Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis

Dorst, Johannes; Ludolph, Albert C.; Huebers, Annemarie

doi:10.1177/1756285617734734

Cited by 75 publications

(67 citation statements)

References 104 publications

(143 reference statements)

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“…In terms of disease‐modifying treatment options, several drugs have been tested in large multicentre trials for ALS, but albeit encouraging results, only riluzole and edaravone are FDA‐approved therapeutics available to patients . The present study establishes that the administration of histidine during the symptomatic phase enhancing histaminergic transmission in the SOD1‐G93A transgenic mouse model mitigates a broad range of disease phenotypes associated with ALS.…”

Section: Discussionmentioning

confidence: 62%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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Background Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti‐inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine‐mediated therapeutic strategy in ALS mice. Methods We adopted an integrative multi‐omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)‐G93A mice that recapitulate key ALS features, with the brain‐permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1‐G93A motor neuron‐like cells. Results We identified 13 histamine‐related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine‐related genes overlapped with genomic regions disrupted by DNA copy number and with ALS‐linked pathogenic variants. Histidine treatment in SOD1‐G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro . Conclusions Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine‐related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi‐gene network responsible for ALS and, furthermore, in the drug development process.

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Section: Discussionmentioning

confidence: 62%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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“…Single‐factor or single‐target treatments such as antioxidants alone seem unlikely to stop ALS progression due to the multifactorial nature of ALS . Multifactorial combination therapy or multitargets therapy may be a choice for ALS treatment such as riluzole, which not only modulates glutamatergic transmission, but also modulates sodium channel current and inhibits neurotransmitter release . As an old drug for the treatment of epilepsy, CBZ also shows neuroprotective effects through a variety of mechanisms including inhibition of glutamate release, antagonizing glutamate receptor and modulating signal transduction .…”

Section: Discussionmentioning

confidence: 99%

Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model

et al. 2018

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“…The first one is riluzole, a drug targeting excitotoxicity, the second one is edavarone, an antioxidant agent able to scavenge lipid peroxides and hydroxyl radicals . However, both these therapies only provide a mitigation of the symptoms . Regarding other antioxidants for ALS treatment, AEOL 10150 is the most promising.…”

Section: Neurological Diseases Associated To Oxidative Stressmentioning

confidence: 99%

Antioxidants and Nanotechnology: Promises and Limits of Potentially Disruptive Approaches in the Treatment of Central Nervous System Diseases

Martinelli

Pucci

Battaglini

et al. 2019

Adv Healthcare Materials

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Many central nervous system (CNS) diseases are still incurable and only symptomatic treatments are available. Oxidative stress is suggested to be a common hallmark, being able to cause and exacerbate the neuronal cell dysfunctions at the basis of these pathologies, such as mitochondrial impairments, accumulation of misfolded proteins, cell membrane damages, and apoptosis induction. Several antioxidant compounds are tested as potential countermeasures for CNS disorders, but their efficacy is often hindered by the loss of antioxidant properties due to enzymatic degradation, low bioavailability, poor water solubility, and insufficient blood–brain barrier crossing efficiency. To overcome the limitations of antioxidant molecules, exploitation of nanostructures, either for their delivery or with inherent antioxidant properties, is proposed. In this review, after a brief discussion concerning the role of the blood–brain barrier in the CNS and the involvement of oxidative stress in some neurodegenerative diseases, the most interesting research concerning the use of nano‐antioxidants is introduced and discussed, focusing on the synthesis procedures, functionalization strategies, in vitro and in vivo tests, and on recent clinical trials.

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Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis

Cited by 75 publications

References 104 publications

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model

Antioxidants and Nanotechnology: Promises and Limits of Potentially Disruptive Approaches in the Treatment of Central Nervous System Diseases

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