MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
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DOI：
10.1073/pnas.96.22.12866
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Bonventre, JV
中科院分区：
文献类型：
--
作者：
Alessandrini, A;Namura, S;Bonventre, JV
MEK1 （MAP激酶/ERK激酶）/ERK（细胞外信号响应激酶）通路与细胞生长和分化有关[Seger， R. & Krebs， E.（1995）中华医学杂志，9,726-735]。本研究表明，MEK/ERK通路在局灶性脑缺血期间被激活，并可能在诱导损伤中发挥作用。mek1特异性抑制剂PD98059对缺血前30min小鼠的治疗[j]， Alessi， D. R., Cuenda， A., Cohen， P., Dudley， D. T. & Saltiel， A. R.（1995）。脑中动脉短暂闭塞后，缺血22小时局灶性梗死体积减少55%。这伴随着磷酸化erk1 /2免疫组化染色的减少。MEK1抑制也导致缺血72小时后脑损伤减少，局灶性梗死体积减少36%。本研究表明，MEK1/ERK通路参与局灶性脑缺血时的脑损伤，而MEK1特异性拮抗剂PD98059是一种有效的神经保护剂。
The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]. Here we show that the MEK/ERK pathway is activated during focal cerebral ischemia and may play a role in inducing damage. Treatment of mice 30 min before ischemia with the MEK1-specific inhibitor PD98059 [Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489-27494] reduces focal infarct Volume at 22 hr after ischemia by 55% after transient occlusion of the middle cerebral artery. This is accompanied by a reduction in phospho-ERK1/2 immunohistochemical staining. MEK1 inhibition also results in reduced brain damage 72 hr after ischemia, with focal infarct Volume reduced by 36%. This study indicates that the MEK1/ERK pathway contributes to brain injury during focal cerebral ischemia and that PD98059, a MEK1-specific antagonist is a potent neuroprotective agent.