Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
J Biochem Mol Toxicol. 2024 Mar;38(3):e23669. doi: 10.1002/jbt.23669.
Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-β synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.
紫杉醇（PTX）是一种广泛用于治疗多种肿瘤的化疗药物。然而，PTX 诱导的周围神经病变（PIPN）是一种由长期使用 PTX 引起的不良反应，严重影响生活质量。坏死性凋亡参与了多种神经退行性疾病的发生。背根神经节神经元的坏死性凋亡触发了 PIPN 的发病机制。因此，本研究旨在探讨脊髓神经元坏死性凋亡在 PIPN 中的作用，并探索小胶质细胞极化在坏死性凋亡中的潜在作用。我们通过隔日给予 quartic PTX 给药（累积剂量：8mg/kg）建立 PIPN 大鼠模型。PTX 诱导明显的神经元坏死性凋亡，并上调脊髓背角中受体相互作用蛋白激酶（RIP3）和混合谱系激酶结构域样蛋白（MLKL）的表达。这些作用被坏死性凋亡途径抑制剂 necrostatin-1（Nec-1）抑制。通过给予米诺环素抑制 PTX 诱导的脊髓小胶质细胞 M1 极化，阐明了小胶质细胞极化对调节脊髓坏死性凋亡的作用。我们观察到米诺环素对脊髓细胞中 PTX 诱导的坏死性凋亡具有显著的抑制作用，这表现在 RIP3 和 MLKL 表达下调，以及肿瘤坏死因子-α和 IL-β合成受到抑制。此外，米诺环素改善了 PIPN 大鼠的痛觉过敏症状。总的来说，这项研究表明，PTX 诱导的脊髓小胶质细胞极化导致 RIP3/MLKL 调节的坏死性凋亡，从而导致 PIPN。这些发现为预防和治疗神经性疼痛提供了一个潜在的靶点。
