Neuroprotective effects of riluzole in early phase Parkinson's disease on clinically relevant parameters in the marmoset MPTP model

Verhave, Peternella S.; Jongsma, Marjan J.; Berg, R.M. van den; Vanwersch, R.A.P.; Smit, August B.; Philippens, Ingrid H.C.H.M.

doi:10.1016/j.neuropharm.2011.11.016

Cited by 28 publications

(12 citation statements)

References 41 publications

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“…Riluzole has also consistently been demonstrated to provide neuroprotection in MPTP-treated mice, when administered before the lesion [19-21]. In non-human primates riluzole administration either 1 hour prior to, or one hour after MPTP administration, followed by additional administrations also caused neuroprotection [22-25]. Our data therefore confirms that riluzole is an effective neuroprotective agent, at least when administration commences 1 h before the experimental lesion.…”

Section: Discussionsupporting

confidence: 80%

“…The apparent discrepancy between the data sets most likely relates to the doses used. While it is difficult to accurately scale doses from humans to lower species, the riluzole doses used in this study (4 mg/kg or 8 mg/kg), typical of the doses required to produce positive effects in rodents [25,32], are five to ten fold higher than the dose of riluzole used clinically for the treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS/MND). In ALS/MND patients, 50 mg twice daily is administered, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…This dose has been evaluated as providing the best benefit:risk ratio in ALS/MND [33], though doses of up to 200 mg/day are tolerated [33,34]. Riluzole doses such as those used clinically have never been reported to be effective in primate models of Parkinson's disease, indeed the primate data suggests that higher doses of riluzole, between 4-10 mg/kg daily are required for efficacy [22-25], i.e. equivalent to a dose range in man between 200 mg/day and 1 g/day.…”

Section: Discussionmentioning

confidence: 99%

“…We chose our lowest dose on the basis of previous work in rodent stroke models which used 4 mg/kg to see protective effects [32], and the highest dose on the basis of doses which have already been suggested to show protection in PD models, for example a recent primate studies which used 10 mg/kg riluzole to produce protective effects [25]. …”

Section: Methodsmentioning

confidence: 99%

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Riluzole neuroprotection in a parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

2012

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BackgroundRiluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson's disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle.ResultsRats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration, assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss. Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion.ConclusionsThe results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson's disease. Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum. Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Riluzole neuroprotection in a parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

2012

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“…Another postulated mechanism associated with beneficial role of riluzole application is related to observed increase of serum concentrations of brain-derived neurotrophic factor (BDNF) (Katoh-Semba et al, 2002), which neurotrophic factor is known to be significantly diminished in the brains of HD patients, and its level seems to be correlated with diseases onset progression and severity (Gauthier et al, 2004). Moreover, riluzole was shown to be effective in attenuating several clinically relevant symptoms in a variation of an animal MPTP model representing the early phase of Parkinson’s disease (PD) (Verhave et al, 2012). Nevertheless, there are still concerns about its utility due to rather modest clinical efficacy (Miller, Mitchell & Moore, 2012).…”

Section: Introductionmentioning

confidence: 99%

Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration

Kreiner

Rafa-Zabłocka

Chmielarz

et al. 2017

PeerJ

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BackgroundHuntington’s disease (HD) is a rare familial autosomal dominant neurodegenerative disorder characterized by progressive degeneration of medium spiny neurons (MSNs) located in the striatum. Currently available treatments of HD are only limited to alleviating symptoms; therefore, high expectations for an effective therapy are associated with potential replacement of lost neurons through stimulation of postnatal neurogenesis. One of the drugs of potential interest for the treatment of HD is riluzole, which may act as a positive modulator of adult neurogenesis, promoting replacement of damaged MSNs. The aim of this study was to evaluate the effects of chronic riluzole treatment on a novel HD-like transgenic mouse model, based on the genetic ablation of the transcription factor TIF-IA. This model is characterized by selective and progressive degeneration of MSNs.MethodsSelective ablation of TIF-IA in MSNs (TIF-IAD1RCre mice) was achieved by Cre-based recombination driven by the dopamine 1 receptor (D1R) promoter in the C57Bl/6N mouse strain. Riluzole was administered for 14 consecutive days (5 mg/kg, i.p.; 1× daily) starting at six weeks of age. Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4–40 r.p.m.; 5 min). To visualize the potential effects of riluzole treatment, the striata of the animals were stained by immunohistochemistry (IHC) and/or immunofluorescence (IF) with Ki67 (marker of proliferating cells), neuronal markers (NeuN, MAP2, DCX), and markers associated with neurodegeneration (GFAP, 8OHdG, FluoroJade C). Additionally, the morphology of dendritic spines of neurons was assessed by a commercially available FD Rapid Golgi Stain™ Kit.ResultsA comparative analysis of IHC staining patterns with chosen markers for the neurodegeneration process in MSNs did not show an effect of riluzole on delaying the progression of MSN cell death despite an observed enhancement of cell proliferation as visualized by the Ki67 marker. A lack of a riluzole effect was also reflected by the behavioral phenotype associated with MSN degeneration. Moreover, the analysis of dendritic spine morphology did not show differences between mutant and control animals.DiscussionDespite the observed increase in newborn cells in the subventricular zone (SVZ) after riluzole administration, our study did not show any differences between riluzole-treated and non-treated mutants, revealing a similar extent of the neurodegenerative phenotype evaluated in 13-week-old TIF-IAD1RCre animals. This could be due to either the treatment paradigm (relatively low dose of riluzole used for this study) or the possibility that the effects were simply too weak to have any functional meaning. Nevertheless, this study is in line with others that question the effectiveness of riluzole in animal models and raise concerns about the utility of this drug due to its rather modest clinical efficacy.

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REM Sleep Behavior Disorder

Schenck¹

2015

Disorders of Sleep and Circadian Rhythms in Parkinson's Disease

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Neuroprotective effects of riluzole in early phase Parkinson's disease on clinically relevant parameters in the marmoset MPTP model

Cited by 28 publications

References 41 publications

Riluzole neuroprotection in a parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

Riluzole neuroprotection in a parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration

REM Sleep Behavior Disorder

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