Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China; Tianjin Institute of Orthopedic Innovation and Transformation, Tianjin, China.
Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin, China; Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China; Tianjin Institute of Orthopedic Innovation and Transformation, Tianjin, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113227. doi: 10.1016/j.intimp.2024.113227. Epub 2024 Sep 25.
Ferroptosis, characterized by iron-dependent accumulation of lipid peroxides, plays an important role in spinal cord injury (SCI). Berberine (BBR), as a lipid peroxide scavenger, has been widely used in treating other diseases; however, its role in ferroptosis has not been fully elucidated. Therefore, here, to test our hypothesis that BBR can reduce the severity of SCI and promote motor function recovery by inhibiting neuronal ferroptosis, we evaluated the changes in ferroptosis-related indicators after BBR administration by establishing a cellular ferroptosis model and an SCI contusion model. We found that BBR administration significantly reduces lipid peroxidation damage, maintains normal mitochondrial function, reduces excessive accumulation of iron ions, enhances antioxidant capacity, and activates the ferroptosis defense system in vivo and in vitro. Mechanistically, BBR alleviates neuronal ferroptosis by inducing adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and up-regulating nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) protein expression to promote glutathione production. BBR administration also significantly improves motor function recovery in SCI rats. Meanwhile, applying the AMPK inhibitor Compound C blocks the neuroprotective and all other effects of BBR. Collectively, our findings demonstrate that BBR can attenuate neuronal ferroptosis after SCI by activating the AMPK-NRF2-HO-1 pathway.
铁死亡是一种依赖铁的脂质过氧化积累的细胞死亡方式，在脊髓损伤（SCI）中起着重要作用。小檗碱（BBR）作为一种脂质过氧化物清除剂，已被广泛用于治疗其他疾病；然而，其在铁死亡中的作用尚未完全阐明。因此，在这里，为了验证我们的假设，即 BBR 通过抑制神经元铁死亡来减轻 SCI 的严重程度并促进运动功能恢复，我们通过建立细胞铁死亡模型和 SCI 挫伤模型来评估 BBR 给药后与铁死亡相关的指标变化。我们发现，BBR 给药可显著减轻脂质过氧化损伤，维持正常的线粒体功能，减少铁离子的过度积累，增强抗氧化能力，并激活体内和体外的铁死亡防御系统。在机制上，BBR 通过诱导一磷酸腺苷激活蛋白激酶（AMPK）磷酸化以及上调核因子红细胞 2 相关因子 2（NRF2）和血红素加氧酶-1（HO-1）蛋白表达来减轻神经元铁死亡，从而促进谷胱甘肽的产生。BBR 给药还显著改善了 SCI 大鼠的运动功能恢复。同时，应用 AMPK 抑制剂 Compound C 可阻断 BBR 的神经保护和其他所有作用。总之，我们的研究结果表明，BBR 通过激活 AMPK-NRF2-HO-1 通路来减轻 SCI 后的神经元铁死亡。
