Department of Orthopedics, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121000, China.
Departments of Endocrinology, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121000, China.
Mol Neurobiol. 2023 Aug;60(8):4450-4471. doi: 10.1007/s12035-023-03364-1. Epub 2023 Apr 28.
Spinal cord injury (SCI) is a devastating neurological disorder characterized by high morbidity and disability. However, there is still a lack of effective treatments for it. The identification of drugs that promote autophagy and inhibit apoptosis in neurons is critical for improving patient outcomes following SCI. Previous studies have shown that increasing the activity of silent information regulator 1 (SIRT1) and downstream protein AMP-activated protein kinase (AMPK) in rat models of SCI is highly neuroprotective. Oxymatrine (OMT), a quinolizidine alkaloid, has exhibited neuroprotective effects in various central nervous system (CNS) diseases. However, its explicit effect and molecular mechanism in SCI are still unclear. Herein, we aimed to investigate the therapeutic effects of OMT and explore the potential role of autophagy regulation following SCI in rats. A modified compressive device (weight 35 g, time 5 min) was applied to induce moderate SCI in all groups except the sham group. After treatment with drugs or vehicle (saline), our results indicated that OMT treatment significantly reduced the lesion size, promoted survival of motor neurons, and subsequently attenuated motor dysfunction following SCI in rats. OMT significantly enhanced autophagy activity, inhibited apoptosis in neurons, and increased SIRT1 and p-AMPK expression levels. Interestingly, these effects of OMT on SCI were partially prevented by co-treatment with SIRT1 inhibitor EX527. Furthermore, combining OMT with the potent autophagy inhibitor chloroquine (CQ) could effectively abolish its promotion of autophagic flux. Taken together, these data revealed that OMT exerts a neuroprotective role in functional recovery against SCI in rats, and these effects are potentially associated with OMT-induced activation of autophagy via the SIRT1/AMPK signaling pathway.
脊髓损伤 (SCI) 是一种破坏性的神经系统疾病，其发病率和致残率都很高。然而，目前仍然缺乏有效的治疗方法。鉴定能够促进神经元自噬和抑制细胞凋亡的药物对于改善 SCI 患者的预后至关重要。先前的研究表明，在 SCI 大鼠模型中增加沉默信息调节因子 1 (SIRT1) 和下游蛋白 AMP 激活的蛋白激酶 (AMPK) 的活性具有高度的神经保护作用。氧化苦参碱 (OMT) 是一种喹诺里西啶生物碱，在多种中枢神经系统 (CNS) 疾病中表现出神经保护作用。然而，其在 SCI 中的明确作用和分子机制尚不清楚。在此，我们旨在研究 OMT 的治疗效果，并探讨 SCI 后自噬调节的潜在作用。除假手术组外，所有组均应用改良压缩装置（重量 35 g，时间 5 min）诱导中度 SCI。在药物或载体（盐水）治疗后，我们的结果表明，OMT 治疗可显著减小损伤体积，促进运动神经元存活，并随后减轻 SCI 大鼠的运动功能障碍。OMT 可显著增强自噬活性，抑制神经元凋亡，并增加 SIRT1 和 p-AMPK 的表达水平。有趣的是，SIRT1 抑制剂 EX527 可部分阻断 OMT 对 SCI 的这些作用。此外，将 OMT 与强效自噬抑制剂氯喹 (CQ) 联合使用可有效消除其对自噬流的促进作用。综上所述，这些数据表明 OMT 对 SCI 大鼠的功能恢复具有神经保护作用，这些作用可能与 OMT 通过 SIRT1/AMPK 信号通路诱导自噬有关。
