MEK1蛋白激酶抑制可预防局灶性脑缺血造成的损伤。
MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia.
作者信息
Alessandrini A, Namura S, Moskowitz M A, Bonventre J V
机构信息
Medical Services, Massachusetts General Hospital, Charlestown, MA 02129, USA.
出版信息
Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12866-9. doi: 10.1073/pnas.96.22.12866.
Abstract
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.
摘要
MEK1（丝裂原活化蛋白激酶/细胞外信号调节激酶激酶）/ERK（细胞外信号反应激酶）信号通路与细胞生长和分化有关[Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726 - 735]。在此我们表明，MEK/ERK信号通路在局灶性脑缺血期间被激活，可能在诱导损伤中起作用。在缺血前30分钟用MEK1特异性抑制剂PD98059 [Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489 - 27494]处理小鼠，在大脑中动脉短暂闭塞后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抑制还导致缺血72小时后脑损伤减轻，局灶性梗死体积减少36%。本研究表明，MEK1/ERK信号通路在局灶性脑缺血期间导致脑损伤，并且MEK1特异性拮抗剂PD98059是一种有效的神经保护剂。
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