Back to Search
Start Over
Genetic enhancement of Ras-ERK pathway does not aggravate L-DOPA-induced dyskinesia in mice but prevents the decrease induced by lovastatin
- Source :
- Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018), Scientific Reports, Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela, instname
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
Abstract
- Increasing evidence supports a close relationship between Ras-ERK1/2 activation in the striatum and L-DOPA-induced dyskinesia (LID). ERK1/2 activation by L-DOPA takes place through the crosstalk between D1R/AC/PKA/DARPP-32 pathway and NMDA/Ras pathway. Compelling genetic and pharmacological evidence indicates that Ras-ERK1/2 inhibition prevents LID onset and may even revert already established dyskinetic symptoms. However, it is currently unclear whether exacerbation of Ras-ERK1/2 activity in the striatum may further aggravate dyskinesia in experimental animal models. Here we took advantage of two genetic models in which Ras-ERK1/2 signaling is hyperactivated, the Nf1+/− mice, in which the Ras inhibitor neurofibromin is reduced, and the Ras-GRF1 overexpressing (Ras-GRF1 OE) transgenic mice in which a specific neuronal activator of Ras is enhanced. Nf1+/− and Ras-GRF1 OE mice were unilaterally lesioned with 6-OHDA and treated with an escalating L-DOPA dosing regimen. In addition, a subset of Nf1+/− hemi-parkinsonian animals was also co-treated with the Ras inhibitor lovastatin. Our results revealed that Nf1+/− and Ras-GRF1 OE mice displayed similar dyskinetic symptoms to their wild-type counterparts. This observation was confirmed by the lack of differences between mutant and wild-type mice in striatal molecular changes associated to LID (i.e., FosB, and pERK1/2 expression). Interestingly, attenuation of Ras activity with lovastatin does not weaken dyskinetic symptoms in Nf1+/− mice. Altogether, these data suggest that ERK1/2-signaling activation in dyskinetic animals is maximal and does not require further genetic enhancement in the upstream Ras pathway. However, our data also demonstrate that such a genetic enhancement may reduce the efficacy of anti-dyskinetic drugs like lovastatin.
- Subjects :
- Male
0301 basic medicine
Genetically modified mouse
Dyskinesia, Drug-Induced
Parkinson's disease
Dopamine Agents
L-DOPA
lcsh:Medicine
Mice, Transgenic
Pharmacology
Article
Levodopa
Mice
03 medical and health sciences
0302 clinical medicine
Genetic model
medicine
Animals
Lovastatin
Extracellular Signal-Regulated MAP Kinases
lcsh:Science
Mice, Knockout
Neurons
Ras Inhibitor
Neurofibromin 1
Multidisciplinary
Behavior, Animal
biology
Dyskinesia
Chemistry
lcsh:R
nervous system diseases
Disease Models, Animal
030104 developmental biology
ras Proteins
biology.protein
NMDA receptor
Genetic enhancement
Female
lcsh:Q
Hydroxymethylglutaryl-CoA Reductase Inhibitors
medicine.symptom
030217 neurology & neurosurgery
Signal Transduction
medicine.drug
FOSB
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018), Scientific Reports, Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela, instname
- Accession number :
- edsair.doi.dedup.....33ada8cf35aff7dfa94df96aeb87458b