Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys

Morissette, Marc; Bourque, Mélanie; Tremblay, Marie‐Ève; Paolo, Thérèse Di

doi:10.3390/cells11040691

Cited by 12 publications

(13 citation statements)

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“… Ohlin et al (2011) using post-mortem basal ganglia tissue from PD patients and a brain tissue from a rat model of LID revealed increased angiogenesis, up-regulation of vascular endothelial growth factor, and altered brain-blood barrier properties. Other pre-clinical studies have shown an inflammatory environment in the dopamine-depleted striatum, with sustained activation of astrocytes, microglia, cicloxigenase-2 (COX-2), and recruitment of immune elements contributing to the pathophysiology of LID ( Bortolanza et al, 2015a , 2021 ; Del-Bel et al, 2016 ; Morissette et al, 2022 ; Mulas et al, 2016 ; Zhang et al, 2021 ). Supporting this hypothesis, long after the neurotoxin 6-hydroxydopamine (6OHDA) has been cleared from the brain, the striatum of lesioned rats receiving L-DOPA treatment displayed sustained neuroinflammation signals ( Bortolanza et al, 2015a , 2015b , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline

et al. 2023

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Levo-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson's disease (PD) patients improves motor symptoms, but long-term treatment induces side effects such as abnormal involuntary movements (levodopa-induced dyskinesia – LID). Increasing evidence has linked LID with neuroinflammatory reaction in the striatum involving microglia and astrocytes. The nerve/glial antigen-2 cells (NG2-glia) are recognized as a glial cell whose function in the adult brain is poorly understood. Here, we used immunohistochemistry, confocal microscopy, and western blot to characterize the cellular distribution of NG2-glia in the dorsal striatum of unilaterally 6OHDA-lesioned rats presenting LID. The effect of doxycycline on NG2-glia cells was determined. Dopamine depletion revealed a minor density increase of NG2-glia in the dorsolateral striatum and an activated phenotype. LID development promotes a decrease in NG2-glia cell density and protein level, maintaining the cell-activated feature. Doxycycline antidyskinetic therapy restores the cells to the control density profile. These results indicated the cellular distribution of NG2-glia in the striatum, but the interaction between these cells and other glial types in this model was unanswered and therefore we carried out a double labeling of NG2 and OX-42 (microglia) and GFAP (astrocyte). In LID, there was a decrease in the possible NG2 and OX-42 positive cells interaction, with no effect in the astrocytes. Doxycycline treatment restored the control characteristic. The ability of NG2-glia to regulate their dynamics in response to PD and LID is the first indication of an active link between them. The results suggest that NG2 cells may play important roles other than serving as oligodendrocyte precursor cells. Summary Statement NG2-glia alters its dynamics in response to L-DOPA-induced dyskinesia. In these animals, striatal NG2-glia density was reduced with cells presenting activated phenotype while doxycycline antidyskinetic therapy promotes a return to NG2-glia cell density and protein to a not activated state.

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Section: Introductionmentioning

confidence: 99%

Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline

et al. 2023

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“…The onset and progression of LID are also thought to depend on other pro-inflammatory factors, such as cytokines released by activated glial cells. This is the case in both rodents ( Del-Bel et al, 2016 ; Carta et al, 2017 ; Pisanu et al, 2018 ; Junior et al, 2020 ) and non-human primates ( Morissette et al, 2022 ). In the present study, we show that the 20-mg.kg −1 dose of Doxy totally prevented the rise in striatal TNF-α observed in dyskinetic mice and only partially that of IL-1β.…”

Section: Discussionmentioning

confidence: 96%

“…The neurotransmitter imbalance in the basal ganglia of dyskinetic animals also leads to neuroinflammation, another critical hallmark of LID ( Del-Bel et al, 2016 ; Carta et al, 2017 ; Pisanu et al, 2018 ; Morissette et al, 2022 ). Experimental data collected over recent years revealed, for instance, that pro-inflammatory enzymes, such as cyclooxygenase-2 (COX-2) and the inducible nitric oxide synthase (iNOS), are activated in the basal ganglia structures of rodents with l -DOPA-induced AIMs ( Bortolanza et al, 2015a ; Bortolanza et al, 2015b ).…”

Section: Introductionmentioning

confidence: 99%

Doxycycline attenuates l-DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model

et al. 2022

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The pharmacological manipulation of neuroinflammation appears to be a promising strategy to alleviate l-DOPA-induced dyskinesia (LID) in Parkinson’s disease (PD). Doxycycline (Doxy), a semisynthetic brain-penetrant tetracycline antibiotic having interesting anti-inflammatory properties, we addressed the possibility that this compound could resolve LID in l-DOPA-treated C57BL/6 mice presenting either moderate or intermediate lesions of the mesostriatal dopaminergic pathway generated by intrastriatal injections of 6-OHDA. Doxy, when given subcutaneously before l-DOPA at doses of 20 mg kg−1 and 40 mg kg−1, led to significant LID reduction in mice with moderate and intermediate dopaminergic lesions, respectively. Importantly, Doxy did not reduce locomotor activity improved by l-DOPA. To address the molecular mechanism of Doxy, we sacrificed mice with mild lesions 1) to perform the immunodetection of tyrosine hydroxylase (TH) and Fos-B and 2) to evaluate a panel of inflammation markers in the striatum, such as cyclooxygenase-2 and its downstream product Prostaglandin E2 along with the cytokines TNF-α, IL-1β and IL-6. TH-immunodetection revealed that vehicle and Doxy-treated mice had similar striatal lesions, excluding that LID improvement by Doxy could result from neurorestorative effects. Importantly, LID inhibition by Doxy was associated with decreased Fos-B and COX-2 expression and reduced levels of PGE2, TNF-α, and IL-1β in the dorsolateral striatum of dyskinetic mice. We conclude 1) that Doxy has the potential to prevent LID regardless of the intensity of dopaminergic lesioning and 2) that the anti-inflammatory effects of Doxy probably account for LID attenuation. Overall, the present results further indicate that Doxy might represent an attractive and alternative treatment for LID in PD.

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“…It is now well‐acknowledged that chronic neuroinflammation occurs concurrently with PD pathology and may contribute to DA neuron degeneration (Gelders et al., 2018; McGeer et al., 1988; Qian et al., 2010). Conceivably, as recently suggested, neuroinflammation may also be mechanistically linked to the development of LIDs (Morissette et al., 2022; Mulas et al., 2016; Rentsch et al., 2020). In particular, Morissette et al.…”

Section: Introductionmentioning

confidence: 90%

“…It is now well-acknowledged that chronic neuroinflammation occurs concurrently with PD pathology and may contribute to DA neuron degeneration (Gelders et al, 2018;McGeer et al, 1988;Qian et al, 2010). Conceivably, as recently suggested, neuroinflammation may also be mechanistically linked to the development of LIDs (Morissette et al, 2022;Mulas et al, 2016;Rentsch et al, 2020). In particular, Morissette et al found a positive correlation between dyskinesia scores and all (IBA1+) and activated (CD68+) microglia in the putamen of MPTP lesioned monkeys and Mulas et al demonstrated an increase in activated microglia only in rats that received a L-Dopa regime leading to LID (Morissette et al, 2022;Mulas et al, 2016).…”

Section: Introductionmentioning

confidence: 92%

The ratio of M1 to M2 microglia in the striatum determines the severity of L‐Dopa‐induced dyskinesias

Rentsch,

Egan,

Kuriakose

et al. 2023

Journal of Neurochemistry

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L‐Dopa, while treating motor symptoms of Parkinson's disease, can lead to debilitating L‐Dopa‐induced dyskinesias, limiting its use. To investigate the causative relationship between neuro‐inflammation and dyskinesias, we assessed if striatal M1 and M2 microglia numbers correlated with dyskinesia severity and whether the anti‐inflammatories, minocycline and indomethacin, reverse these numbers and mitigate against dyskinesia. In 6‐OHDA lesioned mice, we used stereology to assess numbers of striatal M1 and M2 microglia populations in non‐lesioned (naïve) and lesioned mice that either received no L‐Dopa (PD), remained non‐dyskinetic even after L‐Dopa (non‐LID) or became dyskinetic after L‐Dopa treatment (LID). We also assessed the effect of minocycline/indomethacin treatment on striatal M1 and M2 microglia and its anti‐dyskinetic potential via AIMs scoring. We report that L‐Dopa treatment leading to LIDs exacerbates activated microglia numbers beyond that associated with the PD state; the severity of LIDs is strongly correlated to the ratio of the striatal M1 to M2 microglial numbers; in non‐dyskinetic mice, there is no M1/M2 microglia ratio increase above that seen in PD mice; and reducing M1/M2 microglia ratio using anti‐inflammatories is anti‐dyskinetic. Parkinson's disease is associated with increased inflammation, but this is insufficient to underpin dyskinesia. Given that L‐Dopa‐treated non‐LID mice show the same ratio of M1/M2 microglia as PD mice that received no L‐Dopa, and, given minocycline/indomethacin reduces both the ratio of M1/M2 microglia and dyskinesia severity, our data suggest the increased microglial M1/M2 ratio that occurs following L‐Dopa treatment is a contributing cause of dyskinesias.

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Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys

Cited by 12 publications

References 122 publications

Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline

Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline

Doxycycline attenuates l-DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model

The ratio of M1 to M2 microglia in the striatum determines the severity of L‐Dopa‐induced dyskinesias

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