莫诺苷对大鼠脊髓损伤的保护作用及其机制

Oxidative stress and inflammation play important roles in pathological process of spinal cord injury (SCI), which are key targets to find drugs for SCI treatment. It has been reported that morroniside, a primary active ingredient in the Chinese herb Corni Fructus, plays important roles in antioxidation, anti-inflammation and anti-apoptosis. Our preliminary study also confirmed that morroniside inhibited the death of H2O2- and TNF-α-induced neurons and oligodendrocytes and improved the behavioral score of SCI rats, which suggest that morroniside may play a protective role against injured spinal cord and is expected to be applied in the treatment of clinical SCI. Thus, in this study, SCI rat model will be prepared, and the effects of morroniside on repairing of the injured tissue, survival of neural cells, protection of myelination and recovery of neurologic function in SCI rats will be observed to confirm the effectiveness of morroniside for SCI treatment. On this basis, the roles of morroniside in antioxidation, anti-inflammation, anti-apoptosis and inducing polarization of macrophages and T helper (Th) cells in injured spinal cord tissue will be investigated. Moreover, the analysis of high-throughput transcriptomics and functional analysis in vitro and in vivo will be used to find new molecules which are concerned with neural protection of morroniside. Finally, the mechanism of the neural protective role of morroniside in SCI repair will be clarified. This study is expected to find new drugs and strategies for treatment of SCI and provides theoretical and experimental basis for their further application in clinic.

在脊髓损伤（SCI）的病理过程中，氧化应激和炎症具有重要作用，是寻找SCI治疗药物的重要靶点。莫诺苷是中药山茱萸的主要活性成分，具有抗氧化应激、抗炎和抗凋亡等作用。我们的前期实验证实：莫诺苷可以抑制H2O2和TNF-α诱导的神经元和少突胶质细胞凋亡，改善SCI大鼠的行为学，提示它对损伤的脊髓具有神经保护作用，有望应用于SCI治疗。因此，本研究拟采用大鼠SCI模型，进一步观察莫诺苷对SCI大鼠组织修复、神经细胞存活、髓鞘保护和功能恢复的影响，明确莫诺苷对SCI的疗效。同时，深入探讨莫诺苷在损伤脊髓内抗氧化应激、抗炎、调节巨噬细胞和Th细胞极化等作用及其机制；并应用转录组学技术，结合体内外功能分析，寻找与莫诺苷神经保护作用有关的新分子和信号通路，进一步阐明莫诺苷对SCI发挥保护作用的机制。本项目有望找到治疗SCI的新药物、新策略，并为其临床应用提供理论基础和实验依据。

项目的背景：脊髓损伤（SCI）病理过程中，氧化应激和炎症是引发脊髓二次损伤的关键病理环节，也是药物治疗的重要靶标。莫诺苷是中药山茱萸的主要活性成分，具有抗氧化应激、抗炎和抗凋亡等作用。预实验表明：莫诺苷可以抑制过氧化氢和肿瘤坏死因子-α诱导的神经元和少突胶质细胞凋亡，改善SCI大鼠的行为学，提示它对损伤的脊髓具有神经保护作用，有望应用于SCI治疗。.主要研究内容：本项目采用大鼠SCI模型，观察莫诺苷对SCI后脊髓组织修复、神经细胞存活、髓鞘保护和脊髓神经功能恢复的影响，明确莫诺苷对SCI的治疗效果；同时，分析莫诺苷对损伤脊髓氧化应激、炎症、巨噬细胞和Th细胞活化的作用；此外，通过体内外研究相结合，探寻与莫诺苷神经保护作用有关的信号通路，阐明莫诺苷作用的分子机制。. 重要结果和关键数据：项目研究结果显示：1）莫诺苷治疗可以促进SCI大鼠脊髓运动功能的恢复，该行为学的改善与莫诺苷保护神经元和少突胶质细胞，进而增强髓鞘和组织修复能力有关；2）在此基础上结合体内外实验，分析莫诺苷的作用途径，证明莫诺苷具有抗炎、抗神经细胞凋亡、减少氧自由基的产生和增加抗氧化酶活性的作用；3）在体内外研究的基础上，结合转录组学检测，证实莫诺苷对SCI的作用可能和PI3K/Akt等信号调控有关。. 科学意义： 1）证实SCI背景下，天然植物化合物莫诺苷可通过调控炎症和氧化应激反应等途径保护神经功能，为SCI的治疗提供了临床前研究参考，同时可供具有相似病理过程疾病的治疗性研究提供借鉴；2）证实莫诺苷主要通过调控PI3K/Akt信号发挥对SCI的保护性作用，提示PI3K/Akt信号在脊髓损伤病理进展中的关键作用。