Therapeutic Developments Targeting Toll-like Receptor-4-Mediated Neuroinflammation.
Therapeutic Developments Targeting Toll-like Receptor-4-Mediated Neuroinflammation.
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DOI：
10.1002/cmdc.201500188
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发表时间：
2016-01-19
期刊：
影响因子：
3.4
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Li J;Csakai A;Jin J;Zhang F;Yin H
Toll样受体（Toll like receptor，TLR）在免疫系统中起着重要作用，具有显著的药理学潜力。TLR的激活需要特定PAMP（病原体相关分子模式）和辅助蛋白如MD 2（髓样分化蛋白2）、LBP（脂多糖结合蛋白）和CD-14的参与。TLR 4-MD 2-LPS复合物的组装在TLR 4活化中是必不可少的。最近的研究表明，TLR 4激活是神经系统中信号传导通路的重要触发因素，可导致慢性疼痛以及阿片类药物耐受和依赖。TLRs及其辅助蛋白分子结构的研究为合成TLRs激动剂和拮抗剂（如曲马多）打开了一扇大门。小分子TLR 4调节剂如MD 2-I和三环类抗抑郁药因其方便的口服使用和较低的价格而比肽类药物具有更广阔的应用前景。本文就TLR 4激动剂和拮抗剂的作用机制及临床应用前景作一综述。Toll样受体（TLR）是对细胞先天免疫应答至关重要的膜蛋白家族。疼痛是当今人们面临的最棘手和最普遍的情况之一。在免疫系统和疼痛的十字路口是TLR 4。本文就TLRs及其信号通路对疼痛的影响作一综述。此外，这篇综述还考虑了能够调节TLR 4信号传导的分子作为潜在的候选药物。
Toll-like receptors (TLRs) have been shown to play an important role in the immune system, which warrants their remarkable pharmacological potentials. Activation of TLRs requires participation from specific PAMPs (pathogen associated molecular patterns) and accessory proteins such as MD2 (myeloid differentiation protein 2), LBP (lipopolysaccharide binding protein), and CD-14. Assembly of the TLR4-MD2-LPS complex is essential in TLR4 activation. Recent studies have revealed that TLR4 activation is a significant trigger of signal transmission pathways in the nervous system, which could result in chronic pain as well as opioid tolerance and dependence. Researchers of the molecular structure of TLRs and their accessory proteins have opened a door to syntheses of TLRs agonists and antagonists, such as Eritoran. Small molecule modulators of TLR4, such as MD2-I and tricyclic anti-depressants, offer more promising prospects than peptides for their convenient oral usage and lower cost. We mainly discuss the mechanism and clinical prospect of TLR4 agonists and antagonists in this review. Toll-like receptors (TLRs) are a family of membrane proteins crucial to the cellular innate immune response. Pain is one of the most intractable and widespread conditions that people face today. At the crossroads of the immune system and pain is TLR4. This review aims to provide a brief summary about TLRs and how they their signaling affects pain. Furthermore, this review also takes a look at the molecules that are able to modulate TLR4 signaling as potential drug candidates.