Protein Kinase Inhibition in Late Cerebral Ischemia after Subarachnoid Hemorrhage

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The cerebral ischemia that occur after a subarachnoid hemorrhage (SAH) often results in death or severe disability and is a significant cause of stroke. Our hypothesis is that cerebral ischemia leads to pathophysiological receptor changes on the vascular smooth muscle cells. The changes may lead to a stronger vasoconstriction than normal in response to endogenous ligands. We are focusing on the endothelin (ET), 5-hydroxytryptamine (5-HT) and angiotensin II receptor-ligand systems.

Previous studies have shown an upregulation of contractile ETB, 5-HT1B and AT1 receptors in cerebral arteries following experimental induced SAH. There is data to suggest that the intracellular pathways responsible for this upregulation involve protein kinase C (PKC) and mitogen activated protein kinase (MAPK).

The aim of this thesis was to determine in detail the intracellular signaling mechanisms involved in the receptor changes in SAH.

The results show that SAH induce upregulation of the contractile ETB, 5-HT1B and AT1 receptors in a time-dependent manner both at functional and molecular levels. We also showed that the PKC and MAPK pathways are involved in the late cerebral ischemia after SAH. By administrating inhibitors of PKC or ERK1/2 to the SAH rats we were able to prevent the upregulation of contractile receptors, the associated reduction in the regional CBF and neurological deterioration. Similar results were seen when the ERK1/2 inhibitor was given 6 h after the induced SAH.

The main findings of this thesis, suggest that kinase inhibition is a novel target for treatment of cerebrovascular disorders such as cerebral ischemia after SAH.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Medicine, Lund
Supervisors/Advisors
  • Edvinsson, Lars, Supervisor
Award date2007 Mar 31
Publisher
ISBN (Print)978-91-85559-20-6
Publication statusPublished - 2007

Bibliographical note

Defence details

Date: 2007-03-31
Time: 09:00
Place: BMC GK-salen, University of Lund

External reviewer(s)

Name: Krause, Diana
Title: Professor
Affiliation: University of Irvine, CA, USA

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<div class="article_info">Saema Ansar, Petter Vikman, Marianne Nielsen and Lars Edvinsson. <span class="article_issue_date">2007</span>. <span class="article_title">Cerebrovascular receptor upregulation correlates with reduction in regional CBF after SAH.</span> (submitted)</div>
<div class="article_info">Saema Ansar and Lars Edvinsson. <span class="article_issue_date">2007</span>. <span class="article_title">Increased ICP and subarachnoid blood equally contribute to CBF reduction and receptor upregulation after SAH.</span> (submitted)</div>
<div class="article_info">Saema Ansar and Lars Edvinsson. <span class="article_issue_date">2006</span>. <span class="article_title">Subtype activation and interaction of PKC and MAPK controlling receptor expression in cerebral arteries and microvessels following ischemia of rat.</span> (submitted)</div>
<div class="article_info">Saema Beg, Jacob Hansen-Schwartz, Petter Vikman, Cang-Bao Xu and Lars Edvinsson. <span class="article_issue_date">2007</span>. <span class="article_title">Protein kinase C inhibition prevents upregulation of ETB and 5-HT1B receptors and reverses cerebral blood flow reduction in subarachnoid hemorrhage in rats.</span> <span class="journal_series_title">Journal of Cerebral Blood Flow and Metabolism</span>, <span class="journal_volume">vol 27</span> <span class="journal_pages">pp 21-32</span>.</div>
<div class="article_info">Saema Beg, Jacob Hansen-Schwartz, Petter Vikman, Cang-Bao Xu and Lars Edvinsson. <span class="article_issue_date">2006</span>. <span class="article_title">ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ETB and 5-HT1B receptor upregulation after subarachnoid hemorrhage in rat.</span> <span class="journal_series_title">Journal of Cerebral Blood Flow and Metabolism</span>, <span class="journal_volume">vol 26</span> <span class="journal_pages">pp 846-56</span>.</div>
<div class="article_info">Saema Ansar and Lars Edvinsson. <span class="article_issue_date">2007</span>. <span class="article_title">Inhibition of cerebrovascular raf activation reduces late cerebral ischemia after subarachnoid hemorrhage.</span> (submitted)</div>

Subject classification (UKÄ)

  • Other Clinical Medicine

Keywords

  • Neurology
  • neuropsychology
  • neurophysiology
  • Neurologi
  • protein kinase
  • cerebral ischemia
  • subarachnoid hemorrage
  • neurofysiologi
  • neuropsykologi

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