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Research ArticleNEUROPHARMACOLOGY

Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK1 Protein Kinase in Mice: Exploration of Potential Mechanism Associated with Apoptosis

Xinkang Wang, Hugh Wang, Lin Xu, Dennis J. Rozanski, Taku Sugawara, Pak H. Chan, James M. Trzaskos and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics January 2003, 304 (1) 172-178; DOI: https://doi.org/10.1124/jpet.102.040246
Xinkang Wang
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Hugh Wang
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Lin Xu
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Dennis J. Rozanski
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Taku Sugawara
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Pak H. Chan
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James M. Trzaskos
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Giora Z. Feuerstein
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Abstract

MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2. In the present study we explored the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor, SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. Western blot analysis demonstrated the immediate activation of MEK/ERK after reperfusion (within the first 10 min) in the ischemic brain; this activation was dose dependently blocked by SL327 (10–100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15 min before or 25 min after the onset of ischemia resulted in 63.6% (n = 18, p< 0.001) and 50.7% (n = 18, p< 0.01) reduction in infarct size, respectively, compared with vehicle-treated mice. Similarly, SL327 significantly reduced neurological deficits 1 to 3 days after reperfusion (n = 12, p < 0.01). The salutary effect of SL327-induced neuroprotection was independent of mitochondrial cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of MEK1/2 results in neuroprotection from reperfusion injury and that this protection may be associated with the reduction in apoptosis.

Footnotes

  • DOI: 10.1124/jpet.102.040246

  • Abbreviations:
    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated kinase
    JNK
    c-Jun N-terminal kinase
    ECA
    external common carotid
    ICA
    internal common carotid
    MCA
    middle cerebral artery
    DMSO
    dimethyl sulfoxide
    CBF
    cerebral blood flow
    MCAO
    occlusion of the middle cerebral artery
    TTC
    2,3,5-triphenyltetrazolium chloride
    ELISA
    enzyme-linked immunoassay
    COX
    cytochrome oxidase
    • Received June 11, 2002.
    • Accepted September 17, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 1
1 Jan 2003
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Research ArticleNEUROPHARMACOLOGY

Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK1 Protein Kinase in Mice: Exploration of Potential Mechanism Associated with Apoptosis

Xinkang Wang, Hugh Wang, Lin Xu, Dennis J. Rozanski, Taku Sugawara, Pak H. Chan, James M. Trzaskos and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 172-178; DOI: https://doi.org/10.1124/jpet.102.040246

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Research ArticleNEUROPHARMACOLOGY

Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK1 Protein Kinase in Mice: Exploration of Potential Mechanism Associated with Apoptosis

Xinkang Wang, Hugh Wang, Lin Xu, Dennis J. Rozanski, Taku Sugawara, Pak H. Chan, James M. Trzaskos and Giora Z. Feuerstein
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 172-178; DOI: https://doi.org/10.1124/jpet.102.040246
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