Peer Review #2 of "Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration (v0.2)"
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Background.Huntington'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.Methods.Selective ablation of TIF-IA in MSNs (TIF-IA D1RCre 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.; 1x daily) starting at 6 weeks of age.Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4 to 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. Results.A 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.Discussion.Despite 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-IA D1RCre 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.Keywords:
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Treatment with riluzole may provide clinical benefits for patients with amyotrophic lateral sclerosis, including longer survival time, reduced risk of disease progression, and minor reversible adverse events, compared to no treatment with riluzole or a placebo.
We did not find any studies meeting our selection criteria on the clinical effectiveness of riluzole for patients with amyotrophic lateral sclerosis compared to alternative pharmacological therapies.
Riluzole may be cost-effective at generic drug costs for patients with amyotrophic lateral sclerosis. Evidence supporting this finding is limited, and further research is required to inform decision-making.
Riluzole is recommended for the treatment of amyotrophic lateral sclerosis, except for patients with progressive muscular atrophy, primary lateral sclerosis, or hereditary spastic paraplegia, and should be initiated promptly following disease diagnosis.
A patient with lived experience of riluzole treatment for amyotrophic lateral sclerosis was involved in this report. They identified outcomes that are important to patients, including slowing the progression of amyotrophic lateral sclerosis and minimal side effects from the medication.
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Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis.
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Around one in 20,000 adults in the UK will develop amyotrophic lateral sclerosis, the commonest variant of motor neurone disease. Riluzole (Rilutek-Rhône-Poulenc Rorer) was launched in the UK in August 1996 as "the first anti-excitotoxic agent proven to extend life in amyotrophic lateral sclerosis". We review the clinical data on the effectiveness of riluzole and assess its place in the management of amyotrophic lateral sclerosis, a condition that is invariably fatal and has a median survival time from symptom onset of about 2.5 years.
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Glutamate-mediated excitotoxicity is one of the mechanisms responsible for motor neuron damage in amyotrophic lateral sclerosis. Decreased glutamate transport may result in elevated extracellular glutamate levels,1and both riluzole and gabapentin block presynaptic release of glutamine.2Riluzole prevents neuronal degeneration in vitro3and delays progression of disease in patients with amyotrophic lateral sclerosis.4Fasciculations, a hallmark of amyotrophic lateral sclerosis, are a manifestation of "sick" motor neurons. They typically decrease with progression of the disease. While waiting for riluzole to be made available, we have been using gabapentin for our patients with amyotrophic lateral sclerosis with the expectation that it will act like riluzole in preventing progression of disease. Of 31 patients who were prescribed gabapentin, 10 reported a decrease in fasciculations within 2 weeks of reaching the dose of 300 mg 3 times a day. In 5 of these patients, the reduction was described as
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Background: In an attempt to better understand and define the progression of amyotrophic lateral sclerosis (ALS), we developed a classification of 5 discrete health states that reflect patients' activities of daily living.These health states were used to determine whether patients with ALS who are treated with riluzole differed from those treated with placebo.Setting: Clinics for patients with ALS.Design: Placebo-controlled trial of riluzole treatment in 959 patients with ALS.Interventions: Treatment with riluzole or placebo. Main Dependent Measures:A Cox model was used to assess whether, from the initial randomization to the end of an 18-month follow-up, there was a difference in the times of transition into subsequent health states between patients treated with riluzole and those treated with placebo.Results: Our analysis showed a significant difference in the time to transit between the riluzole and the placebo groups in less severely affected cases, ie, state 2 and state A (the milder states) of ALS. Conclusion:Patients receiving riluzole remained in the milder health states longer (PϽ.05).
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Background and aim: There is no study on the use of riluzol in patients with amyotrophic lateral sclerosis in Costa Rica. The objective of this study was to assess the impact of riluzole on clinical
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Background: amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease with high mortality and few therapies. One of these is riluzole, inspite of uncertainty effectiveness. Objective: the aim of this study was to evaluate the survival rate associated with the use of this medication in the treatment of ALS. Methods: The study was based on a narrative review of the scientific articles that used randomized controled trials with riluzole for ALS. We selected articles published in english during the period of January 1th, 2000 to December 31th, 2020. The MeSH terms “amyotrophic lateral sclerosis” or “motor neuron disease” and “riluzole” or “rilutek” were used in Pubmed and Lilacs databases. Studies that used only patients with advanced stage ALS were excluded. The t-Student test between sample means was applied to determine the significance of the difference between the survival time (years) of the riluzole and placebo treatment, for a 95% confidence level. Results: through the search, four articles were obtained (Table 1). Conclusion: Data analysis showed that riluzole is only effective in the first year. From the second onward, it does not exceed the results of the placebo.
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