c-Raf 抑制剂 GW5074 通过 MEK-ERK 和 Akt 非依赖性机制在体外和神经退行性变动物模型中提供神经保护。,Journal of Neurochemistry

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c-Raf 抑制剂 GW5074 通过 MEK-ERK 和 Akt 非依赖性机制在体外和神经退行性变动物模型中提供神经保护。
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2004 Aug , DOI: 10.1111/j.1471-4159.2004.02530.x
Paul C Chin ₁ , Li Liu , Bradley E Morrison , Ambreena Siddiq , Rajiv R Ratan , Teodoro Bottiglieri , Santosh R D'Mello

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当从含有高钾 (HK) 的培养基切换到低钾 (LK) 培养基时，小脑颗粒神经元会发生凋亡。LK 诱导的细胞死亡被 GW5074 [5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone] 阻断，GW5074 是一种在体外抑制 c-Raf 活性的合成药物。在体外测定时，GW5074 对几种凋亡相关激酶的活性没有直接影响。与其在体外的作用相反，用 GW5074 处理神经元会导致 c-Raf 激活（在没有药物的情况下在体外测量时）并刺激 Raf-MEK-ERK 通路。用 GW5074 处理神经元还导致 B-Raf 活性增加，在体外，在药物发挥神经保护作用的浓度下，该活性不受 GW5074 抑制。PD98059 和 U0126，两种不同的 MEK 抑制剂，GW5074 阻断 ERK 的激活，但对其防止细胞死亡的能力没有影响。显性阴性形式的 Akt 的过表达不会降低 GW5074 的功效，证明了一种不依赖于 Akt 的作用机制。神经保护受到 SN-50 的抑制，SN-50 是一种核因子-kappa B (NF-kappaB) 的特异性抑制剂，而 Ras 抑制剂 S-trans、trans-farnesylthiosalicylic acid (FTS) 则暗示 NF-kappaB 和 Ras 在激活的神经保护信号通路中通过 GW5074。除了防止 LK 诱导的细胞凋亡外，GW5074 治疗还可以防止 MPP+ 和甲基汞对小脑颗粒神经元的神经毒性作用，以及谷胱甘肽消耗诱导的皮质神经元氧化应激。此外，GW5074 可防止神经退行性变并改善亨廷顿动物模型的行为结果 s 病。鉴于其对不同类型的培养神经元的神经保护作用，响应不同的神经毒性刺激，以及在神经退行性变的动物模型中，GW5074 可能对人类的神经退行性疾病具有治疗价值。

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The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism.

Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 [5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone], a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-kappaB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-kappaB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

更新日期：2017-01-31

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