Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Using specific queries for literature search on PubMed, we review here the role of oxidative stress -related mechanisms in Amyotrophic lateral sclerosis, including the involvement of altered mitochondrial function with repercussions in neurodegeneration

Teresa Cunha-Oliveira; Liliana Montezinho; Catarina Mendes; Omidreza Firuzi; Luciano Saso; Paulo J. Oliveira; Filomena S. G. Silva

2020

Scholarcy highlights

  • Amyotrophic lateral sclerosis, known as Lou Gehrig’s disease or Charcot disease, is the most common fatal motor neuron disorder
  • If it is accepted that the excessive reactive oxygen species production is a common pathological feature in ALS patients, there are doubts whether oxidative damage represents a primary cause or a secondary consequence of this disease and what is the real contribution of oxidative stress in ALS progression, considering the different subtypes of patients
  • The mechanisms of OS and mitochondrial dysfunction represent promising therapeutic targets to slow the disease progression, it is of utmost importance to characterize the different OS profiles present in different types of patients, in order to develop personalized therapies that allow retarding the progression of the disease according to the OS profiles of patients
  • Some reasons evidenced are the lack of proper blinding measurements, uniform exclusion criteria, or statistical power associated with the use of a small number of samples per group in animal assays that can lead to false-positive results and confounding biological results
  • It is necessary to invest more on the development of ALS models that can be representative of the different subtypes of this disease, which can support preclinical trials before proceeding to clinical trials
  • Effects Slowed disease progression, delayed Disease onset, did not affect survival time Did not affect the quality of life Did not affect survival time Slowed ALS progression Reduction mROS Increased ATP levels Increased viability Prolonged the survival time Improved motor performance Did not affect survival time Did not affect disease progression Prolonged the survival time No effect on survival time No significant differences between treatment and placebo groups
  • Preclinical trials using other animal models of the disease should be done in parallel with the common mutant SOD1 models, including chromosome 9 open reading frame 72 and TAR DNA-Binding Protein 43 mice models that represent the most prevalent mutation in ALS and the formation of ubiquitinated TDP-43 cytoplasmic inclusions that are expressed in the majority of patients, respectively
  • It is necessary to establish limits of the disease progression, based on oxidative stress profiles, that allow understanding until what stage of the disease a certain compound may have any beneficial effect

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