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Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway

Aida Maddahi1, Lars Edvinsson

  • 1Department of Internal Medicine, Institute of Clinical Sciences, Lund University, Sweden. lars.edvinsson@med.lu.se

Journal of Neuroinflammation
|March 2, 2010
PubMed
Abstract

Insights

Inhibition of the MEK/ERK pathway with U0126 following cerebral ischemia significantly reduced infarct size and inflammation. Combined receptor blockade also decreased brain damage, highlighting the MEK/ERK pathway

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pathophysiology

Background:

  • Middle cerebral artery (MCA) occlusion causes cerebral ischemia, leading to inflammation and receptor activation.
  • The mitogen-activated protein kinase (MAPK) pathway is activated, reducing cerebral blood flow and increasing inflammatory mediators.

Purpose of the Study:

  • To investigate the effect of MEK1/2 inhibitor (U0126) on cerebrovascular inflammation.
  • To determine if combined angiotensin and endothelin receptor blockade reduces infarct size and improves neurological scores.

Main Methods:

  • Rats underwent middle cerebral artery occlusion (MCAO) for 2 hours, followed by 48 hours of reperfusion.
  • Animals received U0126 at 0, 6, or 12 hours post-occlusion, or a combination of Candesartan and ZD1611.
  • Immunohistochemistry analyzed inflammatory markers (TNF-α, IL-1β, IL-6, iNOS) and phosphorylated ERK1/2.

Main Results:

  • U0126 administered at 0 or 6 hours post-MCAO reduced infarct volume and normalized phosphorylated ERK1/2 levels.
  • Treatment with U0126 prevented the elevation of inflammatory markers.
  • Combined receptor antagonists reduced infarct volume but had minimal effect on inflammatory marker expression.

Conclusions:

  • Microvascular expression of TNF-α, IL-1β, IL-6, and iNOS increases after focal ischemia.
  • This inflammatory response is transcriptionally regulated by the MEK/ERK pathway.

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