Autism

Targeting Oxidative Stress in Patients with Autism: Possible Management Strategies

oxidative stress autism

When parents of children with autism spectrum disorder (ASD) ask what causes the condition, the answers are never satisfying. Indeed, treatment would be far easier if researchers could pinpoint a single causative factor, but the reality is that there is a wide range of genetic and environmental forces that come together to initiate cellular processes that ultimately contribute to the characteristic symptoms. Given this complex etiology, the most promising therapeutic strategies for managing autism involve targeting the cellular processes that are believed to contribute most to the development and exacerbation of the condition. Today, researchers understand oxidative stress as one of the key cellular processes, spurring interest in finding all-natural nutritional supplements that reduce oxidative stress in order to improve outcomes for patients with autism.

Oxidative Stress in Patients with Autism

Within the biomedical community, oxidative stress is broadly defined as a state in which the production of reactive oxidative species outweighs the cell’s antioxidant defenses. In the brain, this imbalance has the potential to trigger neurotoxic pathways that fundamentally damage brain cells and may have functional effects ranging from memory loss to the exacerbation of symptoms of psychiatric disorders. Currently, there is a strong body of scholarly literature linking high levels of oxidative stress to autism. Based on a systematic review of meta-analyses from 2012 published in the journal Free Radical Biology & Medicine, researchers were able to conclude that there are multiple oxidative stress-related biomarkers associated with autism, including lower plasma levels of reduced glutathione (GSH), higher levels of oxidized glutathione (GSSG), and lower levels of glutathione peroxidase, methionine, and cysteine. The data from this comprehensive systematic review supports the notion that oxidative stress plays a central role in the pathogenesis of autism. Therefore, oxidative stress-related cellular pathways may be ideal targets for innovative therapies in the future.

The Relationship Between Glutathione Levels and Autism

As a naturally occurring antioxidant in the brain, glutathione is heavily involved in the protection of neurons from the damage that can result from oxidative stress. However, multiple studies have shown that patients with autism have unusually low levels of glutathione, and the ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is also altered in patients with autism. Specifically, the proportion of the reduced form (GSH) is lower than the proportion of the oxidized form (GSSG), suggesting a chronic state of oxidative stress. The recognition of the imbalance between GSH and GSSG has led researchers to consider whether restoring GSH levels in patients with autism may help alleviate symptoms, since oxidative stress may damage brain cells in ways that have direct clinical impacts.

Although the evidence supporting the benefits of glutathione supplementation for patients with autism is limited, the early results are promising. In 2011, a group of researchers associated with the University of Texas Southwestern Medical Center conducted a small-scale, open-label study in which 13 male patients with autism between the ages of 3 and 13 took oral and transdermal formulations of glutathione. They observed a significant increase in plasma levels of reduced glutathione (GSH), as well as other antioxidants like sulfate and cysteine. This suggests that glutathione may be an effective nutritional supplement for patients with autism. Therefore, the researchers called for more comprehensive studies in the future, with larger sample sizes and greater attention to the behavioral effects of the treatment.

Promising Links: Oxidative Stress, Mitochondrial Function, and Butyrate

One of the ways in which oxidative stress specifically harms brain cells is by interfering with the function of mitochondria. Mitochondria are key organelles that are involved in essential aspects of cellular function, including energy metabolism and longevity, and some studies suggest that the significant effects of oxidative stress in patients with autism are mediated by an increase in mitochondrial dysfunction. Intriguingly, one possible way to combat this phenomenon may be to increase cellular exposure to butyrate, a short chain fatty acid. Butyrate is normally derived from bacteria in the gut microbiome when they digest fiber, but the latest research indicates that the microbiomes of patients with autism are different from those of healthy patients. This may result in a butyrate deficiency, which could be resolved through butyrate supplementation.

This proposal was recently supported by a cutting-edge 2018 study out of the University of Arkansas, in which researchers conducted an in vitro study using cell lines from the brains of young male patients with autism. They found that when the cells were exposed to butyrate during oxidative stress, it enhanced mitochondrial function. These results suggest that the compound may rescue mitochondrial function during oxidative stress, thereby interfering with the oxidative stress-related physiological processes that underpin autism. Although future clinical studies on butyrate supplementation are needed to confirm this laboratory evidence and assess the potential real-world implications for patients, this early research provides an exciting opening for researchers and clinicians who are interested in finding ways to help patients with autism by reducing the impacts of oxidative stress.

Acting on the Connections Between Oxidative Stress and Autism

Right now, there is not yet enough research evidence to definitively determine whether therapeutic strategies to combat oxidative stress will lead to observable effects in patients with autism. However, given the strong evidentiary backing that oxidative stress plays a key role in the pathophysiology of the disorder, there is no doubt within the research community that it is an avenue worth exploring. For patients and practitioners dealing with autism, it may be worth acting on these connections by trying supplementation with compounds like glutathione and butyrate in order to assess the possible impacts on individual patients.

Foundational Medicine Review examines cutting-edge studies alongside the established research literature to help patients, parents, practitioners, and investigators understand the complexities of conditions like autism, as well as a wide range of other diseases and disorders. Join our mailing list today to stay up-to-date with the latest in biomedical science.

Works Cited

Bhanizadeh A, Azkhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A. 2012. Glutathione-related factors and oxidative stress in autism, a review. Current Medicinal Chemistry. 19(23): 4000-5. https://www.ncbi.nlm.nih.gov/pubmed/22708999

Burton GJ, Jauniaux E. 2011. Oxidative stress. Best Practice and Research in Clinical Obstetrics and Gynecology. 25(3): 287-99. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101336/

Calabrese V, Lodi R, Tonon C, D’Agata V, Sapienza M et al. 2005. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedrich’s ataxia. Journal of the Neurological Sciences. 2333(1-2): 145-62. https://www.ncbi.nlm.nih.gov/pubmed/15896810

Frustaci A, Neri M, Cesario A, Adams JB, Domenici E et al. 2012. Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radical Biology & Medicine. 52(10): 2128-41. https://www.ncbi.nlm.nih.gov/pubmed/22542447

Kern JK, Geier DA, Adams JB, Carver CL, Audhya T, Geier MR. 2011. A clinical trial of glutathione supplementation in autism spectrum disorders. Medical Science Monitor. 17(12): CR677-82. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628138/

Matsuzaki H, Iwata K, Manabe T, Mori N. 2012. Triggers for autism: Genetic and environmental factors. Journal of Central Nervous System Disease. 4: 27-36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619552/

Rose S, Bennuri S, Davis J, Wynne R, Slattery JC et al. 2018. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. Translational Psychiatry. 8:42. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804031/

Rossignol DA, Frye RE. 2014. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Frontiers in Physiology. 5: 150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001006/

Strati F, Cavelieri D, Albanese D, DeFelice C, Donati C, Hayek J, et al. 2017. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 5:24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320696/

Yui K, Kawasaki Y, Yamada H, Ogawa S. 2016. Oxidative stress and nitric oxide in autism spectrum disorder and other neuropsychiatric disorders. CNS & Neurological Disorders Drug Targets. 15(5): 587-96. https://www.ncbi.nlm.nih.gov/pubmed/27071787

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