In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

Kukharsky, Michail S.; Skvortsova, Veronika; Бачурин, С. О.; Buchman, Vladimir L.

doi:10.1002/med.21725

Cited by 17 publications

(12 citation statements)

References 248 publications

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“…In the pursuit of alternative and more efficacious treatments, a promising strategy relies on drug repurposing for the identification of novel uses (outside the scope of original medical indications) of drugs already approved by the US Food and Drug Administration (FDA) [11,12].…”

Section: Highlightsmentioning

confidence: 99%

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis

et al. 2021

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The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.

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Section: Highlightsmentioning

confidence: 99%

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis

et al. 2021

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“…A colony stimulating factor 1R receptor (CSF1R) and c-kit inhibitor, masitinib ( Figure 12 ), is effective against microglial, macrophage and mast cell activation. It has been given the orphan drug status and screened for treatment of various disorders [ 173 , 174 ]. Masitinib restrained CSF-induced proliferation, cell migration and the expression of inflammatory mediators in microglia cultures from symptomatic SOD1 G93A spinal cords [ 175 ] and post paralysis treatment of SOD1 G93A mice.…”

Section: Therapeutic Strategies For Als Targetsmentioning

confidence: 99%

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Sever

Çi̇ftçi̇

DeMi̇rci̇

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

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“…Suggested mechanisms of action for these two drugs are different; Riluzole is believed to be neuroprotective because of its ability to block glutamate excitotoxicity, whereas Edaravone acts as a scavenger of oxygen radicals (reviewed in Refs1,2). A growing number of re‐purposed and new drugs as well as alternative therapeutic approaches entering clinical trials (for recent review, see Refs3,4) raise hope that efficient treatment of different forms of familial and sporadic ALS could be achieved by designing tailored combinations of traditional pharmacological and modern biomedical approaches. Therefore, a search for potential components of efficient ALS therapy should include various types of potentially neuroprotective drugs, particularly those with pleiotropic effects on physiological and pathological processes in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

et al. 2021

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Aims To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre‐symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA‐seq was used to compare the spinal cord transcriptomes of wild‐type, untreated, and DF402‐treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre‐symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.

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In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

Cited by 17 publications

References 248 publications

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

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