Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor
Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor
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DOI：
10.1007/s00125-004-1354-2
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发表时间：
2004-04-01
期刊：
影响因子：
8.2
通讯作者：
Mizisin, AP
中科院分区：
文献类型：
--
作者：
Calcutt, NA;Freshwater, JD;Mizisin, AP
目的/假设。糖尿病患者的感觉神经病变通常表现为热感觉的进行性丧失，而一些患者描述并发的自发性疼痛、异常性疼痛或痛觉过敏。糖尿病大鼠发生热痛觉减退和触觉异常性疼痛的机制尚不清楚。我们通过醛糖还原酶研究了大鼠的感觉障碍是否与葡萄糖代谢有关。我们还探讨了外源性神经营养因子的治疗潜力。在正常大鼠和链脲佐菌素诱导的糖尿病大鼠中进行热敏感性和触觉敏感性的行为评估。部分大鼠给予胰岛素、醛糖还原酶抑制剂、睫状神经营养因子或脑源性神经营养因子治疗。糖尿病8周后出现热痛觉减退，并通过胰岛素治疗（维持正常血糖）、醛糖还原酶抑制剂Statil或睫状神经营养因子预防。脑源性神经营养因子没有影响。当糖尿病大鼠在较短的糖尿病持续时间后进行测试时，它们在4周后表现出短暂的热痛觉过敏，8周后发展为热痛觉减退。在糖尿病发作时给予的醛糖还原酶抑制剂IDD 676（Lidorestat）可预防热痛觉过敏的发生，并且在糖尿病8周期间的最后4周内给予时也可阻止热痛觉减退的进展。神经营养因子或醛糖还原酶抑制剂治疗不能预防触觉异常性疼痛。短暂的热痛觉过敏和随后的进行性热痛觉减退发生在糖尿病大鼠继发于通过多元醇途径的过度流量。由多元醇途径介导的睫状神经营养因子的耗竭可能参与热痛觉减退的病因学。
Aims/hypothesis. Sensory neuropathy in diabetic patients frequently presents itself as progressive loss of thermal perception, while some patients describe concurrent spontaneous pain, allodynia or hyperalgesia. Diabetic rats develop thermal hypoalgesia and tactile allodynia by unknown mechanisms. We investigated whether sensory disorders in rats were related to glucose metabolism by aldose reductase. We also explored the therapeutic potential of exogenous neurotrophic factors.Methods. Behavioural assessments of thermal and tactile sensitivity were performed in normal rats and in rats with streptozotocin-induced diabetes. Some of the rats were treated with insulin, aldose reductase inhibitors, ciliary neurotrophic factor or brain-derived neurotrophic factor.Results. Thermal hypoalgesia was present after 8 weeks of diabetes and was prevented by insulin treatment, which maintained normoglycaemia, by the aldose reductase inhibitor Statil or by ciliary neurotrophic factor. Brain-derived neurotrophic factor did not have an effect. When diabetic rats were tested after shorter durations of diabetes, they showed transient thermal hyperalgesia after 4 weeks which progressed to thermal hypoalgesia after 8 weeks. The aldose reductase inhibitor IDD 676 (Lidorestat), given from the onset of diabetes, prevented the development of thermal hyperalgesia and also stopped progression to thermal hypoalgesia when delivered in the last 4 weeks of an 8-week period of diabetes. Tactile allodynia was not prevented by neurotrophic factor or aldose reductase inhibitor treatment.Conclusions/interpretation. Transient thermal hyperalgesia and subsequent progressive thermal hypoalgesia occur in diabetic rats secondary to exaggerated flux through the polyol pathway. A depletion of ciliary neurotrophic factor mediated by the polyol pathway may be involved in the aetiology of thermal hypoalgesia.