR) (IC50 = 2.4 x 10(-6) M) and poor inhibitory activity against several adenine nucleotide-requiring enzymes. Against rat lens AR, TAT exhibited an uncompetitive inhibition at a concentration of 1.0 x 10(-8) M and a mixed type inhibition at higher concentrations. TAT inhibited sorbitol accumulation in the isolated rat sciatic nerve (IC50 = 1.0 x 10(-6) M), rat lens (IC50 = 5.7 x 10(-6) M), human erythrocytes (IC50 = 2.5 x 10(-7) M), and rabbit erythrocytes (IC50 = 2.1 x 10(-7) M) incubated with high glucose concentrations. The oral administration of TAT (5-100 mg/kg/day) to streptozotocin (STZ)-induced diabetic rats during a 5-day treatment period decreased the sorbitol content in the sciatic nerve, dose-dependently (ED50: 8.8 mg/kg/day for the prevention and 9.0 mg/kg/day for the reversal). Moreover, TAT (2.5-40 mg/kg/day) improved the decreased motor nerve conduction velocity (MNCV) after a 14-day treatment period. There was a significant correlation between MNCV and sciatic nerve sorbitol content. From these results, TAT is expected to be useful for the clinical treatment of diabetic complications.