Significance of NF-κΒ as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis
Significance of NF-κΒ as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis
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发表时间：
2015-04
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通讯作者：
M. Srinivasan;D. Lahiri
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作者：
M. Srinivasan;D. Lahiri
前言：分子发病机制的研究进展表明，慢性炎症是阿尔茨海默病(AD)、多发性硬化症(MS)等临床表现多样的多种神经退行性疾病的共同发病机制。受限的细胞更新和再生能力使神经组织极易受到不受控制的炎症过程的影响，从而导致不可逆转的组织损伤。覆盖的区域：炎症信号增加的一个主要后果是转录因子核因子−κΒ(NF−κΒ)上调，随后的神经保护或有害作用取决于信号的强度和被激活的NF−κΒ二聚体的类型。我们讨论了神经炎症和神经退行性变之间的相互作用，重点讨论了与神经退行性病变、AD和MS相关的多条途径的汇合点--NF-κΒ信号转导途径。专家意见：开发有效的神经退行性疾病的NF-κΒ抑制剂是人们非常感兴趣的。该综述包括天然化合物和合理设计的抑制NF−κΒ和介导AD和MS神经保护的药物的概述。天然化合物和合成化合物的关键化学部分为开发有效的小分子抑制剂提供了有效的线索，这些小分子抑制剂选择性地靶向于NF−κΒ的激活，这将导致预期的风险治疗效果。
INTRODUCTION: Advances in molecular pathogenesis suggest that the chronic inflammation is a shared mechanism in the initiation and progression of multiple neurodegenerative diseases with diverse clinical manifestations such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Restricted cell renewal and regenerative capacity makes the neural tissues extremely vulnerable to the uncontrolled inflammatory process leading to irreversible tissue damage. AREAS COVERED: A predominant consequence of increased inflammatory signaling is the upregulation of the transcription factor, nuclear factorkappa B (NF−κΒ) with subsequent neuroprotective or deleterious effects depending on the strength of the signal and the type of NF−κΒ dimers activated. We discuss the interplay between neuroinflammation and neurodegeneration keeping in focus NF-κΒ signaling as the point of convergence of multiple pathways associated with the development of the neurodegenerative pathologies, AD and MS. EXPERT OPINION: Considerable interest exists in developing efficient NF-κΒ inhibitors for neurodegenerative diseases. The review includes an overview of natural compounds and rationally designed agents that inhibit NF−κΒ and mediate neuroprotection in AD and MS. The key chemical moieties of the natural and the synthetic compounds provide efficient leads for the development of effective small molecule inhibitors that selectively target NF−κΒ activation; this would result in the desired benefit to risk therapeutic effects.