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
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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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