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Neuroplasticity and neurorestoration in the treatment of Parkinson's Disease: Experimental studies in the mouse

Francardo, Veronica LU (2013) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2013:59.
Abstract (Swedish)
Popular Abstract in English

Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s... (More)
Popular Abstract in English

Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s endogenous regenerative mechanisms either by neurotrophic factor delivery or by treatments that increase the production of trophic factors. These treatments recruit some of the same pathways that are involved in neuroplasticity.

In this thesis work, we have used mice with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) projections as a model of PD in order to examine the modulation of neuroplasticity pathways by both symptomatic and neurorestorative treatments. In a first study, we optimized the 6-OHDA lesion model in mice by examining the molecular and behavioural effects of 6-OHDA injections performed either in the medial forebrain bundle (MFB), in the substantia nigra, or in the striatum. The results showed that MFB lesions are the most suitable model for studying L-DOPA-induced dyskinesia, while intrastriatal 6-OHDA lesions should be the model of choice to study the effects of neurorestorative treatments. The second study focuses on the role of striatal Ras-ERK1/2 signaling in the development of L-DOPA-induced dyskinesia. Genetic ablation of Ras-GRF1 (a neuronal-specific activator of Ras-ERK1/2 signaling downstream of G-protein-coupled receptors) resulted in a reduced development of dyskinesia in the mouse. A collaborative study was undertaken to assess the role of Ras-ERK1/2 signaling in a monkey model of PD. The results of this study show that the severity of L-DOPA-induced dyskinesia can be reduced through lentiviral-mediated inactivation of Ras-GRF1 and ERK2 in the striatum.

We did also utilize mice with intrastriatal 6-OHDA lesions in order to examine the effects of potential neurorestorative treatments for PD. In the third study of thesis, we evaluated the time course of behavioural recovery and nigrostriatal neurorestoration induced by striatal lentiviral delivery of the neurotrophic factor, GDNF. The intervention caused a progressive increase in the levels of phosphorylated ERK1/2 both in nigrostriatal neurons and in their projection areas, and this effect correlated with a local neuritic sprouting response. In the last study we evaluated the effects of PRE-084, a selective agonist of the sigma-1 receptor (which is an intracellular protein involved in many cellular functions). Chronic treatment with PRE-084 for 5 weeks resulted in a gradual and significant motor recovery, partial neuroprotective and neurorestorative effects on the nigrostriatal DA pathway. This was accompanied by striatal and nigral upregulation of GDNF and activation of ERK1/2.

Taken together, the results of this thesis indicate that treatments stimulating a physiological activation of neuroplasticity pathways (such as ERK1/2 signaling) have neurorestorative potential in PD, while an excessive activation of these pathway by dopaminergic therapies may result in unwanted effects, such as dyskinesia. (Less)
Abstract
Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s endogenous regenerative mechanisms either by... (More)
Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s endogenous regenerative mechanisms either by neurotrophic factor delivery or by treatments that increase the production of trophic factors. These treatments recruit some of the same pathways that are involved in neuroplasticity.

In this thesis work, we have used mice with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) projections as a model of PD in order to examine the modulation of neuroplasticity pathways by both symptomatic and neurorestorative treatments. In a first study, we optimized the 6-OHDA lesion model in mice by examining the molecular and behavioural effects of 6-OHDA injections performed either in the medial forebrain bundle (MFB), in the substantia nigra, or in the striatum. The results showed that MFB lesions are the most suitable model for studying L-DOPA-induced dyskinesia, while intrastriatal 6-OHDA lesions should be the model of choice to study the effects of neurorestorative treatments. The second study focuses on the role of striatal Ras-ERK1/2 signaling in the development of L-DOPA-induced dyskinesia. Genetic ablation of Ras-GRF1 (a neuronal-specific activator of Ras-ERK1/2 signaling downstream of G-protein-coupled receptors) resulted in a reduced development of dyskinesia in the mouse. A collaborative study was undertaken to assess the role of Ras-ERK1/2 signaling in a monkey model of PD. The results of this study show that the severity of L-DOPA-induced dyskinesia can be reduced through lentiviral-mediated inactivation of Ras-GRF1 and ERK2 in the striatum. We did also utilize mice with intrastriatal 6-OHDA lesions in order to examine the effects of potential neurorestorative treatments for PD. In the third study of thesis, we evaluated the time course of behavioural recovery and nigrostriatal neurorestoration induced by striatal lentiviral delivery of the neurotrophic factor, GDNF. The intervention caused a progressive increase in the levels of phosphorylated ERK1/2 both in nigrostriatal neurons and in their projection areas, and this effect correlated with a local neuritic sprouting response. In the last study we evaluated the effects of PRE-084, a selective agonist of the sigma-1 receptor (which is an intracellular protein involved in many cellular functions). Chronic treatment with PRE-084 for 5 weeks resulted in a gradual and significant motor recovery, partial neuroprotective and neurorestorative effects on the nigrostriatal DA pathway. This was accompanied by striatal and nigral upregulation of GDNF and activation of ERK1/2.

Taken together, the results of this thesis indicate that treatments stimulating a physiological activation of neuroplasticity pathways (such as ERK1/2 signaling) have neurorestorative potential in PD, while an excessive activation of these pathway by dopaminergic therapies may result in unwanted effects, such as dyskinesia. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD, PhD Svenningsson, Per, Laboratory of Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2013:59
pages
202 pages
publisher
Basal Ganglia
defense location
Segerfalksalen, Wallenbergs Neuroscience Center, Sölvegatan 17, Lund.
defense date
2013-05-30 13:15
ISSN
1652-8220
ISBN
978-91-87449-29-1
language
English
LU publication?
yes
id
c3aa2792-4636-43d5-bd31-cd973633eaf2 (old id 3736728)
date added to LUP
2013-05-29 08:02:09
date last changed
2019-05-22 00:45:00
@phdthesis{c3aa2792-4636-43d5-bd31-cd973633eaf2,
  abstract     = {Neuroplasticity is the brain´s capacity to respond to inner and outer challenges with functional and structural reorganizations. An aberrant activation of neuroplasticity pathways may contribute to the development of neurological disease. In the case of Parkinson’s disease (PD), the induction of motor complications by L-DOPA pharmacotherapy is generally regarded as an example of maladaptive plasticity. Indeed, L-DOPA-induced dyskinesia is associated with an aberrant striatal activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pathway that normally governs processes of synaptic plasticity and motor learning. The term neurorestoration refers to a stimulation of brain´s endogenous regenerative mechanisms either by neurotrophic factor delivery or by treatments that increase the production of trophic factors. These treatments recruit some of the same pathways that are involved in neuroplasticity.<br/><br>
In this thesis work, we have used mice with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) projections as a model of PD in order to examine the modulation of neuroplasticity pathways by both symptomatic and neurorestorative treatments. In a first study, we optimized the 6-OHDA lesion model in mice by examining the molecular and behavioural effects of 6-OHDA injections performed either in the medial forebrain bundle (MFB), in the substantia nigra, or in the striatum. The results showed that MFB lesions are the most suitable model for studying L-DOPA-induced dyskinesia, while intrastriatal 6-OHDA lesions should be the model of choice to study the effects of neurorestorative treatments. The second study focuses on the role of striatal Ras-ERK1/2 signaling in the development of L-DOPA-induced dyskinesia. Genetic ablation of Ras-GRF1 (a neuronal-specific activator of Ras-ERK1/2 signaling downstream of G-protein-coupled receptors) resulted in a reduced development of dyskinesia in the mouse. A collaborative study was undertaken to assess the role of Ras-ERK1/2 signaling in a monkey model of PD. The results of this study show that the severity of L-DOPA-induced dyskinesia can be reduced through lentiviral-mediated inactivation of Ras-GRF1 and ERK2 in the striatum. We did also utilize mice with intrastriatal 6-OHDA lesions in order to examine the effects of potential neurorestorative treatments for PD. In the third study of thesis, we evaluated the time course of behavioural recovery and nigrostriatal neurorestoration induced by striatal lentiviral delivery of the neurotrophic factor, GDNF. The intervention caused a progressive increase in the levels of phosphorylated ERK1/2 both in nigrostriatal neurons and in their projection areas, and this effect correlated with a local neuritic sprouting response. In the last study we evaluated the effects of PRE-084, a selective agonist of the sigma-1 receptor (which is an intracellular protein involved in many cellular functions). Chronic treatment with PRE-084 for 5 weeks resulted in a gradual and significant motor recovery, partial neuroprotective and neurorestorative effects on the nigrostriatal DA pathway. This was accompanied by striatal and nigral upregulation of GDNF and activation of ERK1/2.<br/><br>
Taken together, the results of this thesis indicate that treatments stimulating a physiological activation of neuroplasticity pathways (such as ERK1/2 signaling) have neurorestorative potential in PD, while an excessive activation of these pathway by dopaminergic therapies may result in unwanted effects, such as dyskinesia.},
  author       = {Francardo, Veronica},
  isbn         = {978-91-87449-29-1},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {202},
  publisher    = {Basal Ganglia},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Neuroplasticity and neurorestoration in the treatment of Parkinson's Disease: Experimental studies in the mouse},
  volume       = {2013:59},
  year         = {2013},
}