Department of Pain, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China.
J Cell Mol Med. 2024 Apr;28(7):e18240. doi: 10.1111/jcmm.18240.
Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) in both patients and NP models induced by peripheral nerve injury. However, the underlying mechanisms remain incompletely understood. Ferroptosis, a novel form of programmed cell death, has been found to be activated during NP development, while EA has shown potential in promoting neurological recovery following acute cerebral injury by targeting ferroptosis. In this study, to investigate the detailed mechanism underlying EA intervention on NP, male Sprague-Dawley rats with chronic constriction injury (CCI)-induced NP model received EA treatment at acupoints ST36 and GV20 for 14 days. Results demonstrated that EA effectively attenuated CCI-induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats. Moreover, EA reversed the oxidative stress-mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), malondialdehyde levels and iron overload. Furthermore, EA increased the immunofluorescence co-staining of GPX4 in neurons cells of the spinal cord of CCI rats. Mechanistic analysis unveiled that the inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of Nrf2 signalling.
越来越多的证据支持电针（EA）在治疗慢性神经性疼痛（NP）方面的镇痛疗效，无论是在接受外周神经损伤诱导的 NP 患者还是 NP 模型中均有疗效。然而，其潜在机制仍不完全清楚。铁死亡，一种新的程序性细胞死亡形式，已被发现会在 NP 发展过程中被激活，而 EA 已被证明通过靶向铁死亡，在急性脑损伤后具有促进神经恢复的潜力。在这项研究中，为了研究 EA 干预 NP 的详细机制，慢性坐骨神经结扎（CCI）诱导 NP 模型的雄性 Sprague-Dawley 大鼠接受了 14 天的 ST36 和 GV20 穴位 EA 治疗。结果表明，EA 有效减轻了 CCI 引起的痛觉过敏，并减轻了 NP 大鼠脊髓中的神经元损伤和丢失。此外，EA 通过上调 xCT、谷胱甘肽过氧化物酶 4（GPX4）、铁蛋白重链（FTH1）和超氧化物歧化酶（SOD）水平，下调酰基辅酶 A 合成酶长链家族成员 4（ACSL4）、丙二醛水平和铁过载的表达，逆转了氧化应激介导的脊髓铁死亡表型。此外，EA 增加了 CCI 大鼠脊髓神经元细胞中 GPX4 的免疫荧光共染色。机制分析揭示，通过其特异性抑制剂 ML385 抑制 Nrf2 信号通路的抗氧化途径，可显著拮抗 EA 对 NP 大鼠神经元铁死亡的保护作用，同时轻微减弱其镇痛作用。这些发现表明，ST36 和 GV20 穴位的 EA 治疗可能通过抑制脊髓神经元铁死亡来预防 NP，部分通过激活 Nrf2 信号通路。
