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Edaravone for the Treatment of Amyotrophic Lateral Sclerosis
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Edaravone for the Treatment of Amyotrophic Lateral Sclerosis

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 22347

Special Issue Editor

Dr. Hiide Yoshino

E-Mail Website
Guest Editor
Yoshino Neurology Clinic, Ichikawa, Japan
Interests: amyotrophic lateral sclerosis (ALS); edaravone; free radicals; oxidative stress

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Most patients die within 3–5 years from onset. All ALS patients are desperate for new treatment. It took almost 20 years after riluzole approval in 1995 until edaravone was approved in Japan in 2015 and in US in 2017. Although the first phase 3 trial collecting a wide variety of ALS patients failed to show the efficacy of edaravone, the second phase 3 trial succeeded in proving its efficacy in inhibiting the deterioration of motor functions by approximately 33% compared to placebo. The results of these clinical trials tell us early diagnosis is critically important for the benefit of ALS patients to prolong better motor functions for longer. Development of biomarkers for early diagnosis is critically important. At present, edaravone is limited to intravenous administration. The oral formula of edaravone is under clinical trial for 12 months of safety assessment. In order to investigate more efficacious edaravone treatment options, a double-blind study is being launched to show the efficacy of everyday administration compared to current protocol with 10 days in 4 weeks administration. As free radical scavenging has been proven to be a key treatment strategy, further development of new therapeutic agents that target free radicals could lead to better outcomes for ALS treatment.

Dr. Hiide Yoshino
Guest Editor

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Keywords

  • ALS
  • diagnosis
  • treatment
  • edaravone
  • biomarker
  • free radicals
  • oxidative stress
  • clinical trial

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Published Papers (4 papers)

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Research

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17 pages, 2404 KiB  
Article
The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing
by Aki Soejima-Kusunoki, Kinya Okada, Ryuta Saito and Kazuhiko Watabe
Pharmaceuticals 2022, 15(7), 842; https://doi.org/10.3390/ph15070842 - 8 Jul 2022
Cited by 12 | Viewed by 3481
Abstract
Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) [...] Read more.
Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) within the cytoplasm of motor neurons. This study revealed the efficacy of edaravone in preventing neuronal cell death in a TDP-43 proteinopathy model and analyzed the molecular changes associated with the neuroprotection. The viability of the neuronal cells expressing TDP-43 was reduced by oxidative stress, and edaravone (≥10 μmol/L) protected in a concentration-dependent manner against the neurotoxic insult. Differential gene expression analysis revealed changes among pathways related to nuclear erythroid 2-related-factor (Nrf2)-mediated oxidative stress response in cells expressing TDP-43. In edaravone-treated cells expressing TDP-43, significant changes in gene expression were also identified among Nrf2-oxidative response, unfolded protein response, and autophagy pathways. In addition, the expression of genes belonging to phosphatidylinositol metabolism pathways was modified. These findings suggest that the neuroprotective effect of edaravone involves the prevention of TDP-43 misfolding and enhanced clearance of pathological TDP-43 in TDP-43 proteinopathy. Full article
(This article belongs to the Special Issue Edaravone for the Treatment of Amyotrophic Lateral Sclerosis)
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7 pages, 372 KiB  
Article
Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan
by Hideki Houzen, Takahiro Kano, Kazuhiro Horiuchi, Masahiro Wakita, Azusa Nagai and Ichiro Yabe
Pharmaceuticals 2021, 14(8), 705; https://doi.org/10.3390/ph14080705 - 21 Jul 2021
Cited by 9 | Viewed by 5098
Abstract
Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between [...] Read more.
Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2–64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan–Meier analysis, which revealed that the median survival durations were 49 (9–88) and 25 (8–41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS. Full article
(This article belongs to the Special Issue Edaravone for the Treatment of Amyotrophic Lateral Sclerosis)
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Review

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18 pages, 2033 KiB  
Review
Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets
by Kazumoto Shibuya, Ryo Otani, Yo-ichi Suzuki, Satoshi Kuwabara and Matthew C. Kiernan
Pharmaceuticals 2022, 15(4), 433; https://doi.org/10.3390/ph15040433 - 31 Mar 2022
Cited by 11 | Viewed by 4521
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised. Full article
(This article belongs to the Special Issue Edaravone for the Treatment of Amyotrophic Lateral Sclerosis)
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14 pages, 1075 KiB  
Review
Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis
by HaEun Cho and Surabhi Shukla
Pharmaceuticals 2021, 14(1), 29; https://doi.org/10.3390/ph14010029 - 31 Dec 2020
Cited by 82 | Viewed by 7953
Abstract
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive and fatal neurodegenerative disease that leads to a loss of muscle control due to nerve cells being affected in the brain and spinal cord. Some of the common clinical presentations [...] Read more.
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive and fatal neurodegenerative disease that leads to a loss of muscle control due to nerve cells being affected in the brain and spinal cord. Some of the common clinical presentations of ALS include weakness of muscles, changes in behavior, dysfunction in speech, and cognitive difficulties. The cause of ALS is uncertain, but through several studies, it is known that mutations in SOD1 or C9orf72 genes could play a role as a factor of ALS. In addition, studies indicate that an excessive amount of free radicals, the reactive oxygen species (ROS), leads to neuronal damage by the peroxidation of unsaturated fatty acids in the neuronal cells. Edaravone, the newly approved antioxidant drug for ALS, halts the progression of ALS in the early stages through its cytoprotective effect and protects the nerves by reducing ROS. In this review, different aspects of ALS will be discussed, including its pathology, genetic aspect, and diagnosis. This review also focuses on edaravone as a treatment option for ALS, its mechanism of action, and its pharmacological properties. Clinical trials and adverse effects of edaravone and care for ALS patient are also discussed. Full article
(This article belongs to the Special Issue Edaravone for the Treatment of Amyotrophic Lateral Sclerosis)
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