Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity.
Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity.
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DOI：
10.1016/j.neuroscience.2010.03.067
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发表时间：
2010-06-30
期刊：
影响因子：
3.3
通讯作者：
Watkins, L. R.
中科院分区：
文献类型：
--
作者：
Hutchinson, M. R.;Loram, L. C.;Zhang, Y.;Shridhar, M.;Rezvani, N.;Berkelhammer, D.;Phipps, S.;Foster, P. S.;Landgraf, K.;Falke, J. J.;Rice, K. C.;Maier, S. F.;Yin, H.;Watkins, L. R.
阿片类药物已被发现具有Toll样受体(TLR)活性，而不是经典阿片受体的作用。这提出了一个问题，即其他止痛药物疗法是否也具有TLR活性，从而促进或反对它们的临床效果。我们发现三环可以改变TLR4和TLR2信号。在电子计算机模拟中，几个三环化合物与阿片类药物一样，对接到TLR辅助蛋白MD-2上的同一结合口袋。我们测试了八种三环化合物对过表达人TLR4的HEK293细胞中TLR4信号的影响。6例表现为轻度(地昔帕明)、中度(米安色林、环苯扎平、伊米普明、酮替芬)或强(阿米替林)TLR4抑制，无TLR4激活。卡马西平和奥卡西平分别表现出轻度和强烈的TLR4激活，没有TLR4抑制作用。在类似的细胞系中，阿米替林也显著抑制TLR2信号，但卡马西平没有。RAW264.7细胞TLR4激活和BV-2小胶质细胞释放TLR4依赖的白介素1的实时成像显示阿米替林阻断了TLR4信号转导。最后，对无(卡马西平)、中度(环苯扎普林)和强(阿米替林)TLR4抑制作用的三环类药物进行了鞘内试验(大鼠)和阿米替林在野生型和基因敲除小鼠(TLR4或MyD88)中的系统试验。虽然三环类药物对基础疼痛反应没有影响，但它们作为TLR4抑制剂的效力依次增强了吗啡的止痛作用。这是以TLR4/MyD88依赖的方式发生的，因为在这些基因敲除的小鼠中，阿米替林没有增强吗啡的镇痛作用。这表明，TLR2和TLR4的抑制可能通过与MD2的相互作用，在体内参与了三环类药物的作用。这些研究提供了几个三环类药物或其活性代谢物可能部分通过调节TLR4和TLR2信号而发挥其生物学作用的证据，并提示抑制TLR4和TLR2信号可能有助于三环类药物治疗慢性疼痛的疗效和增强阿片类药物的止痛效果。
Opioids have been discovered to have Toll-like receptor (TLR) activity, beyond actions at classical opioid receptors. This raises the question whether other pharmacotherapies for pain control may also possess TLR activity, contributing to or opposing their clinical effects. We document that tricyclics can alter TLR4 and TLR2 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein, MD-2, as do opioids. Eight tricyclics were tested for effects on TLR4 signaling in HEK293 cells over-expressing human TLR4. Six exhibited mild (desipramine), moderate (mianserin, cyclobenzaprine, imiprimine, ketotifen) or strong (amitriptyline) TLR4 inhibition, and no TLR4 activation. In contrast, carbamazepine and oxcarbazepine exhibited mild and strong TLR4 activation, respectively, and no TLR4 inhibition. Amitriptyline but not carbamazepine also significantly inhibited TLR2 signaling in a comparable cell line. Live imaging of TLR4 activation in RAW264.7 cells and TLR4-dependent interleukin-1 release from BV-2 microglia revealed that amitriptyline blocked TLR4 signaling. Lastly, tricyclics with no (carbamazepine), moderate (cyclobenzeprine), and strong (amitriptyline) TLR4 inhibition were tested intrathecally (rats) and amitriptyline tested systemically in wildtype and knockout mice (TLR4 or MyD88). While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This occurred in a TLR4/MyD88-dependent manner as no potentiation of morphine analgesia by amitriptyline occurred in these knockout mice. This suggests that TLR2 and TLR4 inhibition, possibly by interactions with MD2, contributes to effects of tricyclics in vivo. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 and TLR2 signaling and suggest that inhibition of TLR4 and TLR2 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids.
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影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
影响因子：
8.8
作者：
EISENACH, JC;GEBHART, GF
通讯作者：
GEBHART, GF
影响因子：
2
作者：
Cuschieri, Joseph;Bulger, Eileen;Maier, Ronald V
通讯作者：
Maier, Ronald V
DOI：
10.1016/s0192-0561(99)00042-9
发表时间：
1999-10-01
期刊：
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY
影响因子：
--
作者：
Dredge, K;Connor, TJ;Leonard, BE
通讯作者：
Leonard, BE
影响因子：
4.7
作者：
Hwang, Jaegyu;Zheng, Long Tai;Suk, Kyoungho
通讯作者：
Suk, Kyoungho