About this item:

228 Views | 241 Downloads

Author Notes:

Correspondence: Cassie S. Mitchell cassie.mitchell@bme.gatech.edu

LB: data collection, statistical analysis of in vivo data, results interpretation, drafting of initial manuscript.

KB: framing of study concept, data collection, statistical analysis of HSP data, drafting of initial manuscript.

PM: data collection, statistical analysis of In vitro data, drafting of initial manuscript.

KS: data collection, analysis of in vivo data, review of critical content.

HS: data collection, analysis of In vitro data, review of critical content.

CM: framing of study, project oversight, results interpretation, drafting of final manuscript, review of critical content.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

Financial support provided by National Institute of Health grant NS069616, NS081426, and NS098228 to CM.

Keywords:

  • HSP70
  • oxidants
  • glutamate
  • rotarod
  • motoneuron disease
  • antioxidants
  • vitamins

A metadata analysis of oxidative stress etiology in preclinical Amyotrophic Lateral Sclerosis: Benefits of antioxidant therapy

Tools:

Journal Title:

Frontiers in Neuroscience

Volume:

Volume 12, Number JAN

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1) accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70-90% of cell death coincides to inducer exposure equivalent to 30-50% peak concentration (p < 0.05). A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs) revealed HSP levels are 30% lower in muscle than spine (p < 0.1). Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05). Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p < < 0.001) but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature. Nonetheless, antioxidant-treated SOD1-G93A ALS mice have significantly increased motor performance (p < 0.05) measured via rotarod. With a colossal aggregate preclinical effect size average of 59.6%, antioxidants are promising for increasing function/quality of life in clinical ALS patients, a premise worth exploration via low-risk nutritional supplements. Finally, more direct, quantitative measures of oxidative stress, antioxidant levels and bioavailability are key to developing powerful antioxidant therapeutics that can assert measurable impacts on redox homeostasis in the brain and spinal cord.

Copyright information:

© 2018 Bond, Bernhardt, Madria, Sorrentino, Scelsi and Mitchell.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote