Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Medical Quality Management, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Eur J Pain. 2021 Jul;25(6):1227-1240. doi: 10.1002/ejp.1737. Epub 2021 Apr 13.
Relationships between iron-dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.
Forty Sprague-Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI + LIP group; CCI + Veh group; and CCI group. Liproxstatin-1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI + LIP or CCI + Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti-acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.
CCI-induced NeP was followed by iron accumulation, increased lipid peroxidation and dysregulation of ACSL4 and GPX4. Moreover transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin-1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.
Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin-1 as potential therapies for hypersensitivity induced by peripheral nerve injury.
The spinal ferroptosis-like cell death was involved in the development of neuropathic pain resulted from peripheral nerve injury, and inhibition of ferroptosis by liproxstatin-1 could alleviate mechanical and thermal hypersensitivities. This knowledge suggested that ferroptosis could represent a potential therapeutic target for neuropathic pain.
铁依赖性细胞铁死亡与神经系统疾病之间的关系最近已被揭示。然而，细胞铁死亡在神经病理性疼痛（NeP）中的作用仍有待阐明。因此，我们旨在研究脊髓中的细胞铁死亡是否与坐骨神经慢性缩窄性损伤（CCI）引起的 NeP 有关。
40 只 Sprague-Dawley 大鼠接受 CCI 或假手术，并随机分为以下四组：假手术组；CCI+LIP 组；CCI+Veh 组；CCI 组。手术后连续 3 天，CCI+LIP 或 CCI+Veh 组分别腹腔内注射洛普司他汀-1或玉米油。手术后测试机械和热感觉过敏。还评估了脊髓中与细胞铁死亡相关的生化和形态变化。这些变化包括铁含量、谷胱甘肽过氧化物酶 4（GPX4）和抗酰基辅酶 A 合成酶长链家族成员 4（ACSL4）的表达、脂质过氧化测定以及线粒体形态。
CCI 诱导的 NeP 后伴随着铁积累、脂质过氧化增加以及 ACSL4 和 GPX4 的失调。此外，透射电子显微镜证实了线粒体异常形态变化的存在，如线粒体缩小和膜破裂。此外，洛普司他汀-1在 CCI 大鼠中的给药减轻了过敏反应，降低了铁水平，减少了脊髓脂质过氧化，恢复了 GPX4 和 ACSL4 水平的失调，并防止了 CCI 引起的线粒体形态变化。
我们的研究结果表明，细胞铁死亡参与了 CCI 诱导的 NeP，并且提示细胞铁死亡抑制剂，如洛普司他汀-1，可能是治疗周围神经损伤引起的过敏反应的潜在治疗方法。
脊髓中铁死亡样细胞死亡参与了外周神经损伤引起的神经病理性疼痛的发展，洛普司他汀-1抑制铁死亡可减轻机械和热过敏。这一知识表明，铁死亡可能成为神经病理性疼痛的潜在治疗靶点。
