Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes.
Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes.
复制标题
动力蛋白系统的拮抗作用可防止和逆转糖尿病小鼠模型中的异常性和炎症。
DOI：
10.1371/journal.pone.0146259
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Franchi S
中科院分区：
文献类型：
--
作者：
Castelli M;Amodeo G;Negri L;Lattanzi R;Maftei D;Gotti C;Pistillo F;Onnis V;Congu C;Panerai AE;Sacerdote P;Franchi S
神经性疼痛是一种严重的糖尿病并发症，其治疗效果并不令人满意。它与参与疼痛产生和慢性化的神经炎症相关事件有关。前动力蛋白是一个新的趋化因子家族，已成为免疫系统、炎症和疼痛的关键参与者。我们研究了前动力蛋白及其受体作为实验性糖尿病神经病理性疼痛和炎症反应调节剂的作用。在链脲佐菌素诱导的小鼠糖尿病中，评估了脊髓和坐骨神经中前动力素及其受体的时程表达，并与机械性异常性疼痛相关。以蛋白质和 mRNA 的形式测量脊髓和坐骨神经促炎和抗炎细胞因子，并研究脊髓 GluR 亚基表达。评估了前动力蛋白受体拮抗剂 PC1 的预防和治疗对行为和生化参数的影响。通过测量巨噬细胞和 T 辅助细胞因子的产生来评估外周免疫激活。糖尿病小鼠的脊髓和神经中存在前动力素系统的上调，并且与异常性疼痛相关。治疗性 PC1 可以逆转异常性疼痛，而预防性治疗则可以阻止其发展。 PC1 使前动力蛋白水平正常化，并阻止脊髓中 GluN2B 亚基的上调。该拮抗剂恢复了脊髓和神经中改变的促炎/抗炎细胞因子平衡，还减少了糖尿病小鼠的外周免疫系统激活，减少了巨噬细胞促炎细胞因子和 T 辅助细胞 1 表型。前动力素系统有助于改变糖尿病神经病变的敏感性，其抑制作用可阻断疾病引起的异常性疼痛和炎症事件。
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.