Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future

Harikrishnareddy, Dibbanti; Misra, Shubham; Upadhyay, Sujata; Modi, Manish; Medhi, Bikash

doi:10.1515/revneuro-2014-0057

Cited by 7 publications

(4 citation statements)

References 56 publications

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“…In this regard, neuroinflammation and the associated increased oxidative stress damage has been implicated in the pathogenesis of several diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and others (reviewed in refs. [10][11][12][13][14][15]. Given the important role of peripheral blood mononuclear cells (PBMCs) in humoral and cell-mediated immunity (indicating their need for a readily available intracellular source of energy) and that FMR1 is highly expressed in PBMCs (16), it is tempting to propose that deficits recorded in PBMCs mirror the ones in neurons, which are more relevant to a disease with neurologic and emotional deficits.…”

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confidence: 99%

Warburg effect linked to cognitive‐executive deficits inFMR1premutation

et al. 2016

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A 55-200 CGG repeat expansion in the 5'-UTR of the fragile X mental retardation 1 (FMR1) gene is known as a premutation. Some carriers are affected by the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency, and neurobehavioral impairments. Based on the mitochondrial dysfunction observed in fibroblasts and brain samples from carriers, as well as in neurons and brains from a mouse model of the premutation, we evaluated the presence of the Warburg effect in peripheral blood mononuclear cells (PBMCs) from 30 premutation carriers with either a rebalance of the metabolism [increasing glycolysis while decreasing oxidative phosphorylation (oxphos)] or a metabolic amplification (increasing glycolysis while maintaining/increasing oxphos). Deficits in oxphos-more pronounced in FXTAS-affected subjects-were accompanied by a shift toward glycolysis, suggesting increased glycolysis despite aerobic conditions. Differential proteomics extended these findings, unveiling a decreased antioxidant response, translation, and disrupted extracellular matrix and cytoskeleton organization with activation of prosenescence pathways. Lower bioenergetics segregated with increased incidence of low executive function, tremors, below-average IQ, and FXTAS. The combination of functional and proteomic data unveiled new mechanisms related to energy production in the premutation, showing the potential of being applicable to other psychiatric disorders to identify endophenotype-specific responses relevant to neurobiology.-Napoli, E., Song, G., Schneider, A., Hagerman, R., Eldeeb, M. A. A. A., Azarang, A., Tassone, F., Giulivi, C. Warburg effect linked to cognitive-executive deficits in FMR1 premutation.

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confidence: 99%

Warburg effect linked to cognitive‐executive deficits inFMR1premutation

et al. 2016

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“…A new GSK-3β inhibitor, 6-chloro-8-((3-(pyridin-4-yl)propyl)amino)-[ 1 , 2 , 4 ]triazolo[4,3- a ]pyridin-3(2 H )-one (JGK-263) ( Figure 17 ) was developed, and its improved viability and neuroprotection was determined in normal and SOD1 wild/mutant NSC34 cell lines [ 209 ]. It was also observed that JGK-263 improved motor function and delayed the time until symptom onset and death in SOD1 G93A ALS mice model.…”

Section: Therapeutic Strategies For Als Targetsmentioning

confidence: 99%

“…Furthermore, sialorrhea usually occurs in ALS patients owing to dysphagia, and increased saliva production can result in aspiration pneumonia. In general, ALS patients also suffer from depression and anxiety [ 3 , 4 ].…”

Section: Introductionmentioning

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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“…Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens [8]. However, r ecent knowledge in the molecular pathways behind ALS together with new trends in clinical trial design s has provided hope for effective therapies in the future [9,10]. Here, Table 1 New ALS biomarkers in clinical studies 2.…”

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confidence: 99%

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis

Martı́nez

Palomo

Pérez

et al. 2017

Expert Opinion on Investigational Drugs

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Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.

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Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future

Cited by 7 publications

References 56 publications

Warburg effect linked to cognitive‐executive deficits inFMR1premutation

Warburg effect linked to cognitive‐executive deficits inFMR1premutation

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

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis

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