Caputi Francesca Felicia, Di Cesare Mannelli Lorenzo, Rullo Laura, Micheli Laura, Stamatakos Serena, Posa Luca, Ghelardini Carla, Romualdi Patrizia, Candeletti Sanzio
Dept. of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Dept. of Neuroscience, Psychology Drug Research and Child Health Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
Biochem Pharmacol. 2020 Dec;182:114255. doi: 10.1016/j.bcp.2020.114255. Epub 2020 Oct 1.
Oxaliplatin-induced neuropathy (OXAIN) is a major adverse effect of this antineoplastic drug, widely used in the treatment of colorectal cancer. Although its molecular mechanisms remain poorly understood, recent evidence suggest that maladaptive neuroplasticity and oxidative stress may participate to the development of this neuropathy. Given the role played on protein remodeling by ubiquitin-proteasome system (UPS) in response to oxidative stress and in neuropathic pain, we investigated whether oxaliplatin might cause alterations in the UPS-mediated degradation pathway, in order to identify new pharmacological tools useful in OXAIN. In a rat model of OXAIN (2.4 mg kg i.p., daily for 10 days), a significant increase in chymotrypsin-(β5) like activity of the constitutive proteasome 26S was observed in the thalamus (TH) and somatosensory cortex (SSCx). In addition, the selective up-regulation of β5 and LMP7 (β5i) subunit gene expression was assessed in the SSCx. Furthermore, this study revealed that oprozomib, a selective β5 subunit proteasome inhibitor, is able to normalize the spinal prodynorphin gene expression upregulation induced by oxaliplatin, as well as to revert mechanical allodynia and thermal hyperalgesia observed in oxaliplatin-treated rats. These results underline the relevant role of UPS in the OXAIN and suggest new pharmacological targets to counteract this severe adverse effect. This preclinical study reveals the involvement of the proteasome in the oxaliplatin-induced neuropathy and adds useful information to better understand the molecular mechanism underlying this pain condition. Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy.
奥沙利铂诱导的神经病变（OXAIN）是这种抗肿瘤药物的主要不良反应，该药物广泛用于治疗结直肠癌。尽管其分子机制仍知之甚少，但最近的证据表明，适应性不良的神经可塑性和氧化应激可能参与了这种神经病变的发展。鉴于泛素 - 蛋白酶体系统（UPS）在应对氧化应激和神经性疼痛时对蛋白质重塑所起的作用，我们研究了奥沙利铂是否可能导致UPS介导的降解途径发生改变，以便确定对OXAIN有用的新的药理学工具。在OXAIN大鼠模型中（腹腔注射2.4mg/kg，每日一次，共10天），在丘脑（TH）和体感皮层（SSCx）中观察到组成型26S蛋白酶体的胰凝乳蛋白酶样（β5）活性显著增加。此外，还评估了SSCx中β5和LMP7（β5i）亚基基因表达的选择性上调。此外，本研究表明，选择性β5亚基蛋白酶体抑制剂奥普佐米能够使奥沙利铂诱导的脊髓前强啡肽基因表达上调正常化，并能逆转在奥沙利铂处理的大鼠中观察到的机械性异常性疼痛和热痛觉过敏。这些结果强调了UPS在OXAIN中的相关作用，并提出了对抗这种严重不良反应的新药理学靶点。这项临床前研究揭示了蛋白酶体参与奥沙利铂诱导的神经病变，并为更好地理解这种疼痛状况的分子机制提供了有用的信息。此外，尽管还需要进一步的证据，但这些发现表明奥普佐米可能是对抗化疗诱导的神经病变的一种治疗选择。
