Pre-clinical study of 21 approved drugs in the mdx mouse

Carre-Pierrat, Maïté; Lafoux, Aude; Tanniou, Guillaume; Chambonnier, Lucie; Divet, Alexandra; Fougerousse, Françoise; Huchet-Cadiou, Corinne; Ségalat, Laurent

doi:10.1016/j.nmd.2011.01.005

Cited by 20 publications

(14 citation statements)

References 46 publications

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“…The reason for this neutralization is unclear. Similar loss of beneficial effects has been shown, for instance, for imipramine in mdx mice [49]. As known from human clinical trials, the dose of a drug has to be optimized as an increase may abolish beneficial effects, due, for instance, by inducing unwanted side effects.…”

Section: Discussionsupporting

confidence: 56%

Influence of Methylene Blue on Microglia-Induced Inflammation and Motor Neuron Degeneration in the SOD1G93A Model for ALS

et al. 2012

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Mutations in SOD1 cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Pathophysiology of the disease is non-cell-autonomous, with toxicity deriving also from glia. In particular, microglia contribute to disease progression. Methylene blue (MB) inhibits the effect of nitric oxide, which mediates microglial responses to injury. In vivo 2P-LSM imaging was performed in ALS-linked transgenic SOD1G93A mice to investigate the effect of MB on microglia-mediated inflammation in the spinal cord. Local superfusion of the lateral spinal cord with MB inhibited the microglial reaction directed at a laser-induced axon transection in control and SOD1G93A mice. In vitro, MB at high concentrations inhibited cytokine and chemokine release from microglia of control and advanced clinical SOD1G93A mice. Systemic MB-treatment of SOD1G93A mice at early preclinical stages significantly delayed disease onset and motor dysfunction. However, an increase of MB dose had no additional effect on disease progression; this was unexpected in view of the local anti-inflammatory effects. Furthermore, in vivo imaging of systemically MB-treated mice also showed no alterations of microglia activity in response to local lesions. Thus although systemic MB treatment had no effect on microgliosis, instead, its use revealed an important influence on motor neuron survival as indicated by an increased number of lumbar anterior horn neurons present at the time of disease onset. Thus, potentially beneficial effects of locally applied MB on inflammatory events contributing to disease progression could not be reproduced in SOD1G93A mice via systemic administration, whereas systemic MB application delayed disease onset via neuroprotection.

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Section: Discussionsupporting

confidence: 56%

Influence of Methylene Blue on Microglia-Induced Inflammation and Motor Neuron Degeneration in the SOD1G93A Model for ALS

et al. 2012

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“…In addition, amitriptyline reduced muscle inflammation, which may not only contribute to improvements in skeletal muscle function in mdx mice (Carre‐Pierrat et al . ), but may also help to ameliorate emotional disturbances related to inflammation. These data provide evidence for beneficial effects of amitriptyline in treating dystrophin deficiency‐related dysfunction both in the brain and in skeletal muscle.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, changes in the muscular state following amitriptyline treatment could contribute to a reduction of periods of immobility in the TST, but this would challenge findings of a beneficial effect of amitriptyline on muscle function in mdx mice (Carre‐Pierrat et al . ).…”

Section: Discussionmentioning

confidence: 97%

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Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy

Manning

Kulbida

Rai

et al. 2014

Experimental Physiology

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New Findings r What is the central question of this study?Individuals suffering from Duchenne muscular dystrophy show progressive deterioration of muscle function associated with muscle inflammation and are susceptible to anxiety and depression. The central question in this study is whether the tricyclic antidepressant amitriptyline can alleviate symptoms of anxiety and depression, and at the same time has anti-inflammatory effects in mdx mice, which are a model of Duchenne muscular dystrophy. r What is the main finding and its importance?Amitriptyline reduced inflammation and cytokines in mdx skeletal muscle, and had anxiolytic and antidepressant effects in mdx mice. Moreover, amitriptyline elevated the level of serotonin but reduced the expression of the cytokine interleukin-6 in the amygdala of mdx mice.Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin-deficient mdx mice are considered a model for Duchenne muscular dystrophy (DMD). Individuals with DMD are also susceptible to mood disorders, such as depression and anxiety. Therefore, the study objectives were to investigate the effects of the tricyclic antidepressant amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline-induced effects (10 mg kg −1 daily s.c. injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice, and mood-associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. The mdx mice exhibited increased levels of anxiety and depressive-like behaviour compared with wild-type mice. Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour

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“…The available evidence therefore suggests that fluoxetine can prevent the establishment of dystrophy but may not be able to reverse the pathology once it has become established. It is noteworthy that serotonin was discovered to reduce muscle degeneration in a C. elegans model of dystrophin-deficiency [104] but not when evaluated in the mdx mouse [105].…”

Section: Selective Serotonin Re-uptake Inhibitorsmentioning

confidence: 99%

Discovery of Novel Therapeutics for Muscular Dystrophies using Zebrafish Phenotypic Screens

Widrick

Kawahara

Alexander

et al. 2019

JND

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The recent availability and development of mutant and transgenic zebrafish strains that model human muscular dystrophies has created new research opportunities for therapeutic development. Not only do these models mimic many pathological aspects of human dystrophies, but their small size, large clutch sizes, rapid ex utero development, body transparency, and genetic tractability enable research approaches that would be inconceivable with mammalian model systems. Here we discuss the use of zebrafish models of muscular dystrophy to rapidly screen hundreds to thousands of bioactive compounds in order to identify novel therapeutic candidates that modulate pathologic phenotypes. We review the justification and rationale behind this unbiased approach, including how zebrafish screens have identified FDA-approved drugs that are candidates for treating Duchenne and limb girdle muscular dystrophies. Not only can these drugs be re-purposed for treating dystrophies in a fraction of the time and cost of new drug development, but their identification has revealed novel, unexpected directions for future therapy development. Phenotype-driven zebrafish drug screens are an important compliment to the more established mammalian, target-based approaches for rapidly developing and validating therapeutics for muscular dystrophies.

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Pre-clinical study of 21 approved drugs in the mdx mouse

Cited by 20 publications

References 46 publications

Influence of Methylene Blue on Microglia-Induced Inflammation and Motor Neuron Degeneration in the SOD1G93A Model for ALS

Influence of Methylene Blue on Microglia-Induced Inflammation and Motor Neuron Degeneration in the SOD1G93A Model for ALS

Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy

Discovery of Novel Therapeutics for Muscular Dystrophies using Zebrafish Phenotypic Screens

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