Abstract
BackgroundMEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126.Methods and resultRats were subjected to a 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 48-h and the ischemic area was calculated. The expression of phosphorylated ERK1/2 and Elk-1, and of endothelin ETA and ETB, angiotensin AT1, and 5-hydroxytryptamine 5-HT1B receptors were analyzed with immunohistochemistry using confocal microscopy in cerebral arteries, microvessels and in brain tissue. The expression of endothelin ETB receptor was analyzed by quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors in the MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score.ConclusionOur results show that MCAO results in upregulation of cerebrovascular ETB, AT1 and 5-HT1B receptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the enhanced vascular receptor expression and the associated cerebral infarction.
Highlights
MEK1/2 is a serine/threonine protein that phosphorylates extracellular signalregulated kinase (ERK1/2)
We present the novel observations that there is upregulation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2), the transcription factor Elk-1, and the contractile receptors for endothelin (ETA and ETB), angiotensin II AT1, and 5-hydroxytryptamine 5-HT1B receptors in both the middle cerebral artery (MCA) leading to the ischemic region and in microvessels within the infarct area but not in adjacent brain tissue
Signal transduction after MCA occlusion Distal middle cerebral artery occlusion (MCAO) resulted in an abrupt decrease in cerebral blood flow (CBF) over the dorsolateral cortex; flow was reduced to 15 ± 3% of the baseline flow in the ischemic region
Summary
MEK1/2 is a serine/threonine protein that phosphorylates extracellular signalregulated kinase (ERK1/2). BMC Neuroscience 2008, 9:85 http://www.biomedcentral.com/1471-2202/9/85 relationship to the penumbra has focused on electrical and membrane failure in brain tissue [2,3], and it has been suggested that the ischemic depolarization increases the metabolic burden, thereby exacerbates the energy deficit, and enlarges the infarct [4]. This view has by and large neglected the fact that stroke primarily is a cerebrovascular disorder. They suggest that by reducing the adverse vascular effects of tissue depolarization is a possible way the neuroprotective drugs act to reduce the tissue injury
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