Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.
Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.
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DOI：
10.1016/j.bbi.2016.11.003
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发表时间：
2017-02
影响因子：
15.1
通讯作者：
Shubayev, Veronica I.
中科院分区：
文献类型：
--
作者：
Hong, Sanghyun;Remacle, Albert G.;Shiryaev, Sergei A.;Choi, Wonjun;Hullugundi, Swathi K.;Dolkas, Jennifer;Angert, Mila;Nishihara, Tasuku;Yaksh, Tony L.;Strongin, Alex Y.;Shubayev, Veronica I.
髓鞘碱性蛋白（MBP）是一种自身抗原，能够从无害的机械刺激（机械异常性疼痛）诱导顽固性疼痛。引起这种痛觉MBP活性的机制仍然不清楚。本研究表明，膜型基质金属蛋白酶1（MT 1-MMP/MMP-14）从受损的髓鞘中释放出具有镇痛作用的MBP肽，从而增强神经中MT 1-MMP的表达以维持异常性疼痛状态。具体而言，MT 1-MMP的表达和活性在大鼠坐骨神经慢性压迫性损伤（CCI）后第3天开始逐渐增加。在CCI后第3天通过神经内注射功能阻断性人DX 2400单克隆抗体抑制MT 1-MMP活性减少了机械性异常性疼痛和沃勒变性的神经病理学体征，包括轴突脱髓鞘、变性、水肿和髓鞘卵形体的形成。与其在异常性疼痛中的作用一致，MBP的MT 1-MMP蛋白水解在体外产生了含有MBP 69 -86的表位序列。一致地，DX 2400疗法减少了CCI神经中MBP 69 -86表位的释放。最后，神经内注射镇痛MBP 69 -86和对照MBP 2 -18肽差异诱导神经中的MT 1-MMP和MMP-2表达。有了这些数据，我们提供了一个新的，持续性异常性疼痛的自我维持机制，通过MT 1-MMP和痛觉MBP肽之间的正反馈回路。因此，MT 1-MMP活性的短期抑制提供了一种可行的药理学方法来干预该分子回路和神经病理性疼痛的发展。
Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.
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影响因子：
3.7
作者：
Kim Y;Remacle AG;Chernov AV;Liu H;Shubayev I;Lai C;Dolkas J;Shiryaev SA;Golubkov VS;Mizisin AP;Strongin AY;Shubayev VI
通讯作者：
Shubayev VI
DOI：
10.1016/j.bbi.2016.03.003
发表时间：
2016-08
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Ko JS;Eddinger KA;Angert M;Chernov AV;Dolkas J;Strongin AY;Yaksh TL;Shubayev VI
通讯作者：
Shubayev VI
影响因子：
5.3
作者：
Liu, Huaqing;Shubayev, Veronica I.
通讯作者：
Shubayev, Veronica I.
影响因子：
64.8
作者：
KADLUBOWSKI, M;HUGHES, RAC
通讯作者：
HUGHES, RAC
影响因子：
82.9
作者：
Kawasaki, Yasuhiko;Xu, Zhen-Zhong;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong