Abstract
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.
Highlights
Amyotrophic Lateral Sclerosis (ALS), known as Lou Gehrig’s or Charcot disease, is characterized by progressive deterioration of the upper and lower motor neurons in the brain and spinal cord, which leads to muscle weakness, paralysis and, death due to respiratory failure within three to five years after the onset of the symptoms
Another dopamine receptor agonist used in the treatment of Parkinson’s disease (PD), ropinirole (Figure 5), was identified as a potential therapeutic candidate for Amyotrophic lateral sclerosis (ALS) treatment from a large number of agents screened for the evaluation of multiple-phenotype rescue of sub-classified sALS models generated by using induced pluripotent stem cells (iPSCs) [66]
Ebselen forms a covalent bond with SOD1-Cys111 and repairs the monomer–dimer equilibrium of SOD1A4V to wildtype, acting as a potent bifunctional pharmacological chaperone for SOD1 endowed with combinatory properties of human copper chaperone for SOD1 and edaravone
Summary
Amyotrophic Lateral Sclerosis (ALS), known as Lou Gehrig’s or Charcot disease, is characterized by progressive deterioration of the upper and lower motor neurons in the brain and spinal cord, which leads to muscle weakness, paralysis and, death due to respiratory failure within three to five years after the onset of the symptoms. Major breakthroughs great promise for the treatment of both fALS andiPSCs sALS.can iPdifferentiate into specific cell phenotypes, such as motor neurons and astrocytes, the main. Motor neurons generated from iPSCs derived from somatic the main targets in ALS pathophysiology. An ALS-on-a-chip technology using the 3D-model of the motor unit derived from iPSCs was developed to provide a platform for screening drug candidates and researching the pathogenesis of ALS [44]. Another approach for ALS treatment is using non-invasive brain stimulation (NIBS). Some combinatorial approaches such as molecular hybridization, drug repurposing and iPSCs-based phenotypic screening are discussed in order to be useful for future applications in ALS drug discovery
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