PDF(Pubmed)
Abstract：
This study focused on the relationship between extracellular-regulated kinase (ERK) and obesity-induced increases in neuropathic pain. We fed rats a high-fat diet to establish the obesity model, and rats were given surgery to establish the chronic compression of the dorsal root ganglia (CCD) model. U0126 was applied to inhibit ERK, and metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) was applied to cause AMP-activated protein kinase (AMPK) activation. Paw withdrawal mechanical threshold (PWMT) were calculated to indicate the level of neuropathic pain. The data indicated that compared with normal CCD rats, the PWMT of obese CCD rats were decreased, accompanied with an increase of ERK phosphorylation, NAD(P)H oxidase 4 (NOX4) protein expression, oxidative stress and inflammatory level in the L4 to L5 spinal cord and dorsal root ganglia (DRG). Administration of U0126 could partially elevate the PWMT and reduce the protein expression of NOX4 and the above pathological changes in obese CCD rats. In vitro, ERK phosphorylation, NOX4 protein expression increased significantly in DRG neurons under the stimulation of palmitic acid (PA), accompanied with increased secretion of inflammatory factors, oxidative stress and apoptosis level, while U0126 partially attenuated the PA-induced upregulation of NOX4 and other pathological changes. In the rescue experiment, overexpression of NOX4 abolished the above protective effect of U0126 on DRG neurons in high-fat environment. Next, we explore upstream mechanisms. Metformin gavage significantly reduced neuropathic pain in obese CCD rats. For the mechanisms, activating AMPK with metformin (obese CCD rats) or AICAR (DRG neurons in a high-fat environment) not only inhibited the ERK-NOX4 pathway, but also improved oxidative stress and inflammation caused by high-fat. In conclusion, the AMPK-ERK-NOX4 pathway may has a pivotal role in mediating obesity-induced increases in neuropathic pain.
摘要：
这项研究集中在细胞外调节激酶（ERK）与肥胖引起的神经性疼痛增加之间的关系。用高脂饮食喂养大鼠建立肥胖模型,手术建立慢性压迫背根神经节(CCD)模型。U0126用于抑制ERK，和二甲双胍或5-氨基咪唑-4-甲酰胺核糖核苷（AICAR）用于引起AMP激活的蛋白激酶（AMPK）激活。计算爪撤回机械阈值（PWMT）以指示神经性疼痛的水平。数据表明,与正常CCD大鼠相比,肥胖CCD大鼠的PWMT降低，伴随着ERK磷酸化的增加，NAD(P)H氧化酶4(NOX4)蛋白表达,L4到L5脊髓和背根神经节（DRG）的氧化应激和炎症水平。U0126可部分升高肥胖CCD大鼠PWMT,降低NOX4蛋白表达及上述病理改变。体外，ERK磷酸化，在棕榈酸(PA)刺激下DRG神经元NOX4蛋白表达显著增加,伴随着炎症因子的分泌增加，氧化应激和凋亡水平，而U0126部分减弱了PA诱导的NOX4上调等病理变化。在救援实验中，NOX4的过表达消除了U0126对高脂环境中DRG神经元的上述保护作用。接下来,我们探索上游机制。二甲双胍灌胃可显著减轻肥胖CCD大鼠的神经病理性疼痛。对于机制，用二甲双胍（肥胖CCD大鼠）或AICAR（高脂环境中的DRG神经元）激活AMPK不仅抑制ERK-NOX4通路，而且还改善了高脂肪引起的氧化应激和炎症。总之,AMPK-ERK-NOX4通路可能在介导肥胖诱导的神经性疼痛增加中发挥关键作用.
