Price Sally A, Hounsom Luke, Purves-Tyson Tertia D, Fernyhough Paul, Tomlinson David R
Division of Neuroscience, 1.124 Stopford Building, University of Manchester, Manchester, M13 9PT, England, United Kingdom.
Ann N Y Acad Sci. 2003 Dec;1010:95-9. doi: 10.1196/annals.1299.015.
Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition of this activation for the ERK and p38 groups prevents nerve damage, and agents that improve neuronal function in diabetic rats-antioxidants and aldose reductase inhibitors-also inhibit activation of ERK and p38 in dorsal root ganglia (DRG). However, these same treatments consistently increase activation of JNK. Thus, in DRG from rats with streptozotocin (STZ)-induced diabetes of 12-week duration, the p54/56 isoforms of JNK were activated by 2.75 compared to controls (P <.05). In DRG from diabetic rats treated with a gamma-linolenic acid and alpha-lipoic acid diester (GLA/LA), the activity of the p54/56 isoform was 3.75 that of controls and the p46 isoform was also increased to 1.75 that of controls (both P <.05 compared to both controls and untreated diabetics). We therefore tested the hypothesis that JNK activation is protective. Exposure of rats to diabetes increased activation of JNK in DRG, but treatment with GLA/LA increased this effect (P <.05). Specific inhibition of JNK in primary cultures of DRG neurons using a peptide inhibitor of JNK (JNKi1, 159-600-R100, 7.5 micro M, Alexis Biochemicals) increased the release of LDH and reduced MTT staining; both findings indicate an increase in neuronal damage. Taken together these findings indicate that multiple isoforms of JNK were activated in sensory neurons of diabetic rats, probably by a combination of raised glucose and oxidative stress, and that this activation of JNK serves to protect the neurons from damage.
糖尿病可激活感觉神经节中的所有三类丝裂原活化蛋白激酶（MAP激酶）。抑制细胞外信号调节激酶（ERK）和p38这两类激酶的这种激活可预防神经损伤，而改善糖尿病大鼠神经元功能的药物（抗氧化剂和醛糖还原酶抑制剂）也可抑制背根神经节（DRG）中ERK和p38的激活。然而，这些相同的治疗方法却始终会增加应激活化蛋白激酶（JNK）的激活。因此，在患有链脲佐菌素（STZ）诱导的、病程为12周的糖尿病大鼠的DRG中，与对照组相比，JNK的p54/56亚型的激活程度增加了2.75倍（P <.05）。在用γ-亚麻酸和α-硫辛酸二酯（GLA/LA）治疗的糖尿病大鼠的DRG中，p54/56亚型的活性是对照组的3.75倍，p46亚型也增加到对照组的1.75倍（与对照组和未治疗的糖尿病大鼠相比，两者P均<.05）。因此，我们检验了JNK激活具有保护作用这一假说。将大鼠暴露于糖尿病环境中会增加DRG中JNK的激活，但用GLA/LA治疗会增强这种效应（P <.05）。使用JNK的肽抑制剂（JNKi1，159 - 600 - R100，7.5 μM，Alexis Biochemicals）在DRG神经元的原代培养物中特异性抑制JNK，会增加乳酸脱氢酶（LDH）的释放并减少噻唑蓝（MTT）染色；这两个结果均表明神经元损伤增加。综合这些发现表明，糖尿病大鼠感觉神经元中的多种JNK亚型被激活，可能是由血糖升高和氧化应激共同作用所致，并且这种JNK的激活有助于保护神经元免受损伤。
