Nakamura J, Koh N, Sakakibara F, Hamada Y, Hara T, Sasaki H, Chaya S, Komori T, Nakashima E, Naruse K, Kato K, Takeuchi N, Kasuya Y, Hotta N
The Third Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan.
J Pharmacol Exp Ther. 1998 Dec;287(3):897-902.
To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.
为了研究多元醇途径活性亢进与肉碱代谢改变在糖尿病神经病变发病机制中的关系，在链脲佐菌素诱导的糖尿病大鼠中，比较了醛糖还原酶抑制剂[5-(3-噻吩基)四氮唑-1-基]乙酸（TAT）和肉碱类似物乙酰-L-肉碱（ALC）对神经功能、生物化学和血流动力学因素的影响。糖尿病大鼠运动神经传导速度显著延迟、R-R间期变异性降低、坐骨神经血流量减少以及红细胞2,3-二磷酸甘油酸浓度降低，经TAT（与含0.05%TAT的大鼠饲料一起给予，约50mg/kg/天）或ALC（通过灌胃，300mg/kg/天）治疗4周后均得到改善。糖尿病大鼠的血小板高聚集活性可被TAT降低，但不能被ALC降低。TAT减少了山梨醇的积累，不仅防止了糖尿病神经中肌醇的消耗，还防止了游离肉碱的缺乏。另一方面，ALC也增加了肌醇以及游离肉碱的含量，而不影响山梨醇的含量。这些观察结果表明，在糖尿病神经病变的发展过程中多元醇途径活性增加与肉碱缺乏之间存在密切关系，并且醛糖还原酶抑制剂TAT和肉碱类似物ALC对糖尿病神经病变具有治疗潜力。
