Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats

Sgroi, Stefania; Capper-Loup, Christine; Paganetti, Paolo; Kaelin‐Lang, Alain

doi:10.1016/j.expneurol.2016.03.024

Cited by 23 publications

(28 citation statements)

References 42 publications

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“…Unilateral 6-OHDA-injection decreased the overall spontaneous locomotor behavior as measured by total walking distance as already shown by others (Kirik et al, 2001; Tamás et al, 2005; Brown et al, 2011; Abedi et al, 2013; Capper-Loup et al, 2013; da Rocha et al, 2013; Sun et al, 2013; Machado-Filho et al, 2014; Chao et al, 2015; Kumari et al, 2015; Ximenes et al, 2015; Das et al, 2016; Sgroi et al, 2016). Reduced locomotion is tentatively interpreted as a result of depletion of striatal DA (Fearnley and Lees, 1991; Schwarting and Huston, 1996; Alam and Schmidt, 2002; Ferro et al, 2005; Carvalho et al, 2013), although there is no clear explanation why a unilateral DA depletion has such a massive effect (about 50% reduction) on total walking distance as a measure of whole body bradykinesia of the hemi-PD rats.…”

Section: Discussionsupporting

confidence: 67%

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Antipova

Holzmann

Schmitt

et al. 2017

Front. Behav. Neurosci.

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Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. The loss of dopaminergic neurons in the substantia nigra leads to a disinhibition of cholinergic interneurons in the striatum. Pharmacotherapeutical strategies of PD-related hypercholinism have numerous adverse side effects. We previously showed that ipsilateral intrastriatal injections of 1 ng in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats inhibit apomorphine-induced rotation behavior significantly up to 6 months. In this study, we extended the behavioral testing of ipsilateral botulinum neurotoxin A (BoNT-A)-injection and additionally investigated the impact of intrastriatal BoNT-A-injections contralateral to the 6-OHDA-lesioned hemisphere on the basal ganglia circuity and motor functions. We hypothesized that the interhemispheric differences of acetylcholine (ACh) concentration seen in unilateral hemi-PD should be differentially and temporally influenced by the ipsilateral or contralateral injection of BoNT-A. Hemi-PD rats were injected with 1 ng BoNT-A or vehicle substance into either the ipsilateral or contralateral striatum 6 weeks after 6-OHDA-lesion and various behaviors were tested. In hemi-PD rats intrastriatal ipsilateral BoNT-A-injections significantly reduced apomorphine-induced rotations and increased amphetamine-induced rotations, but showed no significant improvement of forelimb usage and akinesia, lateralized sensorimotor integration and also no effect on spontaneous locomotor activity. However, intrastriatal BoNT-A-injections contralateral to the lesion led to a significant increase of the apomorphine-induced turning rate only 2 weeks after the treatment. The apomorphine-induced rotation rate decreases thereafter to a value below the initial rotation rate. Amphetamine-induced rotations were not significantly changed after BoNT-A-application in comparison to sham-treated animals. Forelimb usage was temporally improved by contralateral BoNT-A-injection at 2 weeks after BoNT-A. Akinesia and lateralized sensorimotor integration were also improved, but contralateral BoNT-A-injection had no significant effect on spontaneous locomotor activity. These long-ranging and different effects suggest that intrastriatally applied BoNT-A acts not only as an inhibitor of ACh release but also has long-lasting impact on transmitter expression and thereby on the basal ganglia circuitry. Evaluation of changes of transmitter receptors is subject of ongoing studies of our group.

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Section: Discussionsupporting

confidence: 67%

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Antipova

Holzmann

Schmitt

et al. 2017

Front. Behav. Neurosci.

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“…Vilazodone attenuated this dyskinesiogenic c‐Fos induction, a key feature of antidyskinetic compounds . The opioid pre‐cursors PPD and PPE, associated with D 1 direct and D 2 indirect pathway activity, respectively, were also measured to further characterize Vilazodone's effects on medium spiny neuron activity . LID is associated with D 1 direct pathway overactivity, and increased PPD mRNA expression is consistently observed in DA‐lesioned, l ‐dopa‐treated striata .…”

Section: Discussionmentioning

confidence: 99%

Diverse serotonin actions of vilazodone reduce l‐3,4‐dihidroxyphenylalanine–induced dyskinesia in hemi‐parkinsonian rats

et al. 2018

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Background: The serotonergic system is a well‐established modulator of l‐dopa‐induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5‐HT1A) reduces l‐dopa‐induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin‐mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5‐HT1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l‐dopa‐induced dyskinesia without compromising l‐dopa‐mediated motor improvements. Objectives: The goal of the present study was to characterize Vilazodone's effects on l‐dopa‐induced behaviors, neurochemistry and gene expression in unilateral 6‐hydroxydopamine‐lesioned hemi‐parkinsonian rats. Methods: In experiments 1 and 2, l‐dopa‐naïve and l‐dopa‐primed animals were coadministered Vilazodone and l‐dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5‐HT1A or serotonin receptor subtype 1B blockade prior to Vilazodone–l‐dopa coadministration. Results: Vilazodone significantly suppressed developing and established l‐dopa‐induced dyskinesia without compromising the promotor effects of l‐dopa therapy. In the dopamine‐depleted striatum, Vilazodone–l‐dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l‐dopa‐induced c‐Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D1 receptor‐mediated direct pathway overactivity. Only 5‐HT1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter‐dependent effects and 5‐HT1A receptors in Vilazodone's actions. Conclusions: Our findings show Vilazodone has a serotonin‐dependent effect on rodent l‐dopa‐induced dyskinesia and implicate the potential for repositioning Vilazodone against l‐dopa‐induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society

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“…In a recent research, it was also reported that both the dynorphin and enkephalin expression levels were involved in the development of motor complications while being treated with L-Dopa. Sgroi et al pointed out that, on the one hand, the preproenkephalin level was increased before the use of L-Dopa after 6-OHDA lesion, and it remained high after L-Dopa washout; on the other hand, there is a correlation between the rotational AIM and preproenkephalin level in the on state [ 8 ]. All these phenomenons suggested that the increased proenkephalin mRNA level may be a prerequisite to the locomotor sensitization before L-Dopa treatment [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Sgroi et al pointed out that, on the one hand, the preproenkephalin level was increased before the use of L-Dopa after 6-OHDA lesion, and it remained high after L-Dopa washout; on the other hand, there is a correlation between the rotational AIM and preproenkephalin level in the on state [ 8 ]. All these phenomenons suggested that the increased proenkephalin mRNA level may be a prerequisite to the locomotor sensitization before L-Dopa treatment [ 8 ]. On the other hand, the association of prodynorphin with LID is clearer than that with proenkephalin, because it has been consistently proven in several studies [ 5 , 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…All these phenomenons suggested that the increased proenkephalin mRNA level may be a prerequisite to the locomotor sensitization before L-Dopa treatment [ 8 ]. On the other hand, the association of prodynorphin with LID is clearer than that with proenkephalin, because it has been consistently proven in several studies [ 5 , 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Antidyskinetic Treatment with MTEP Affects Multiple Molecular Pathways in the Parkinsonian Striatum

Lin

Liu

Xie

et al. 2017

Parkinson's Disease

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Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways. For this purpose, we examined molecular markers of direct and indirect pathway involvement (prodynorphin and proenkephalin, resp.) in a rat model of LID treated with the mGluR5 antagonist MTEP. Our results show that MTEP cotreatment significantly attenuates the upregulation of prodynorphin mRNA induced by L-Dopa while also decreasing the expression levels of proenkephalin mRNA. We also examined markers of the mGluR5-related PKC/MEK/ERK1/2 signaling pathway, finding that both the expression of PKC epsilon and the phosphorylation of MEK and ERK1/2 had decreased significantly in the MTEP-treated group. Taken together, our results show that pharmacological antagonism of mGluR5 normalizes several abnormal molecular responses in the striatum in this experimental model of LID.

show abstract

Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats

Cited by 23 publications

References 42 publications

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Diverse serotonin actions of vilazodone reduce l‐3,4‐dihidroxyphenylalanine–induced dyskinesia in hemi‐parkinsonian rats

Antidyskinetic Treatment with MTEP Affects Multiple Molecular Pathways in the Parkinsonian Striatum

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