Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice
Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice
复制标题
DOI：
10.1016/j.expneurol.2021.113607
复制
发表时间：
2021-01-23
影响因子：
5.3
通讯作者：
Adalbert, Robert
中科院分区：
文献类型：
--
作者：
Gould, Stacey Anne;White, Matthew;Adalbert, Robert
化疗诱导的周围神经病变（CIPN）是癌症治疗的常见剂量限制性副作用，通常与感觉轴突或其末端区域的变性有关。缓慢沃勒变性蛋白（WLDS）的存在，或无菌α和含TIR基序的蛋白1（SARM 1）的遗传缺失，强烈保护轴突在损伤或轴突运输阻断后免于变性，减轻了几种CIPN模型中的疼痛。然而，奥沙利铂可引起急性疼痛反应，表明疼痛产生的机制不同。在这里，我们测试了WLDS的存在或SARM 1的缺乏是否可以在单次奥沙利铂注射后保护小鼠免受急性奥沙利铂诱导的疼痛。在BL/6和Wld（S）小鼠中，奥沙利铂诱导了显著的机械和冷超敏反应，而在Sarm 1（-/-）小鼠中不存在。尽管存在超敏反应，但奥沙利铂给药后，任何小鼠的足垫中均未出现表皮内神经纤维（IENF）的显著损失，表明疼痛超敏反应的早期阶段可能与轴突变性无关。为了鉴定可能引起疼痛反应的其他变化，在来自每个基因型的治疗和对照小鼠的DRG中进行RNA测序。SARM 1（-/-）小鼠的基因表达变化比BL/6或Wld（S）小鼠少。这与疼痛测量结果一致，表明奥沙利铂治疗后Sarm 1（-/-）DRG保持相对不变，与BL/6和Wld（S）小鼠不同。在三种基因型中，Alas 2、Hba-a1、Hba-a2和Tfrc四种转录物水平的变化与奥沙利铂诱导的疼痛相关或不相关。我们的研究结果表明，靶向SARM 1可能是一种可行的治疗方法，以防止奥沙利铂诱导的急性神经性疼痛。
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLDS), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLDS or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and Wld(S) mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1(-/-) mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1(-/-) mice had fewer gene expression changes than either BL/6 or Wld(S) mice. This is consistent with the pain measurements in demonstrating that Sarm1(-/-) DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and Wld(S) mice. Changes in levels of four transcripts - Alas2, Hba-a1, Hba-a2, and Tfrc - correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain.