Neuroplasticity and neurorestoration in the treatment of Parkinson's Disease: Experimental studies in the mouse
Author
Summary, in English
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.
Department/s
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:59
Document type
Dissertation
Publisher
Basal Ganglia
Topic
- Neurosciences
Status
Published
Research group
- Basal Ganglia Pathophysiology
Supervisor
- Angela Cenci Nilsson
- Cecilia Lundberg
- Niklas Lindgren
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87449-29-1
Defence date
30 May 2013
Defence time
13:15
Defence place
Segerfalksalen, Wallenbergs Neuroscience Center, Sölvegatan 17, Lund.
Opponent
- Per Svenningsson (MD, PhD)