中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2023-2025.doi: 10.4103/1673-5374.308088

• 观点:退行性病与再生 • 上一篇    下一篇

针对多发性硬化症中靶标NF-kB信号传导的药物干预

  

  • 出版日期:2021-10-15 发布日期:2021-03-19

Pharmacological interventions targeting nuclear factor-kappa B signaling in multiple sclerosis

Kim M. A. De Kleijn,  Gerard J. M. Martens*    

  1. Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, 6525AJ Nijmegen, The Netherlands (De Kleijn KMA)
    NeuroDrug Research Ltd, 6525ED Nijmegen, The Netherlands (De Kleijn KMA, Martens GJM)
    Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, 6525AJ Nijmegen, The Netherlands (Martens GJM)
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Gerard J. M. Martens, PhD, g.martens@ncmls.ru.nl.
  • Supported by:
    Figure 1 was created with BioRender (www.Biorender.com). 
    This work was supported by Kelders Beheer Ltd. The authors declare no conflict of interest relating to this work. 

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摘要：

Neural Regen Res：靶标NFκB药物治疗多发性硬化症

 

多发性硬化症 (MS) 被认为主要是由外周免疫细胞的中枢神经系统浸润引起的免疫性疾病，而不是由小胶质细胞/星形胶质细胞和神经变性引起的自身免疫性疾病。然而，美国食品药品管理局批准的许多多发性硬化症药物最近被证明对中枢神经系统细胞NFκB通路有显著影响，因此这些MS药物对小胶质细胞和星形胶质细胞的特异性分子效应有待进一步阐明。此外，寻找新的多发性硬化症药物不仅要着眼于改变脑内免疫细胞群或修复血脑屏障，而且要通过调节NFκB信号来改善脑微环境，使中枢神经系统细胞有效再生。在这方面，一个有待探讨的重要问题是如何特异性地靶向NFκB，因为这种转录因子在某些情况下具有双重甚至相反的作用，例如在应激条件下的促凋亡和抗凋亡作用。鉴于NFκB不仅作为外周免疫细胞炎症过程的介质，而且在小胶质细胞和星形胶质细胞中也起着明显的作用，因此NFκB定向药物在MS中的作用应该从外周和中枢两个层面考虑。NFκB靶向药物从动物模型到人类的中枢神经系统效应的转化并不简单，因为MS动物中导致NFκB活化的病理机制不一定与MS患者中诱导NFκB信号传导的过程相一致。此外，目前用于研究MS的动物模型均未完全再现MS的病理学特征，其中cuprizone主要诱导脱髓鞘和中枢神经系统炎症，实验性自身免疫性脑炎是一个与“由外而内”假说相联系的模型。因此，来自荷兰的Gerard J. M. Martens 博士及其团队认为探索NFκB靶向药物对MS患者来源的三维（3D）干细胞系统的影响可能是一个有吸引力的额外选择。无论如何，NFκB作为MS的中心药物靶点的新观点符合最近提出的MS发病机制的中枢神经系统内在模型，并可能导致目前治疗这种复杂的免疫介导的神经退行性疾病的药物库的扩展。

相关观点文章在《中国神经再生研究（英文版）》杂志2021年 10 月 10  期发表。

https://orcid.org/0000-0003-1761-4570 (Gerard J. M. Martens)

Abstract: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS). Pathological characteristics of the disease include activation of CNS-intrinsic immune cells, such as microglia and astrocytes, and loss of neuronal connections, myelin and blood-brain barrier (BBB) integrity as well as peripheral immune cell infiltration into the brain. MS has long been considered a predominantly immunological disease, which has led to the development of essentially only immune-directed medications. Within this traditional “outside-in” MS hypothesis, a dysregulation of the peripheral immune system causes immune cell infiltration into the CNS, leading to autoreactivity against myelin sheath components and secondary BBB dysfunction. However, recent findings indicate that overactivation of microglia and astrocytes represents an important first step in MS pathology, as appears to be the case for other neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Within this new hypothesis of CNS-intrinsic neuroinflammation in MS – also known as the “inside-out” model (Titus et al., 2020), the transcription factor nuclear factor-kappa B (NFκB) plays a central role in the brain. In CNS cells, various triggers, such as bacterial and viral infections, oxidative stress and other cellular stressors like protein misfolding and DNA damage, lead to NFκB activation in CNS-immune cells and subsequent production of pro-inflammatory cytokines and adhesion molecules, activation of the inflammasome complex, apoptosis and cell cycle arrest. The production of pro-inflammatory molecules causes a microenvironment which provokes CNS-cell degeneration, and is detrimental for (re)myelination by oligodendrocytes and neuronal regeneration. Neuroinflammatory cascades in the CNS also prevent microglia and astrocytes from exerting their regenerative effects on oligodendrocytes and neurons. In addition, microglia and astrocytes reinforce each other’s negative effects via cytokine-mediated feedback mechanisms, which create a negative loop that further affects the environment for CNS-cell regeneration. Targeting the NFκB pathway may be especially attractive for the treatment of MS as this transcription factor is also involved in regulating inflammatory processes within both the innate and the adaptive peripheral immune systems.