PDF(Pubmed)
Abstract：
Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4 mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (.5 and 1.8 mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin ( .5 and 1.8 mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the dorsal root ganglion. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for chemotherapy-induced peripheral neuropathy treatment. PERSPECTIVE: Chemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.
摘要：
化疗引起的周围神经病变是一种具有挑战性的治疗条件，并由于严重而产生，化疗药物如紫杉醇的剂量限制性毒性。这通常会导致感觉和运动缺陷使人衰弱，而现有的治疗干预措施无法有效预防或缓解。最近的研究已经证明了Meteorin的治疗效果，一种神经营养因子,在物理创伤引起的周围神经损伤的啮齿动物模型中逆转神经性疼痛。这里,我们试图使用紫杉醇诱导的雄性和雌性小鼠周围神经病变模型研究重组小鼠Meteorin(rmMeteorin)的潜在抗伤害作用.紫杉醇治疗（4×4mg/kg，i.p.）在治疗后第8天诱导后爪机械超敏反应。此后,在一个逆转的剂量范式中，在9天内重复注射rmMeteorin（分别为0.5和1.8mg/kgs.c.）可显著且持久地减轻男女的机械超敏反应。此外,施用rmMeteorin（0.5和1.8mg/kg），在紫杉醇治疗之前和期间开始(预防给药范例)，减少了后爪机械超敏反应的建立。通过谷氨酰胺合成酶和背根神经节中的连接蛋白43蛋白表达测量，在两种给药范例中重复全身施用rmMeteorin均降低了卫星神经胶质细胞反应性的组织化学迹象。此外,在预防给药模式中,rmMeteorin对紫杉醇诱导的表皮内神经纤维丢失具有保护作用.我们的发现表明，rmMeteorin在紫杉醇诱导的周围神经病变模型中具有强大而持续的抗伤害作用，重组人Meteorin的开发可能是化疗诱导的周围神经病变治疗的新型有效治疗剂。背景：化疗神经病是降低癌症患者和幸存者生活质量的主要临床问题。我们的实验表明，Meteorin治疗减轻疼痛相关的行为，以及紫杉醇神经病变小鼠模型中的神经毒性迹象。
