School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei, China.
School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, Hubei, China.
PLoS One. 2022 Oct 31;17(10):e0275428. doi: 10.1371/journal.pone.0275428. eCollection 2022.
Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.
奥沙利铂（OXA）是一种第三代铂类化合物，在多种实体瘤中具有临床活性。由于化疗周期的重复，OXA 引起的慢性周围神经病表现为感觉异常和疼痛。本研究探讨了化疗疼痛的神经病变，并研究了 2-溴棕榈酸（2-BP）对 OXA 诱导的大鼠疼痛行为的镇痛作用。通过连续五次腹腔注射 OXA（4mg/kg）建立化疗疼痛大鼠模型。在建立 OXA 诱导的大鼠后，进行疼痛行为测试、炎症信号分析和线粒体功能测量。OXA 诱导的大鼠表现出机械性痛觉过敏和脊髓炎症浸润。我们的荧光和 Western blot 分析显示，OXA 大鼠脊髓星形胶质细胞被激活，星形胶质细胞标志物上调。此外，NOD、LRR 和富含吡喃结构域 3（NLRP3）炎性小体介导的炎症信号级联也被激活。炎症是由功能失调的线粒体触发的，其特征在于环氧化酶-2（COX-2）水平和锰超氧化物歧化酶（Mn-SOD）活性增加。鞘内注射 2-BP 可显著减弱动力相关蛋白 1（Drp1）介导的线粒体分裂，恢复线粒体功能，抑制 NLRP3 炎性小体级联，从而降低机械性疼痛敏感性。对于细胞研究，2-BP 处理显著逆转了肿瘤坏死因子-α（TNF-α）诱导的线粒体膜电位不足和高活性氧（ROS）水平。这些发现表明，2-BP 通过减少 Drp1 介导的线粒体功能障碍来降低脊髓炎症并缓解 OXA 诱导的神经病理性疼痛。
