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Review
. 2022 Feb 22;23(5):2400.
doi: 10.3390/ijms23052400.

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

Belgin Sever  1   2 , Halilibrahim Ciftci  2   3   4 , Hasan DeMirci  4 , Hilal Sever  5 , Firdevs Ocak  6 , Burak Yulug  7 , Hiroshi Tateishi  2 , Takahisa Tateishi  8 , Masami Otsuka  2   3 , Mikako Fujita  2 , Ayşe Nazlı Başak  9
Affiliations
Review

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

Belgin Sever et al. Int J Mol Sci. .

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.

Keywords: amyotrophic lateral sclerosis (ALS); apoptosis; axonal degeneration; edaravone; glutamate excitotoxicity; induced pluripotent stem cells (iPSCs); neuroinflammation; oxidative stress; protein aggregation; riluzole.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Some pathologic mechanisms in the central nervous system (CNS) related to the formation of ALS. Illustrations use elements from Servier Medical Art [28].
Figure 2
Figure 2
Design of a phenol-like compound (a), optimization of edaravone (b) [50,51].
Figure 3
Figure 3
Reaction mechanism of edaravone with free radicals [52].
Figure 4
Figure 4
Synthetic route for edaravone.
Figure 5
Figure 5
Therapeutics against oxidative stress.
Figure 6
Figure 6
Therapeutics against oxidative stress via protein aggregation.
Figure 7
Figure 7
Therapeutics against mitochondrial dysfunction.
Figure 8
Figure 8
One-pot synthetic routes for riluzole.
Figure 9
Figure 9
Therapeutics against glutamate-induced excitotoxicity.
Figure 10
Figure 10
Hypothesis of the ALS pathomechanism in dividing and non-dividing cells [146]. Illustrations use elements from Servier Medical Art [28].
Figure 11
Figure 11
Therapeutics for reducing apoptosis and/or boosting autophagy.
Figure 12
Figure 12
Therapeutics against for neuroinflammation.
Figure 13
Figure 13
Fasudil, a promising ROCK inhibitor for alleviation of axonal degeneration.
Figure 14
Figure 14
Therapeutics against skeletal muscle deterioration.
Figure 15
Figure 15
A potential combination of lamivudine, abacavir and dolutegravir to be effective in ALS.
Figure 16
Figure 16
Erlotinib, an important EGFR inhibitor.
Figure 17
Figure 17
Newly synthesized and evaluated compounds as anti-ALS agents.
See this image and copyright information in PMC

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