Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Rehabilitation Medicine College, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
Free Radic Biol Med. 2020 May 20;152:697-714. doi: 10.1016/j.freeradbiomed.2020.01.014. Epub 2020 Jan 31.
Cervical spondylotic myelopathy (CSM) is a leading cause of spinal cord dysfunction with few treatment options. Although mitochondrial dynamics are linked to a wide range of pathological changes in neurodegenerative diseases, a connection between aberrant mitochondrial dynamics and CSM remains to be illuminated. In addition, mechanisms underlying the emerging anti-inflammatory and neuroprotective effects of echinacoside (ECH), the main active ingredient of Cistanche salsa, are poorly understood. We hypothesized that excessive mitochondrial fission plays a critical role in regulating inflammatory responses in CSM, and ECH might alleviate such responses by regulating mitochondrial dynamics. To this end, we assessed the effects of ECH and Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1), in a rat model of chronic cervical cord compression and activated BV2 cells. Our results showed that rats with Mdivi-1 intervention had improved motor function compared with vehicle-treated rats. Indeed, Mdivi-1 treatment attenuated pro-inflammatory cytokine expression, as well as activation of the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, nuclear transcription factor-κB (NF-κB), and Drp1 in lesions. Compared with vehicle-treated rats, compression sites of Mdivi-1-treated animals exhibited elongated mitochondrial morphologies and reduced reactive oxygen species (ROS). Similarly, ECH-treated rats exhibited neurological recovery and suppression of inflammatory response or related signals in the lesion area after treatment. Interestingly, ECH treatment partly reversed aberrant mitochondrial fragmentation and oxidative stress within the lesion area. In vitro data suggested that ECH suppressed activated microglia by modulating activation of the NLRP3 inflammasome and NF-κB signaling. Furthermore, we observed that ECH markedly inhibited Drp1 translocation onto mitochondria, whereby it regulated mitochondrial dynamics and ROS production, which act as regulators of NLRP3 inflammasome activation and NF-κB signaling. Thus, our findings reveal that mitochondrial dynamics modulate inflammatory responses during CSM. Moreover, ECH may attenuate neuroinflammation in rats subjected to chronic cervical cord compression by regulating Drp1-dependent mitochondrial fission and activation of downstream signaling.
脊髓型颈椎病（CSM）是脊髓功能障碍的主要原因，治疗选择有限。尽管线粒体动力学与神经退行性疾病的广泛病理变化有关，但异常线粒体动力学与 CSM 之间的联系仍有待阐明。此外，关于肉苁蓉（Cistanche salsa）的主要活性成分毛蕊花糖苷（ECH）的新兴抗炎和神经保护作用的机制尚不清楚。我们假设过度的线粒体裂变在调节 CSM 中的炎症反应中起着关键作用，而 ECH 可能通过调节线粒体动力学来减轻这种反应。为此，我们评估了 ECH 和 Mdivi-1（一种选择性的二氢乳清酸脱氢酶相关蛋白 1（Drp1）抑制剂）在慢性颈脊髓压迫大鼠模型和激活的 BV2 细胞中的作用。我们的结果表明，与载体处理的大鼠相比，用 Mdivi-1 处理的大鼠运动功能得到改善。事实上，Mdivi-1 治疗减轻了促炎细胞因子的表达，以及核转录因子-κB（NF-κB）和病变中 NOD 样受体家族 pyrin 域包含 3（NLRP3）炎性小体的激活。与载体处理的大鼠相比，Mdivi-1 处理动物的压缩部位显示出伸长的线粒体形态和减少的活性氧（ROS）。类似地，在用 ECH 治疗的大鼠中，在病变区域中观察到神经恢复以及炎症反应或相关信号的抑制。有趣的是，ECH 治疗部分逆转了病变区域内异常的线粒体碎片化和氧化应激。体外数据表明，ECH 通过调节 NLRP3 炎性小体和 NF-κB 信号的激活来抑制激活的小胶质细胞。此外，我们观察到 ECH 显著抑制 Drp1 转位到线粒体，从而调节线粒体动力学和 ROS 产生，这作为 NLRP3 炎性小体激活和 NF-κB 信号的调节剂。因此，我们的研究结果表明，线粒体动力学调节 CSM 期间的炎症反应。此外，ECH 可能通过调节 Drp1 依赖性线粒体裂变和下游信号的激活来减轻慢性颈脊髓压迫大鼠的神经炎症。
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