Characterization of a novel aldose reductase inhibitor, TAT, and its effects on streptozotocin-induced diabetic neuropathy in rats.
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概要
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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 (IC<SUB>50</SUB>=2.1 × 10<SUP>-8</SUP> M), rabbit lens (IC<SUB>50</SUB> =2.3 × 10<SUP>-8</SUP> M)and human placenta (IC<SUB>50</SUB>=2.8 × 10<SUP>-8</SUP> M). On the other hand, TAT had a weak inhibitory activity against mouse liver aldehyde reductase (ALR)(IC<SUB>50</SUB>=2.4 × 10<SUP>-6</SUP> M)and poor inhibitory activity against several adeninenucleotide-requiring enzymes. Against rat lens AR, TAT exhibited an uncompetitive inhibition at a concentration of 1.0 × 10<SUP>-8</SUP> M and a mixed type inhibition at higher concentrations. TAT inhibited sorbitol accumulation in the isolated rat sciatic nerve (IC<SUB>50</SUB>=1.0 × 10<SUP>-6</SUP> M), rat lens (IC<SUB>50</SUB>=5.7 10<SUP>-6</SUP>M), human erythrocytes (IC<SUB>50</SUB>=2.5 × 10<SUP>-7</SUP> M), and rabbit erythrocytes (IC<SUB>50</SUB>=2.1 × 10<SUP>-7</SUP> 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 (ED<SUB>50</SUB>: 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.
- 公益社団法人 日本薬理学会の論文
著者
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Goto Masayoshi
Research And Development Laboratories Hoechst Japan Limited
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AGATA Mitsuji
Research Institute, Wakamoto Pharmaceutical Co. Ltd.
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Goto Masayoshi
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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Inukai Shinji
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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Sato Manami
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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Naitou Akira
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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Matsukawa Hidehiko
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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Agata Mitsuji
Research Department, Wakamoto Pharmaceutical Co., Ltd.
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