12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy.

IF 0.7 Q4 ENDOCRINOLOGY & METABOLISM
Roman Stavniichuk, Alexander A Obrosov, Viktor R Drel, Jerry L Nadler, Irina G Obrosova, Mark A Yorek
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引用次数: 16

Abstract

Background: Increased mitogen-activated protein kinase (MAPK) phosphorylation has been detected in peripheral nerve of human subjects and animal models with diabetes as well as high-glucose exposed human Schwann cells, and have been implicated in diabetic peripheral neuropathy. In our recent studies, leukocytetype 12/15-lipoxygenase inhibition or gene deficiency alleviated large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss in streptozotocin-diabetic mice.

Methods: To address a mechanism we evaluated the potential for pharmacological 12/15-lipoxygenase inhibition to counteract excessive MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy. C57Bl6/J mice were made diabetic with streptozotocin and maintained with or without the 12/15-lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC). Human Schwann cells were cultured in 5.5 mM or 30 mM glucose with or without CDC.

Results: 12(S) HETE concentrations (ELISA), as well as 12/15-lipoxygenase expression and p38 MAPK, ERK, and SAPK/JNK phosphorylation (all by Western blot analysis) were increased in the peripheral nerve and spinal cord of diabetic mice as well as in high glucose-exposed human Schwann cells. CDC counteracted diabetes-induced increase in 12(S)HETE concentrations (a measure of 12/15-lipoxygenase activity), but not 12/15-lipoxygenase overexpression, in sciatic nerve and spinal cord. The inhibitor blunted excessive p38 MAPK and ERK, but not SAPK/ JNK, phosphorylation in sciatic nerve and high glucose exposed human Schwann cells, but did not affect MAPK, ERK, and SAPK/JNK phosphorylation in spinal cord.

Conclusion: 12/15-lipoxygenase inhibition counteracts diabetes related MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy and implies that 12/15-lipoxygenase inhibitors may be an effective treatment for diabetic peripheral neuropathy.

12/15-脂氧合酶抑制在小鼠和糖尿病周围神经病变细胞培养模型中抵消MAPK磷酸化。
背景:在人类受试者和糖尿病动物模型以及高糖暴露的人类雪旺细胞周围神经中检测到丝裂原活化蛋白激酶(MAPK)磷酸化增加,并与糖尿病周围神经病变有关。在我们最近的研究中,白细胞型12/15-脂氧合酶抑制或基因缺乏减轻了链脲佐菌素糖尿病小鼠的大、小神经纤维功能障碍,但没有减轻表皮内神经纤维的损失。方法:在糖尿病神经病变的小鼠和细胞培养模型中,我们评估了药理学12/15-脂氧合酶抑制抑制MAPK过度磷酸化的潜力。用链脲霉素诱导C57Bl6/J小鼠患上糖尿病,并用或不加12/15-脂氧合酶抑制剂肉桂基-3,4-二羟基-α-氰肉桂酸酯(CDC)维持。人雪旺细胞分别在含或不含CDC的5.5 mM或30 mM葡萄糖中培养。结果:12(S) HETE浓度(ELISA)、12/15-脂氧合酶表达和p38 MAPK、ERK、SAPK/JNK磷酸化(均通过Western blot分析)在糖尿病小鼠周围神经和脊髓以及高糖暴露的人雪旺细胞中升高。CDC可以抵消糖尿病引起的坐骨神经和脊髓中12(S)HETE浓度升高(12/15-脂氧合酶活性的一种测量方法),但不能抵消12/15-脂氧合酶过表达。该抑制剂抑制了过量的p38 MAPK和ERK,但对坐骨神经和高糖暴露的人雪旺细胞中SAPK/JNK的磷酸化不起作用,但对脊髓中MAPK、ERK和SAPK/JNK的磷酸化不起作用。结论:12/15-脂氧合酶抑制在小鼠和糖尿病神经病变细胞培养模型中抵消糖尿病相关的MAPK磷酸化,提示12/15-脂氧合酶抑制剂可能是治疗糖尿病周围神经病变的有效方法。
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来源期刊
Diabetes Mellitus
Diabetes Mellitus ENDOCRINOLOGY & METABOLISM-
CiteScore
1.90
自引率
40.00%
发文量
61
审稿时长
7 weeks
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