A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy.

Leila Bond,Katherine Sorrentino,Hailee Scelsi,Kamren Bernhardt,Cassie S Mitchell,Priyank Madria

doi:10.3389/fnins.2018.00010

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons throughout the nervous system (Irvin et al, 2015)
In vivo heat shock proteins were examined in aggregate to quantify the response magnitude of innate biological mechanisms meant to compensate for oxidative stress
In vivo antioxidant treatments were analyzed to determine their aggregate, average impact on temporal functional disease measurements, including muscle function assessed via rotarod, ALS symptom onset age, and time of death

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons throughout the nervous system (Irvin et al, 2015). The multi-factorial and multi-scalar nature of ALS (Mitchell and Lee, 2012b; Irvin et al, 2015; Kim et al, 2016) has made etiological and therapeutic exploration difficult. The precise impact of oxidative stress, one of the first identified contributors to ALS neurodegeneration, has remained elusive. Extensive research continues to be conducted on ALS pathophysiology, including oxidative stress, in transgenic ALS mouse models. The superoxide disumutase-1 glycine 93 to alanine (SOD1-G93A) transgenic mouse is the most common preclinical model for these kinds of research projects (Pfohl et al, 2015). The high copy SOD1-G93A B6SJL transgenic mouse reliably produces an ALS phenotype with an average onset and lifespan of 99 and 130 days, respectively, (Pfohl et al, 2015)

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