Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway.
Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway.
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MEK/ERK途径的抑制剂减弱了血红素氧酶活性和血红蛋白神经毒性。
DOI：
10.1016/j.neuropharm.2009.01.022
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发表时间：
2009-04
影响因子：
4.7
通讯作者：
Regan RF
中科院分区：
文献类型：
--
作者：
Chen-Roetling J;Li Z;Chen M;Awe OO;Regan RF
实验性中枢神经系统出血后，血红蛋白分解可引起铁依赖性神经元损伤，血红素加氧酶（HO）抑制剂可减轻这种损伤。HO酶是在体外通过磷酸化活化的磷蛋白。在测试激酶抑制剂在皮质细胞培养物中的作用时，我们观察到HO活性被MEK抑制剂U0126持续降低。本研究验证了MEK/ERK通路抑制剂降低HO活性和神经元对血红蛋白的脆弱性的假设。MEK抑制剂U0126和SL 327以及ERK抑制剂FR 180204使基线培养HO活性降低35 - 50%，而不改变重组HO-1或HO-2的活性;阴性对照化合物U0124和FR 180289没有影响。血红蛋白暴露16小时产生广泛的神经元损伤，表现为神经元乳酸脱氢酶释放59.2 ± 7.8%，丙二醛增加12倍;激酶抑制剂具有高度保护作用。血红蛋白处理后的HO-1诱导也被U0126、SL 327和FR 180204降低。这些结果表明，HO活性的降低可能有助于MEK和ERK抑制剂对血红素介导的神经元损伤的保护作用。
Hemoglobin breakdown produces an iron-dependent neuronal injury after experimental CNS hemorrhage that may be attenuated by heme oxygenase (HO) inhibitors. The HO enzymes are phosphoproteins that are activated by phosphorylation in vitro. While testing the effect of kinase inhibitors in cortical cell cultures, we observed that HO activity was consistently decreased by the MEK inhibitor U0126. The present study tested the hypothesis that MEK/ERK pathway inhibitors reduce HO activity and neuronal vulnerability to hemoglobin. The MEK inhibitors U0126 and SL327 and the ERK inhibitor FR180204 reduced baseline culture HO activity by 35–50%, without altering the activity of recombinant HO-1 or HO-2; negative control compounds U0124 and FR180289 had no effect. Hemoglobin exposure for 16 hours produced widespread neuronal injury, manifested by release of 59.2±7.8% of neuronal lactate dehydrogenase and a twelve-fold increase in malondialdehyde; kinase inhibitors were highly protective. HO-1 induction after hemoglobin treatment was also decreased by U0126, SL327, and FR180204. These results suggest that reduction in HO activity may contribute to the protective effect of MEK and ERK inhibitors against heme-mediated neuronal injury.
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影响因子：
4.8
作者：
Glading, A;Chang, P;Wells, A
通讯作者：
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