Emerging drugs for amyotrophic lateral sclerosis

Habib, Ali A; Mitsumoto, Hiroshi

doi:10.1517/14728214.2011.604312

Cited by 39 publications

(26 citation statements)

References 245 publications

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“…In familiar cases, which account for only 5 % of all ALS cases, depending on the mutated gene (e.g., TDP-43, FUS, C9orf72), ALS can be accompanied by features of frontotemporal lobar dementia, which supports the idea that, rather than being one disorder, ALS belongs to a spectrum of disorders having motor and cognitive deficits [150]. The disease still lacks an effective treatment for symptoms and/or disease progression, with the antiexcitotoxic agent riluzole (Rilutek, Sanofi Pharmaceuticals, Paris, France) as the only approved medicine [151].…”

Section: Cannabinoids and Chronic Neurodegenerative Disorders: IV Alsmentioning

confidence: 72%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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Section: Cannabinoids and Chronic Neurodegenerative Disorders: IV Alsmentioning

confidence: 72%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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“…Rilutek has been the only drug approved by the US Food and Drug Administration (FDA), but it is limited in efficacy (Habib and Mitsumoto, 2011). Recently, cannabinoids have been shown to have neuroprotective effects in transgenic rodent ALS models (Bilsland and Greensmith, 2008; de Lago et al, 2015, for review).…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Fernández-Trapero

Espejo-Porras

Rodríguez‐Cueto

et al. 2017

Disease Models &Amp; Mechanisms

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Targeting of the CB2 receptor results in neuroprotection in the SOD1G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors are facilitated by their upregulation in the spinal cord of the mutant mice. Here, we investigated whether similar CB2 receptor upregulation, as well as parallel changes in other endocannabinoid elements, is evident in the spinal cord of dogs with degenerative myelopathy (DM), caused by mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in expression of the CB1 receptor (confirmed with CB1 receptor immunostaining) or NAPE-PLD, DAGL, FAAH and MAGL enzymes. In contrast, CB2 receptor levels were significantly elevated in DM-affected dogs determined by qPCR and western blotting, which was confirmed in the grey matter using CB2 receptor immunostaining. Using double-labelling immunofluorescence, CB2 receptor immunolabelling colocalized with GFAP but not Iba-1, indicating upregulation of CB2 receptors on astrocytes in DM-affected dogs. Our results demonstrate a marked upregulation of CB2 receptors in the spinal cord in canine DM, which is concentrated in activated astrocytes. Such receptors could be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.

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“…Characterized by selective and progressive death of motor neurons within the brain and spinal cord, it leads to paralysis of voluntary muscles and, eventually, death within five years of clinical onset [1], [2]. Although most cases of ALS occur sporadically with unknown etiology, approximately 10% are inherited in an autosomal dominant manner [3].…”

Section: Introductionmentioning

confidence: 99%

“…Transgenic mice expressing the same SOD1 mutations as human, in particular the G93A point mutation, exhibit similar histopathological and clinical phenotypes as ALS patients [4], [5], and hence have been widely used to elucidate mechanisms inducing ALS pathology as well as to screen for potential therapeutics [4]. Presently, however, riluzole, an anti-excitotoxic agent that reduces the release of presynaptic glutamate, is the sole agent approved for ALS treatment [1], [2], [6]. Whereas riluzole provides some survival benefit, extending lifespan by 3–5 months, it does not significantly modify muscle strength or functional outcome.…”

Section: Introductionmentioning

confidence: 99%

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Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.

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Emerging drugs for amyotrophic lateral sclerosis

Cited by 39 publications

References 245 publications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

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