Mizuno K, Kato N, Matsubara A, Nakano K, Kurono M
Department of Pharmacology, Mie Research Laboratory, Japan.
Metabolism. 1992 Oct;41(10):1081-6. doi: 10.1016/0026-0495(92)90289-m.
The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
在急性链脲佐菌素（STZ）诱导的糖尿病大鼠中，研究了一种新型醛糖还原酶抑制剂（ARI），即（2S,4S）-6-氟-2',5'-二氧代螺[苯并二氢吡喃-4,4'-咪唑烷]-2-甲酰胺（SNK-860）对运动神经传导速度（MNCV）减慢和坐骨神经代谢异常的影响。STZ注射后2周，糖尿病大鼠的MNCV明显减慢。在接下来的2周内，SNK-860治疗以剂量依赖的方式改善了MNCV。1mg/kg SNK-860的疗效与20mg/kg索比尼尔相当。STZ注射后4周，在糖尿病大鼠的坐骨神经中观察到山梨醇水平升高、肌醇水平降低以及钠钾-三磷酸腺苷（ATPase）活性降低。糖尿病诱导后2周开始给予SNK-860 14天，以剂量依赖的方式抑制了这些代谢异常。SNK-860在2mg/kg的剂量下将所有这些参数恢复到正常水平。此外，在坐骨神经中观察到MNCV与山梨醇水平之间密切相关（r = -0.95），MNCV与肌醇水平之间密切相关（r = 0.93）；在坐骨神经中山梨醇与肌醇水平之间也观察到密切相关（r = -0.86）。因此，提示SNK-860对MNCV减慢的作用是通过使糖尿病患者坐骨神经中的上述代谢异常正常化实现的。因此，SNK-860可能对糖尿病性神经病变的治疗有用。
