ERK Phosphorylation and FosB Expression Are Associated with L-DOPA-Induced Dyskinesia in Hemiparkinsonian Mice

Pavón, Nancy; Martín, Ana Belén Barragán; Mendialdua, Ainhoa; Moratalla, Rosario

doi:10.1016/j.biopsych.2005.05.044

Cited by 307 publications

(313 citation statements)

References 37 publications

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“…The increase in expression of genes encoding phosphoproteins observed in this study is consistent with previous findings that dyskinetic animals have increased phosphorylated DARPP32 (Picconi et al, 2003), ERK (Pavon et al, 2006;Santini et al, 2007;Westin et al, 2007), and MEK (Santini et al, 2007) resulting in increased potentiation at synapses and impaired depotentiation. Drugs that reverse protein phosphorylation (phosphatases) represent a potential treatment avenue that could be used to reduce the phosphorylation of phosphoproteins we have identified as being expressed and potentially rescue depotentiation at synapses in dyskinetic animals.…”

Section: Discussionsupporting

confidence: 92%

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

et al. 2016

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L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of ParkinsonÕs disease. With prolonged treatment (≥5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step towards developing treatments for this debilitating side effect. We used the 6-OHDA rat model of ParkinsonÕs disease treated with a three week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, nondyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 minutes after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence. ¥ Cytoskeletal elements present a potential target for treatments to prevent or ameliorate L-DOPA-induced dyskinesia.

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Section: Discussionsupporting

confidence: 92%

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

et al. 2016

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“…injection of L-DOPA methyl ester hydrochloride (25 mg/kg) (Pavon et al, 2006) and benserazide hydrochloride (12.5 mg/kg), a peripheral DOPA decarboxylase inhibitor. L-DOPA/benserazide treatment and exposure to the wheels lasted two weeks.…”

Section: Hemiparkinsonism Dyskinesia and Exercisementioning

confidence: 99%

“…We only counted paw contacts with extended digits supporting the body weight. Results were expressed as the number of failures of injured paw (left paw, right striatum) as a % of total number of wall contacts, which represents an asymmetry score (contralateral bias) (Pavon et al, 2006).…”

Section: Behavioral Tasksmentioning

confidence: 99%

“…AIMs were manually classified into: orofacial, forelimb, axial or dystonic, and locomotive (Video 1); and severity was scored for 1 min every 20 min using a 0-4 scale as previously defined (Lundblad et al, 2005, Pavon et al, 2006. The video tracking system ANY-maze™ (Stoelting, USA) was used for off-line rating of locomotive AIMs (rotations), where we also scored rearing and grooming, as conventional measures of motor activity.…”

Section: Abnormal Involuntary Movements (Aims)mentioning

confidence: 99%

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Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice

et al. 2013

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Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice, Neuroscience (2013), doi: http://dx.doi.org/10.1016/j.neuroscience. 2013.03.039 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Therefore, transcription factors, which regulate gene expression, are likely to be involved in these molecular processes. Indeed, chronic Fos proteins of the ΔFosB family of transcription factors in the caudate-putamen, which, when coupled with Jun-D, form AP-1 complexes that can modulate the expression of several genes associated with the generation of LIDs in rodent and primate models of PD (Andersson et al, 1999;Doucet et al, 1996;Pavon et al, 2006). In recent years, we have shown that an orphan transcription factor of the nuclear receptor family, namely Nur77 (also known as Nerve-Growth Factor Inducible gene B (NGFI-B) or NR4A1) might also be associated with movement disorders in rodent models of PD (Sgambato-Faure et al, 2005;St-Hilaire et al, 2005;St-Hilaire et al, 2003;van den Munckhof et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

Mahmoudi

Samadi

Gilbert

et al. 2009

Neurobiology of Disease

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We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopainduced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282-288, 2006). In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking placed in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudateputamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a nonhuman primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.

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ERK Phosphorylation and FosB Expression Are Associated with L-DOPA-Induced Dyskinesia in Hemiparkinsonian Mice

Cited by 307 publications

References 37 publications

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

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