Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy - Interactions with aldose reductase
Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy - Interactions with aldose reductase
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DOI：
10.2337/diabetes.53.7.1851
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发表时间：
2004-07-01
期刊：
影响因子：
7.7
通讯作者：
Tomlinson, DR
中科院分区：
文献类型：
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作者：
Price, SA;Agthong, S;Tomlinson, DR
本研究检测了p38丝裂原活化蛋白（MAP）激酶在将高糖转化为糖尿病神经病变特征性神经传导速度（NCV）缺陷中的作用。在用p38抑制剂、醛糖还原酶抑制剂和胰岛素治疗的链脲佐菌素诱导的糖尿病大鼠中测量p38活化和NCV。糖尿病动物的背根神经节（DRG）在糖尿病12周时显示出显著的p38激活。糖尿病12周中最后4周的胰岛素治疗使p38激活正常化。此外，用醛糖还原酶抑制剂非达司他治疗12周完全阻止了活化。免疫细胞化学定位激活p38的DRG中几乎所有的感觉神经元表型的细胞核，和激活是明确的糖尿病，因为是由非达司他和p38抑制剂SB 239063的抑制。在脊髓腹角，p38存在于运动神经元细胞体中;并且再次，糖尿病和非达司他抑制中的激活是明确的。用p38的特异性抑制剂（SB 239063）、非达司他或胰岛素治疗糖尿病动物也可预防运动和感觉NCV的降低。这些发现表明，糖尿病动物中多元醇途径通量增加导致p38激活。这种激活可以介导基因转录和细胞表型的变化，这些变化可能是NCV缺陷的基础。胰岛素和醛糖还原酶抑制剂可以防止过量的多元醇途径通量，因此这些药物可以通过防止p38 MAP激酶活化来防止NCV缺陷。
This study examined the role of p38 mitogen-activated protein (MAP) kinase in transducing high glucose into deficits in nerve conduction velocity (NCV) that are characteristic of diabetic neuropathy. p38 activation and NCV were measured in streptozocin-induced diabetic rats treated with a p38 inhibitor, an aldose reductase inhibitor, and insulin. Dorsal root ganglia (DRG) from diabetic animals showed marked activation of p38 at 12 weeks of diabetes. Insulin treatment for the last 4 of 12 weeks of diabetes normalized p38 activation. Furthermore, activation was completely prevented by 12 weeks' treatment with the aldose reductase inhibitor, fidarestat. Immunocytochemistry localized activation of p38 to the nuclei of virtually all sensory neuronal phenotypes in the DRG, and activation was clear in diabetes, as was inhibition by fidarestat and by the p38 inhibitor SB 239063. In the ventral horn of the spinal cord, p38 was present in motoneuron cell bodies; and again, activation in diabetes and fidarestat inhibition was clear. Treatment of diabetic animals with a specific inhibitor of p38 (SB 239063), fidarestat, or insulin also prevented reductions in both motor and sensory NCV. These findings suggest that increased polyol pathway flux in diabetic animals leads to the activation of p38. This activation can mediate changes in gene transcription and cellular phenotype that are likely to underlie the NCV deficits. Insulin and aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents may prevent NCV deficits by preventing p38 MAP kinase activation.