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The MEK-inhibitor U0126 in focal hyperglycemic ischemic brain injury in the rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
(English)Manuscript (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93492OAI: oai:DiVA.org:uu-93492DiVA: diva2:166982
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2015-06-10Bibliographically approved
In thesis
1. Hyperglycemia and Focal Brain Ischemia: Clinical and Experimental Studies
Open this publication in new window or tab >>Hyperglycemia and Focal Brain Ischemia: Clinical and Experimental Studies
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome.

In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves.

Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls.

Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 75 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 72
Keyword
Internal medicine, cerebrovascular disorders, diabetes mellitus, hyperglycemia, infarction, middle cerebral artery, ischemia, mitogen-activated protein kinases, mortality, rats, reactive oxygen species, reperfusion, signal transduction, therapeutics, Invärtesmedicin
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-5938 (URN)91-554-6345-2 (ISBN)
Public defence
2005-10-14, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 13:00
Opponent
Supervisors
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved

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Lennmyr, Fredrik

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