Advanced

A Path for Improving Stroke Recovery. Effects of MEK-ERK1/2 Inhibition

Mostajeran, Maryam LU (2018)
Abstract
The present thesis aimed to shed more light on the notion of acute inhibition of extracellular-signal regulated kinase (ERK)1/2 pathway as a treatment to improve stroke recovery. Stroke is a major cause of death and long-term disability worldwide, classified as ischemic or hemorrhagic. In ischemic stroke, interruption of blood flow and deprivation of oxygen and glucose activate death signalling pathways within the area directly affected by ischemia so called “core”. In the region adjacent to core, peri-infarct, cells are hypoperfused, functionally inactive and prone to death if therapeutic strategies do not rescue them. Treatments for ischemic stroke are limited to thrombolysis or thrombectomy. Due to narrow time window and risk of... (More)
The present thesis aimed to shed more light on the notion of acute inhibition of extracellular-signal regulated kinase (ERK)1/2 pathway as a treatment to improve stroke recovery. Stroke is a major cause of death and long-term disability worldwide, classified as ischemic or hemorrhagic. In ischemic stroke, interruption of blood flow and deprivation of oxygen and glucose activate death signalling pathways within the area directly affected by ischemia so called “core”. In the region adjacent to core, peri-infarct, cells are hypoperfused, functionally inactive and prone to death if therapeutic strategies do not rescue them. Treatments for ischemic stroke are limited to thrombolysis or thrombectomy. Due to narrow time window and risk of hemorrhagic transformation, few percentages of stroke patients are eligible to receive these treatments. Another approach in stroke therapy is to rescue neurons within peri-infarct region. Despite promising effects of neuroprotective agents in experimental stroke, this approach has failed in clinical trials.
Although the ERK1/2 pathway is involved in recovery processes during later stage of stroke, it is a critical modulator of destructive mechanisms i.e. upregulation of cerebrovascular receptors during acute phase. Our previous studies showed that early inhibition of the ERK1/2 pathway reduced ischemic damage and improved functional outcome after experimental stroke. These findings are the base of the present thesis. Although promising, the beneficial effects were only observed during acute phase in male rats. Our hypothesis is that acute inhibition of ERK1/2 pathway will continue to show benefit beyond the acute phase and not negatively interfere with later recovery processes. Further, the present thesis addresses important aspects that should be considered when developing a new treatment such as sex and clinical relevant time point. Thus, this thesis addressed acute blockade of ERK1/2 pathway with regards to important aspects when developing a new treatment. The important aspects evaluated in the present thesis are as follow: (i) Beneficial outcome beyond acute phase and related recovery mechanisms, (ii) A time-window relevant to the clinic, (iii) Acute detrimental mechanisms and effect of U0126 in female rats and (iv) repair-related molecular changes during recovery phase of stroke in female rats. The experimental setup of the thesis was based on an ischemic model on rat. Inhibition of the pathway was achieved by U0126, a inhibitor of mitogen activated protein kinase kinase (MEK)1/2 which is immediately upstream of ERK1/2. In summary, the results of the present thesis showed that acute inhibition of MEKERK1/ 2 pathway is a promising potential treatment for stroke. It has been applicable in a clinically relevant time-window and beneficial for both sexes with persistence of improved functional outcome beyond acute phase. In addition, repair-related molecular changes and activation of ERK1/2 during recovery phase in female rats further supported the idea that ERK1/2 pathway contributes to recovery processes in later stage of stroke. Thus, a path well-investigated may actually lead to better stroke recovery and a future stroke treatment. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Gonzales, Rayna, Department of Basic Medical Sciences, College of Medicine, The University of Arizona, Phoenix, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Ischemic stroke, Extracellular-signal regulated kinase (ERK)1/2, Mitogen activated protein kinase kinase (MEK)1/2, Recovery, Functional outcome, sex
pages
70 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2018-12-20 09:00
ISBN
978-91-7619-727-1
language
English
LU publication?
yes
id
7381fb75-7d14-4876-b8b7-12a9ea11f156
date added to LUP
2018-11-30 12:26:03
date last changed
2018-11-30 13:50:43
@phdthesis{7381fb75-7d14-4876-b8b7-12a9ea11f156,
  abstract     = {The present thesis aimed to shed more light on the notion of acute inhibition of extracellular-signal regulated kinase (ERK)1/2 pathway as a treatment to improve stroke recovery. Stroke is a major cause of death and long-term disability worldwide, classified as ischemic or hemorrhagic. In ischemic stroke, interruption of blood flow and deprivation of oxygen and glucose activate death signalling pathways within the area directly affected by ischemia so called “core”. In the region adjacent to core, peri-infarct, cells are hypoperfused, functionally inactive and prone to death if therapeutic strategies do not rescue them. Treatments for ischemic stroke are limited to thrombolysis or thrombectomy. Due to narrow time window and risk of hemorrhagic transformation, few percentages of stroke patients are eligible to receive these treatments. Another approach in stroke therapy is to rescue neurons within peri-infarct region. Despite promising effects of neuroprotective agents in experimental stroke, this approach has failed in clinical trials.<br/>Although the ERK1/2 pathway is involved in recovery processes during later stage of stroke, it is a critical modulator of destructive mechanisms i.e. upregulation of cerebrovascular receptors during acute phase. Our previous studies showed that early inhibition of the ERK1/2 pathway reduced ischemic damage and improved functional outcome after experimental stroke. These findings are the base of the present thesis. Although promising, the beneficial effects were only observed during acute phase in male rats. Our hypothesis is that acute inhibition of ERK1/2 pathway will continue to show benefit beyond the acute phase and not negatively interfere with later recovery processes. Further, the present thesis addresses important aspects that should be considered when developing a new treatment such as sex and clinical relevant time point. Thus, this thesis addressed acute blockade of ERK1/2 pathway with regards to important aspects when developing a new treatment. The important aspects evaluated in the present thesis are as follow: (i) Beneficial outcome beyond acute phase and related recovery mechanisms, (ii) A time-window relevant to the clinic, (iii) Acute detrimental mechanisms and effect of U0126 in female rats and (iv) repair-related molecular changes during recovery phase of stroke in female rats. The experimental setup of the thesis was based on an ischemic model on rat. Inhibition of the pathway was achieved by U0126, a inhibitor of mitogen activated protein kinase kinase (MEK)1/2 which is immediately upstream of ERK1/2. In summary, the results of the present thesis showed that acute inhibition of MEKERK1/ 2 pathway is a promising potential treatment for stroke. It has been applicable in a clinically relevant time-window and beneficial for both sexes with persistence of improved functional outcome beyond acute phase. In addition, repair-related molecular changes and activation of ERK1/2 during recovery phase in female rats further supported the idea that ERK1/2 pathway contributes to recovery processes in later stage of stroke. Thus, a path well-investigated may actually lead to better stroke recovery and a future stroke treatment.},
  author       = {Mostajeran, Maryam},
  isbn         = {978-91-7619-727-1},
  keyword      = {Ischemic stroke, Extracellular-signal regulated kinase (ERK)1/2, Mitogen activated protein kinase kinase (MEK)1/2, Recovery, Functional outcome, sex},
  language     = {eng},
  pages        = {70},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {A Path for Improving Stroke Recovery.  Effects of MEK-ERK1/2 Inhibition},
  year         = {2018},
}