Differential involvement of Ras‐GRF1 and Ras‐GRF2 in L‐DOPA‐induced dyskinesia

Bido, Simone; Solari, Nicoletta; Indrigo, Marzia; D'Antoni, Angela; Brambilla, Riccardo; Morari, Michele; Fasano, Stefania

doi:10.1002/acn3.202

Cited by 20 publications

(20 citation statements)

References 44 publications

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“…Interestingly, compounds able to reduce LID also normalized striatal Glu Paolone et al, 2015), suggesting that the increase of striatal Glu release detected during microdialysis experiments might be instrumental in LID appearance. Elevation of dialyzed Glu levels following levodopa challenge was also observed in the SNr but not globus pallidus of dyskinetic rats (Bido et al, 2011;Mela et al, 2012;Paolone et al, 2015) and mice (Bido et al, 2015;Brugnoli et al, 2016). In SNr, elevation of Glu was associated with elevation of GABA, which was proven to be an index of activation of the striato-nigral direct pathway in LID (Mela et al, 2007(Mela et al, , 2012Bido et al, 2011;Marti et al, 2012;Paolone et al, 2015).…”

Section: Introductionmentioning

confidence: 83%

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia

Gardoni

Morari

Kulisevsky

et al. 2018

J Pharmacol Exp Ther

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Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-Daspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia.This work was supported by Zambon S.P.A. F.G. and M.M. contributed equally to this work.

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Section: Introductionmentioning

confidence: 83%

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia

Gardoni

Morari

Kulisevsky

et al. 2018

J Pharmacol Exp Ther

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“…Since ChAT neurons are important regulators of MSN activity (Threlfell et al, 2012; Tozzi et al, 2011), induction of c-Fos in ChAT neurons may subsequently induce molecular changes in MSNs that contribute to the observed alterations in LIDs. In addition, previous studies indicate that other signaling pathways such as ERK play a role (Ding et al, 2011) possibly by eliciting downstream changes in neuronal plasticity and morphology linked to the development of LIDs (Bido et al, 2015; Cenci and Konradi, 2010; Feyder et al, 2011; Huot et al, 2011; Rangel-Barajas et al, 2011; Santini et al, 2009; Zhang et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.

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“…The LV-RasGRF1-shRNA, LV-RasGRF2-shRNA, and LV-scrambled-shRNA were constructed and prepared as previously described (Bido et al, 2015). Briefly, expression plasmids for Ras-GRF1 and Ras-GRF2 RNA interference were obtained from a commercial source (OriGene).…”

Section: Lentiviral Vector (Lv) Productionmentioning

confidence: 99%

The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice

et al. 2019

Self Cite

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Ras/Raf/MEK/ERK (Ras-ERK) signaling has been implicated in the effects of drugs of abuse. Inhibitors of MEK1/2, the kinases upstream of ERK1/2, have been critical in defining the role of the Ras-ERK cascade in drug-dependent alterations in behavioral plasticity, but the Ras family of small GTPases has not been extensively examined in drug-related behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 1 (RasGRF1) and 2 (RasGRF2), upstream regulators of the Ras-ERK signaling cascade, on cocaine selfadministration (SA) in male mice. We first established a role for Ras-ERK signaling in cocaine SA, demonstrating that pERK1/2 is upregulated following SA in C57BL/6N mice in striatum. We then compared RasGRF1 and RasGRF2 KO mouse lines, demonstrating that cocaine SA in RasGRF2 KO mice was increased relative to WT controls, whereas RasGRF1 KO and WT mice did not differ. This effect in RasGRF2 mice is likely mediated by the Ras-ERK signaling pathway, as pERK1/2 upregulation following cocaine SA was absent in RasGRF2 KO mice. Interestingly, the lentiviral knockdown of RasGRF2 in the NAc had the opposite effect to that in RasGRF2 KO mice, reducing cocaine SA. We subsequently demonstrated that the MEK inhibitor PD325901 administered peripherally prior to cocaine SA increased cocaine intake, replicating the increase seen in RasGRF2 KO mice, whereas PD325901 administered into the NAc decreased cocaine intake, similar to the effect seen following lentiviral knockdown of RasGRF2. These data indicate a role for RasGRF2 in cocaine SA in mice that is ERK-dependent, and suggest a differential effect of global versus site-specific RasGRF2 inhibition.

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Differential involvement of Ras‐GRF1 and Ras‐GRF2 in L‐DOPA‐induced dyskinesia

Cited by 20 publications

References 44 publications

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice

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