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Systemic inflammation impairs tissue reperfusion through endothelin-dependent mechanisms in cerebral ischemia

Katie N Murray1, Sylvie Girard1, William M Holmes1

  • 1From the Faculty of Life Sciences (K.N.M., S.M.A.) and Centre for Imaging Science (L.M.P., S.R.W.), University of Manchester, Manchester, United Kingdom; Sainte-Justine Hospital Research Centre, University of Montreal, Canada (S.G.); Glasgow Experimental MRI Centre, The University of Glasgow, Glasgow, United Kingdom (W.M.H.); and University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom (A.R.P.-J.).

Stroke
|September 18, 2014
PubMed
Abstract

Insights

Systemic inflammation, triggered by interleukin-1, severely reduces cerebral blood flow and worsens stroke outcomes in rats. Blocking endothelin-1 receptors improved blood flow and reduced brain damage, suggesting a therapeutic target for stroke recovery.

Area of Science:

  • Neuroscience
  • Immunology
  • Cardiovascular Research

Background:

  • Systemic inflammation is linked to brain pathologies and poor stroke outcomes.
  • Interleukin-1 (IL-1) plays a significant role in inflammatory responses.
  • Cerebral blood flow regulation during reperfusion is critical for stroke recovery.

Purpose of the Study:

  • To investigate the impact of systemic inflammation on cerebral blood flow during reperfusion after experimental cerebral ischemia.
  • To explore the role of endothelin-1 in mediating inflammatory effects on cerebral perfusion.

Main Methods:

  • Wistar rats underwent transient middle cerebral artery occlusion followed by reperfusion.
  • Systemic interleukin-1β or vehicle was administered intraperitoneally.
  • Cerebral blood flow was assessed using diffusion and perfusion-weighted MRI.
  • Endothelin-1 expression and location were analyzed via PCR, ELISA, and immunofluorescence.

Main Results:

  • Systemic IL-1 significantly reduced cerebral blood flow and increased infarct volume compared to controls.
  • Cerebral hypoperfusion correlated with activated cerebral vasculature and upregulated endothelin-1 in the ischemic penumbra.
  • Microthrombi were observed in the vasculature of IL-1 treated rats.
  • Endothelin-1 receptor blockade reversed hypoperfusion, reduced tissue damage, and improved functional outcomes.

Conclusions:

  • Systemic inflammation, particularly via IL-1, impairs cerebral blood flow during reperfusion.
  • Endothelin-1 is a key mediator of this inflammatory-induced hypoperfusion.
  • Targeting endothelin-1 pathways may offer therapeutic benefits for stroke patients with elevated inflammatory profiles.
Keywords:
brain ischemiaendothelin-1inflammationinterleukin-1magnetic resonance imagingreperfusion

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