Inhaling xenon ameliorates <scp>l</scp>‐dopa‐induced dyskinesia in experimental parkinsonism

Baufreton, Jérôme; Milekovic, Tomislav; Li, Qin; McGuire, Stephen A.; Moraud, Eduardo Martin; Porras, Grégory; Sun, Shiqi; Ko, Wai Kin D.; Chazalon, Marine; Morin, Stéphanie; Normand, Elisabeth; Farjot, Géraldine; Milet, Aude; Pype, J L; Pioli, Elsa Y.; Courtine, Grégoire; Bessière, Baptiste; Bézard, Erwan

doi:10.1002/mds.27404

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…The performance in OF test during the 1st min of experiment measures a reaction to novelty rather that general activity [44]. In support of “low exploratory motivation” theory it should be noted that previous studies reported no sedating effects of xenon after 30 min treatment with 50% Xe/50% O 2 gas mixture [41]. In our study the exposure to valproate from pnd 6 to pnd 12 didn’t affect animal performance in the OF test.…”

Section: Discussionsupporting

confidence: 75%

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats

et al. 2019

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BackgroundXenon (Xe) is a noble gas that has been used for the last several decades as an anesthetic during surgery. Its antagonistic effect on glutamate subtype of NMDA (N-methyl-d-aspartate) receptors resulted in evaluation of this gas for treatment of CNS pathologies, including psychoemotional disorders. The aim of this study was to assess the behavioral effects of acute inhalation of subanesthetic concentrations of Xe and to study the outcomes of Xe exposure in valproic acid (VPA)-induced rodent model of autism.MethodsWe have conducted two series of experiments with a battery of behavioral tests aimed to evaluate locomotion, anxiety- and depression-like behavior, and social behavior in healthy, VPA-treated and Xe-exposed young rats.ResultsWe have shown that in healthy animals Xe exposure resulted in acute and delayed decrease of exploratory motivation, partial decrease in risk-taking and depressive-like behavior as well as improved sensorimotor integration during the negative geotaxis test. Acute inhalations of Xe in VPA-exposed animals led to improvement in social behavior, decrease in exploratory motivation, and normalization of behavior in forced-swim test.ConclusionBehavioral modulatory effects of Xe are probably related to its generalized action on excitatory/inhibitory balance within the CNS. Our data suggest that subanesthetic short-term exposures to Xe have beneficial effect on several behavioral modalities and deserves further investigation.

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Section: Discussionsupporting

confidence: 75%

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats

et al. 2019

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“…It is also known that glutamate is crucially involved in the onset of LID: 1) microdialysis assessment revealed that basal extracellular glutamate levels are substantially increased in dyskinetic rodent models ( Jonkers et al, 2002 ; Robelet et al, 2004 ), even if this is still debated ( Nevalainen et al, 2013 ); 2) corticostriatal glutamatergic synapses are overactivated during L-DOPA-induced dyskinesia (LID) ( Morin and Di Paolo, 2014 ; Mellone and Gardoni, 2018 ); 3) LID can be inhibited by several antagonists of NMDA glutamate receptors ( Hadj Tahar et al, 2004 ; Baufreton et al, 2018 ), including amantadine the only approved drug for LID treatment ( Perez-Lloret and Rascol, 2018 ), even though another mechanism probably involving Kir2 K + channel inhibition was proposed for this compound ( Shen et al, 2020 ) and 4) LID reduction can be achieved by activation of DREAM, a protein that negatively regulates NMDA receptors ( Ruiz-DeDiego et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

et al. 2021

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Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.

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“…4A, by an observer blinded to treatment, from video recordings captured while animals were without l -DOPA treatment (OFF), and for 4 h following an l -DOPA treatment dose (ON) according to standard guidelines (Fox et al , 2012). The parkinsonian features scored were motor (0–4), bradykinesia (0–3), posture (0–2), and tremor (0–1) as described previously (Shen et al , 2015; Urs et al , 2015; Ko et al , 2016, 2017; Baufreton et al , 2018). Dyskinesia was scored as chorea (0–4) and dystonia (0–4) (Fox et al , 2012; Shen et al , 2015; Urs et al , 2015; Ko et al , 2016, 2017; Baufreton et al , 2018).…”

Section: Methodsmentioning

confidence: 99%

“…The scoring was done over 10 min every 30 min, i.e. in total eight scores following a single l -DOPA administration (Fox et al , 2012; Shen et al , 2015; Urs et al , 2015; Ko et al , 2016, 2017; Baufreton et al , 2018). The l -DOPA test dose used was individually tailored to the lowest dose that gives maximal recovery in motor function, defined as 100%.…”

Section: Methodsmentioning

confidence: 99%

Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease

Rosenblad

Pioli

et al. 2019

Brain

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Ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-DOPA) therapy has retained its role as the leading standard medication for patients with Parkinson’s disease. With time, however, the shortcomings of oral l-DOPA treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. These side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-DOPA in a more continuous manner. Local gene delivery of the l-DOPA synthesizing enzymes, tyrosine hydroxylase and guanosine-tri-phosphate-cyclohydrolase-1, offers a new approach to a more refined dopaminergic therapy where l-DOPA is delivered continuously at the site where it is needed i.e. the striatum. In this study we have explored the therapeutic efficacy of adeno-associated viral vector-mediated l-DOPA delivery to the putamen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys, the standard non-human primate model of Parkinson’s disease. Viral vector delivery of the two enzymes, tyrosine hydroxylase and guanosine-5’-tri-phosphate-cyclohydrolase-1, bilaterally into the dopamine-depleted putamen, induced a significant, dose-dependent improvement of motor behaviour up to a level identical to that obtained with the optimal dose of peripheral l-DOPA. Importantly, this improvement in motor function was obtained without any adverse dyskinetic effects. These results provide proof-of-principle for continuous vector-mediated l-DOPA synthesis as a novel therapeutic strategy for Parkinson’s disease. The constant, local supply of l-DOPA obtained with this approach holds promise as an efficient one-time treatment that can provide long-lasting clinical improvement and at the same time prevent the appearance of motor fluctuations and dyskinetic side effects associated with standard oral dopaminergic medication.

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Inhaling xenon ameliorates l‐dopa‐induced dyskinesia in experimental parkinsonism

Cited by 15 publications

References 52 publications

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats

Beneficial effects of xenon inhalation on behavioral changes in a valproic acid-induced model of autism in rats

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease

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