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Protein Kinase Inhibition in Late Cerebral Ischemia after Subarachnoid Hemorrhage

Ansar, Saema LU (2007)
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Krause, Diana, University of Irvine, CA, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neurology, neuropsychology, neurophysiology, Neurologi, protein kinase, cerebral ischemia, subarachnoid hemorrage, neurofysiologi, neuropsykologi
publisher
Faculty of Medicine, Lund University
defense location
BMC GK-salen, University of Lund
defense date
2007-03-31 09:00
ISSN
1652-8220
ISBN
978-91-85559-20-6
language
English
LU publication?
yes
id
ac27f31f-9226-420e-b1a3-04c728f5bebf (old id 548312)
date added to LUP
2007-09-07 16:03:18
date last changed
2016-09-19 08:44:59
@phdthesis{ac27f31f-9226-420e-b1a3-04c728f5bebf,
  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.<br/><br>
<br/><br>
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).<br/><br>
<br/><br>
The aim of this thesis was to determine in detail the intracellular signaling mechanisms involved in the receptor changes in SAH.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.},
  author       = {Ansar, Saema},
  isbn         = {978-91-85559-20-6},
  issn         = {1652-8220},
  keyword      = {Neurology,neuropsychology,neurophysiology,Neurologi,protein kinase,cerebral ischemia,subarachnoid hemorrage,neurofysiologi,neuropsykologi},
  language     = {eng},
  publisher    = {Faculty of Medicine, Lund University},
  school       = {Lund University},
  title        = {Protein Kinase Inhibition in Late Cerebral Ischemia after Subarachnoid Hemorrhage},
  year         = {2007},
}