Small molecule inhibitors of PSD95-nNOS protein-protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats.
Small molecule inhibitors of PSD95-nNOS protein-protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats.
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DOI：
10.1016/j.neuroscience.2017.02.055
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发表时间：
2017-05-04
期刊：
影响因子：
3.3
通讯作者：
Hohmann AG
中科院分区：
文献类型：
--
作者：
Carey LM;Lee WH;Gutierrez T;Kulkarni PM;Thakur GA;Lai YY;Hohmann AG
脊髓背角内NMDA受体(NMDAR)信号的过度激活有助于中枢敏化以及病理性疼痛状态的诱导和维持。然而，NMDAR的直接拮抗会产生不良的副作用，限制了它们的临床应用。NMDAR的激活产生中枢敏化，部分是通过启动信号级联，激活神经元型一氧化氮合酶(NNOS)，并产生信号分子一氧化氮(NO)。NMDAR介导的nNOS激活需要一种支架蛋白，突触后密度蛋白95 kDa(PSD95)，它将nNOS与NMDAR捆绑在一起。因此，干扰PSD95和nNOS之间的蛋白质-蛋白质相互作用可能会抑制NMDAR下游的伤害性信号机制，抑制中枢敏化，同时避免与NMDAR拮抗剂相关的不良副作用。我们观察了小分子PSD95-nNOS蛋白-蛋白相互作用抑制剂(ZL006、IC87201)对大鼠伤害性行为和福尔马林诱导的大鼠腰段脊髓背角Fos蛋白表达的影响。与ZL006的非活性类似物ZL007和NMDAR拮抗剂MK-801进行了比较。IC87201和ZL006，而不是ZL007，抑制了福尔马林诱发的疼痛行为的第二相，并减少了福尔马林诱导的与伤害性处理相关的脊髓背角区Fos样免疫反应细胞的数量。MK-801抑制Fos蛋白在背角和腹角的表达。在旋转棒试验中，MK-801产生运动性共济失调，而IC87201和ZL006则不能。在化疗诱导的神经病理性疼痛模型中，ZL006而不是ZL007可抑制紫杉醇诱导的机械性和冷冻性痛觉过敏。免疫共沉淀实验显示，紫杉醇治疗的大鼠腰髓中存在PSD95-nNOS复合体，尽管ZL006在所有受试者中都没有可靠地破坏这种复合体。目前的研究结果证实了小分子PSD95-nNOS蛋白-蛋白相互作用抑制剂作为新型止痛剂的使用，并首次证明这些抑制剂在脊髓背角水平抑制炎症诱发的神经元激活。
Excessive activation of NMDA receptor (NMDAR) signaling within the spinal dorsal horn contributes to central sensitization and the induction and maintenance of pathological pain states. However, direct antagonism of NMDARs produces undesirable side effects which limit their clinical use. NMDAR activation produces central sensitization, in part, by initiating a signaling cascade that activates the enzyme neuronal nitric oxide synthase (nNOS) and generates the signaling molecule nitric oxide (NO). NMDAR-mediated activation of nNOS requires a scaffolding protein, postsynaptic density protein 95 kDa (PSD95), which tethers nNOS to NMDARs. Thus, disrupting the protein-protein interaction between PSD95 and nNOS may inhibit pro-nociceptive signaling mechanisms downstream of NMDARs and suppress central sensitization while sparing unwanted side effects associated with NMDAR antagonists. We examined the impact of small molecule PSD95-nNOS protein-protein interaction inhibitors (ZL006, IC87201) on both nociceptive behavior and formalin-evoked Fos protein expression within lumbar spinal dorsal horn of rats. Comparisons were made with ZL007, an inactive analog of ZL006, and the NMDAR antagonist MK-801. IC87201 and ZL006, but not ZL007, suppressed phase 2 of formalin-evoked pain behavior and decreased the number of formalin-induced Fos-like immunoreactive cells in spinal dorsal horn regions associated with nociceptive processing. MK-801 suppressed Fos protein expression in both dorsal and ventral horns. MK-801 produced motor ataxia in the rotarod test whereas IC87201 and ZL006 failed to do so. ZL006 but not ZL007 suppressed paclitaxel-induced mechanical and cold allodynia in a model of chemotherapy-induced neuropathic pain. Co-immunoprecipitation experiments revealed the presence of the PSD95-nNOS complex in lumbar spinal cord of paclitaxel-treated rats, although ZL006 did not reliably disrupt the complex in all subjects. The present findings validate use of putative small molecule PSD95-nNOS protein-protein interaction inhibitors as novel analgesics and demonstrate, for the first time, that these inhibitors suppress inflammation-evoked neuronal activation at the level of the spinal dorsal horn.
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影响因子：
7.3
作者：
Florio, S. K.;Loh, C.;Lai, Y.
通讯作者：
Lai, Y.
DOI：
10.1111/j.1440-1681.1991.tb01470.x
发表时间：
1991-06-01
影响因子：
2.9
作者：
KOBAYASHI, Y;IKEDA, K;HATTORI, K
通讯作者：
HATTORI, K
影响因子：
3.3
作者：
Nackley, AG;Makriyannis, A;Hohmann, AG
通讯作者：
Hohmann, AG
影响因子：
3.3
作者：
Deng L;Guindon J;Vemuri VK;Thakur GA;White FA;Makriyannis A;Hohmann AG
通讯作者：
Hohmann AG
影响因子：
4.7
作者：
Lee WH;Xu Z;Ashpole NM;Hudmon A;Kulkarni PM;Thakur GA;Lai YY;Hohmann AG
通讯作者：
Hohmann AG