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Vol. 304, Issue 1, 172-178, January 2003

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

Departments of Cardiovascular Sciences (X.W., H.W., L.X., D.J.R., G.Z.F.) and Inflammatory Disease Research (J.M.T.), Bristol-Myers Squibb Company, Wilmington, Delaware, and Department of Neurosurgery (T.S., P.H.C.), Stanford University School of Medicine, Stanford, California

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.

0022-3565/03/3041-0172$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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