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题目译名：“组合”多靶点药物治疗和新制剂可减少炎症并改善创伤性脊髓损伤的内源性髓鞘再生
发表期刊：Cells
发表时间：2023 年 5月
观点提炼：
1.脊髓损伤是难治性疾病
2.NGF已经证实具备神经修复和炎症抑制的作用
3.在本文中，NGF或通过促进M1型小胶质细胞的减少而发挥减轻炎症，促进髓鞘再生的作用
4.脊髓神经损伤是复杂的情况，需要多药物联合治疗，而非单个特效药可以应对
文献精读
脊髓损伤（SCI）的特征是导致感觉和运动障碍的一系列事件。迄今为止，这种情况是不可逆转的，并且无法治愈。为了改善髓磷脂修复（myelin repair）并限制继发性损伤，我们开发了一种基于纳米药物（nanomedicines)（NMeds）的多种疗法，该药物装载了促髓鞘剂三碘甲状腺原氨酸(the promyelinating agent triiodothyronine)（T3），与全身性布洛芬和小鼠神经生长因子（mNGF）结合使用。对聚-L-乳酸-共乙醇酸（PLGA）NMed进行优化并装载T3以促进缓释。体外实验证实了T3-NMeds不同于少突胶质细胞前体细胞的有效性。在大鼠体内进行SCI挫伤实验，探讨NMed的生物分布以及组合药物在短期和长期病变后的疗效。在短期内观察到显著的抗炎作用，M1型小胶质细胞和谷氨酸水平降低，但随后TREM2增加。从长远来看，观察到NG2-IR髓鞘形成的改善，MBP含量的增加和脱髓鞘面积的减少。这些数据表明，NMeds可以成功地用于获得更可控的局部药物递送，并且这种多重治疗可以有效改善SCI的结局。
简介
材料和方法
结果
3.1. T3-NMed 表征
3.2. 体外 T3 释放和细胞摄取(Cell Uptake)
3ד组合”（T3负载NMeds-mNGF-Ibu）对炎症标志物的短期和长期影响。
M1型小胶质细胞通过“组合”治疗显著减少，尽管没有抑制。治疗大鼠病变后8天时脑脊液中小胶质细胞相关标志物TREM2的水平也显著增加。然后，我们使用OX42-IR作为小胶质细胞标记物，使用GFAP-IR作为星形胶质细胞形成的标记物，病变56天后探索脊髓组织中病灶正中侧和尾侧的残余神经炎症。在载体和3ד组合”治疗的动物中，我们观察到相比于非损伤大鼠，病变大鼠免疫染色增加，并且小胶质细胞形态表型在载体和3ד组合”处理的大鼠之间没有显著差异。
3ד组合”疗法对长期髓鞘再生标志物的影响
我们观察到，与载体处理的大鼠相比，3ד组合”组的脱髓鞘区域逐渐减少，总体价值显著降低。
3ד组合”疗法对神经变性标志物的短期和长期影响。
病变56天后通过脊髓取样后的肉眼分析，评估载体组与治疗组大鼠的瘢痕延伸来分析病变稳定程度（图6D，E），分析显示，与载体注射组相比，治疗大鼠的瘢痕面积显著减少。
讨论
在这项研究中，我们测试了一种多靶点方法来限制实验SCI的继发性损伤发作和进展。我们使用了市售药物和新型给药溶液的组合，在实验性损伤后立即给药。在病灶部位局部注射装载T3的NMeds，目的是有利于少突胶质前体细胞（OPCs）的分化和髓鞘修复(myelin repair);布洛芬的全身给药旨在减少炎症的有害影响;局部和全身性NGF用于促进神经保护和调节炎症。这种 3× “组合”疗法被证明可以减少病变诱导的小胶质细胞 1 型活化，同时在短期（病变后8天）增加脑脊液中的 TREM2浓度，有利于髓磷脂保护/修复，并在长期（病变后56 天）恢复运动功能。
结论
向上滑动阅览
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