Background
U0126-EtOH-EtOH (U0126), as a non-ATP competitive and selective inhibitor, a has potent inhibition on MEK1 and MEK2 with IC50s of 72 nM and 58 nM, respectively.[1][6]
In vitro experiment it shown that treatment with 10 μM of U0126-EtOH-EtOH decreased the numbers of migration RA-FLSs induced by Sonic Hedgehog signaling. [2] In vitro, pretreatment with 50?μM SB203580 (the p38 inhibitor) and 50?μM U0126-EtOH-EtOH (ERK1/2 inhibitor) in the microglial cells obviously brogated the effects of isotalatizidine.[3] In addition, H9C2 cells pretreated with 10μM U0126-EtOH reduced ischemia/reperfusion-induced apoptosis and autophagy in myocardium and reduced cisplatin-induced renal injury by decreasing inflammation and apoptosis by inhibition of ERK1/2 phosphorylation.[4] Pretreatment with 10 μM of U0126-EtOH protected PC-12 Cells against hydrogen peroxide-induced cell death independent of MEK inhibition.[6] Moreover, at 1 μM to 20 μM of U0126-EtOH increased the half-width and decay time of action potential in a dose-dependent manner in primary hippocampal neurons. Bath application of 40?μM U0126-EtOH is more potent than 4-AP and TEA in suppressing maximal firing rate of pyramidal neurons in hippocampal slices.[5]
In vivo efficacy test it demonstrated that pretreatment with 1mg/kg U0126-EtOH in in STZ-induced diabetic mice improved cardiac function and ameliorated cardiac hypertrophy.[4] In the acute phase of experimental stroke, 30 mg/kg U0126-EtOH prevent activation of MMP-9, additionly, by adding U0126-EtOH in combination with rt-PA prevent activation of MMP-9 expression leading to BBB leakage and hemorrhagic transformation.[6]
参考文献:
[1]. Favata MF, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998 Jul 17;273(29):18623-32.
[2]. Liu F, et al. Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK/ERK Signaling Pathway. Front Immunol. 2018 Dec 5;9:2847.
[3]. Shao S, et al. Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression. J Neuroinflammation. 2020 Jan 10;17(1):13.
[4]. Wang T, et al. The MEK inhibitor U0126-EtOH ameliorates diabetic cardiomyopathy by restricting XBP1's phosphorylation dependent SUMOylation. Int J Biol Sci. 2021 Jul 13;17(12):2984-2999.
[5]. Orset C, et al. Combination treatment with U0126-EtOH and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke. Sci Rep. 2021 Jun 7;11(1):11993.
[6]. Ong Q, et al. U0126-EtOH protects cells against oxidative stress independent of its function as a MEK inhibitor. ACS Chem Neurosci. 2015 Jan 21;6(1):130-7.
[7]. Wang JZ, et al. Potent block of potassium channels by MEK inhibitor U0126-EtOH in primary cultures and brain slices. Sci Rep. 2018 Jun 11;8(1):8808.
U0126-EtOH-EtOH (U0126) 作为一种非 ATP 竞争性和选择性抑制剂，对 MEK1 和 MEK2 具有有效抑制作用，IC50 分别为 72 nM 和 58 nM。[1][6]
体外实验表明，用 10 μM U0126-EtOH-EtOH 处理可减少由 Sonic Hedgehog 信号传导诱导的迁移 RA-FLS 数量。 [2] 在体外，用 50μM SB203580（p38 抑制剂）和 50μM U0126-EtOH-EtOH（ERK1/2 抑制剂）预处理小胶质细胞明显抑制了异他嗪的作用。[3] 此外，用 10μM U0126-EtOH 预处理的 H9C2 细胞减少了心肌缺血/再灌注诱导的细胞凋亡和自噬，并通过抑制 ERK1/2 磷酸化减少炎症和细胞凋亡来减少顺铂诱导的肾损伤。 [4]用 10 μM U0126-EtOH 预处理可保护 PC-12 细胞免受过氧化氢诱导的细胞死亡，而不受 MEK 抑制的影响。[6]此外，在 1 μM 时至 20 μM U0126-EtOH 在原代海马神经元中以剂量依赖性方式增加动作电位的半宽度和衰减时间。 40μM U0126-EtOH 对海马切片中锥体神经元最大放电率的抑制比 4-AP 和 TEA 更有效。[5]
体内药效试验表明，用 1mg/kg U0126-EtOH 预处理 STZ 诱导的糖尿病小鼠可改善心脏功能并改善心脏肥大。[4] 在实验性卒中的急性期, 30 mg/kg U0126-EtOH 可防止 MMP-9 的激活，此外，通过添加 U0126-EtOH 与 rt-PA 结合可防止 MMP-9 表达的激活导致 BBB 渗漏和出血转化。[6]
Protocol
| Cell experiment [1]: |
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Cell lines
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Fibroblast-like synoviocytes(FLSs)
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Preparation Method
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FLSs were plated at a density of 5 × 104 mL?1 in 6-well plates for 24 h. FLSs were serum starved for 24 h before incubation with Cyclopamine (10 μM) or Purmorphamine (1 μM), or co-treated with U0126-EtOH-EtOH (10 μM) Purmorphamine (1 μM). Cell counting kit-8 assay was performed to examine the cell viability.
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Reaction Conditions
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10 μM; 48 h
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Applications
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U0126-EtOH-EtOH inhibit cell viability and regulate cell cycle distribution of RA-FLSs induced by SHH signaling.
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| Animal experiment [2]: |
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Animal models
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Rats
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Preparation Method
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Rats were subjected to 120?minutes tMCAO and thereafter treated with the MEK1/2 inhibitor U0126-EtOH (30?mg/kg intraperitoneally) at 0 and 24?hours of reperfusion.
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Dosage form
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30?mg/kg; i.p.
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Applications
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After treatment with U0126-EtOH, the vasoconstriction to S6c was markedly reduced. ET-1-induced vasoconstriction was not significantly different in non-occluded and occluded MCAs, and not affected by U0126-EtOH.
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参考文献:
[1]. Liu F, et al. Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK/ERK Signaling Pathway. Front Immunol. 2018 Dec 5;9:2847.
[2]. Ahnstedt H, et al. U0126-EtOH attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats. J Cereb Blood Flow Metab. 2015 Mar;35(3):454-60.
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