Echinacoside attenuates inflammatory response in a rat model of cervical spondylotic myelopathy via inhibition of excessive mitochondrial fission
Echinacoside attenuates inflammatory response in a rat model of cervical spondylotic myelopathy via inhibition of excessive mitochondrial fission
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松果菊苷通过抑制线粒体过度裂变减轻脊髓型颈椎病大鼠模型的炎症反应
DOI：
10.1016/j.freeradbiomed.2020.01.014
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发表时间：
2020-05-20
影响因子：
7.4
通讯作者：
Wang，Yongjun
中科院分区：
文献类型：
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作者：
Zhou，Longyun;Yao，Min;Wang，Yongjun
脊髓型颈椎病（CSM）是脊髓功能障碍的主要原因，治疗选择很少。虽然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，对盐生肉苁蓉的主要活性成分松果菊苷（ECH）的抗炎和神经保护作用的机制知之甚少。我们推测，过度的线粒体分裂在调节CSM的炎症反应中起着至关重要的作用，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（动力蛋白相关蛋白（Drp 1）的选择性抑制剂）在慢性颈髓压迫和激活BV 2细胞的大鼠模型中的作用。我们的研究结果表明，与媒介物治疗的大鼠相比，Mdivi-1干预的大鼠运动功能有所改善。事实上，Mdivi-1治疗减弱了促炎性细胞因子的表达，以及损伤中含pyrin结构域3（NLRP 3）炎性体、核转录因子-κB（NF-κB）和Drp 1的活化。与溶剂处理的大鼠相比，Mdivi-1处理的动物的压迫部位表现出延长的线粒体形态和减少的活性氧（ROS）。类似地，ECH处理的大鼠在处理后表现出神经恢复和损伤区域的炎症反应或相关信号的抑制。有趣的是，ECH处理部分逆转了损伤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NLRP 3炎性小体和NF-κB信号转导抑制活化的小胶质细胞。此外，我们观察到ECH显著抑制Drp 1易位到线粒体上，从而调节线粒体动力学和ROS产生，其作为NLRP 3炎性体活化和NF-κB信号传导的调节剂。因此，我们的研究结果表明，线粒体动力学调节炎症反应在CSM。此外，ECH可能通过调节Drp 1依赖的线粒体分裂和下游信号的激活来减轻慢性颈髓压迫大鼠的神经炎症。
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 ofCistanche 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 vitrodata 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.