Glial TLR4 receptor as new target to treat neuropathic pain: Efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice
Glial TLR4 receptor as new target to treat neuropathic pain: Efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice
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DOI：
10.1002/glia.20699
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发表时间：
2008-09-01
期刊：
影响因子：
6.2
通讯作者：
Costa, Barbara
中科院分区：
文献类型：
--
作者：
Bettoni, Isabella;Comelli, Francesca;Costa, Barbara
神经病理性疼痛是一个普遍存在的临床问题，因为它往往是目前使用的镇痛药反应差，因此，它是至关重要的识别新的潜在的目标和药物。最近的证据表明，脊髓中的小胶质细胞在神经病理性疼痛的发展和维持中起关键作用，其中Toll样受体4（TLR 4）起关键作用。内源性配体与TLR 4的结合可能被认为是调节小胶质细胞在疼痛促进中的活性的重要步骤，这表明旨在抑制这种结合的机制可能对神经性疼痛有效。我们已经合成了具有拮抗活性的TLR 4的新配体。在目前的工作中，我们评估了最有效的TLR 4拮抗剂合成的我们（FP-1），在小鼠疼痛性神经病变。用FP-1（5-10 mg/kg，i.p.）诱发热痛觉过敏和机械异常性疼痛的缓解，而对TLR 4敲除神经病小鼠施用最高剂量揭示在不存在TLR 4受体的情况下，化合物失去其功效。作为TLR 4结合的结果，用FP-1重复处理防止了脊髓中转录因子NF-kB的活化和TNF α的过度产生。总之，我们的研究结果支持了先前的证据表明胶质细胞TLR 4对神经性疼痛的起始的贡献，表明它是治疗这种使人衰弱的疾病的潜在创新靶点，并提出FP-1作为开发新的有效药物的先导化合物。(C)2008 Wiley-Liss，Inc.
Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of neuropathic pain, with a pivotal role of toll-like receptor 4 (TLR4). Binding of an endogenous ligand to TLR4 might be considered an important step in the regulation of microglia activity in pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against neuropathic pain. We have synthesized new ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with painful neuropathy. The repeated treatment of neuropathic mice with FP-1 (5-10 mg/kg, i.p.) evoked a relief of both thermal hyperalgesia and mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with FP-1 prevented the activation of the transcription factor NF-kB and the TNF alpha overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose FP-1 as lead compound for the development of new effective drugs. (C) 2008 Wiley-Liss, Inc.