James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW.
*Department of Pediatrics; and Department of Biostatistics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA.
Research into the metabolic phenotype of autism has been relatively unexplored despite the fact that metabolic abnormalities have been implicated in the pathophysiology of several other neurobehavioral disorders. Plasma biomarkers of oxidative stress have been reported in autistic children; however, intracellular redox status has not yet been evaluated. Lymphoblastoid cells (LCLs) derived from autistic children and unaffected controls were used to assess relative concentrations of reduced glutathione (GSH) and oxidized disulfide glutathione (GSSG) in cell extracts and isolated mitochondria as a measure of intracellular redox capacity. The results indicated that the GSH/GSSG redox ratio was decreased and percentage oxidized glutathione increased in both cytosol and mitochondria in the autism LCLs. Exposure to oxidative stress via the sulfhydryl reagent thimerosal resulted in a greater decrease in the GSH/GSSG ratio and increase in free radical generation in autism compared to control cells. Acute exposure to physiological levels of nitric oxide decreased mitochondrial membrane potential to a greater extent in the autism LCLs, although GSH/GSSG and ATP concentrations were similarly decreased in both cell lines. These results suggest that the autism LCLs exhibit a reduced glutathione reserve capacity in both cytosol and mitochondria that may compromise antioxidant defense and detoxification capacity under prooxidant conditions.-James, S. J., Rose, S., Melnyk, S., Jernigan, S., Blossom, S., Pavliv, O., Gaylor, D.W. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
PMID: 19307255 [PubMed - as supplied by publisher]
1: Neuro Endocrinol Lett. 2005 Oct;26(5):439-46.
· Mutter J,
· Naumann J,
· Schneider R,
· Walach H,
· Haley B.
Institute for Environmental Medicine and Hospital Epidemiology, University Hospital Freiburg, Germany. email@example.com
The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites.
Note: Intracellular glutathione is able to bind to heavy metals such as mercury and make them soluble, to be flushed out of the body naturally, through the urine and the bile.
Prostaglandins Leukot Essent Fatty Acids. 2002 Nov;67(5):341-3.
Investigation of antioxidant enzymes
in children with autistic disorder.
Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T.
GATA Child and Adolescent Psychiatry Department, Etlik, Ankara, Turkey
Impaired antioxidant mechanisms are unable to inactivate free radicals that may induce a number of pathophysiological processes and result in cell injury.
Thus, any abnormality in antioxidant defence systems could affect neurodevelopmental processes and could have an important role in the etiology of autistic disorder.
The plasma levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and erythrocyte levels of GSH-Px were investigated in 45 autistic children and compared with 41 normal controls. Levels of erythrocyte SOD, erythrocyte and plasma GSH-Px were assayed spectrophotometrically.
Activities of erythrocyte SOD,
erythrocyte and plasma GSH-Px in autistic children were significantly lower than
normals. These results indicate that autistic children have low levels of
activity of blood antioxidant enzyme systems; if similar abnormalities are
present in brain, free radical accumulation could damage brain tissue.
PMID: 12445495 [PubMed - in process]
The article above indicates that in cases of autism, glutathione synthesis may be impaired. Glutathione plays a crucial role as a neuro-protectant and facilitates neuro-transmission. As such, replenishing glutathione stores may be beneficial.
36 JANA Vol. 11, No. 1, 2008
Oral Tolerability of Cysteine-Rich Whey Protein Isolate in Autism–A Pilot Study
Janet K. Kern, PhD* University of Texas Southwestern Medical Center, and the Autism Treatment Center, Dallas, Texas, Bruce D. Grannemann, MA; University of Texas Southwestern Medical Center, Dallas, Texas
Jimmy Gutman, MD, FACEP, McGill University, Canada, and Immunotec Corporation, Montreal, Quebec, Canada, Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center, Dallas, Texas
Janet K. Kern, PhD, Autism Treatment Center, 10503 Metric Drive, Dallas, Texas 75243
Phone: 972-644-2076 Fax: 972-644-5650
Purpose: To examine the tolerability of non-denatured whey protein isolate (NWPI) in children with autism. Many children with autism are low in glutathione and have higher levels of oxidative stress. NWPI can raise glutathione levels and reduce oxidative stress. However, anecdotal reports suggest that NWPI may be problematic in children with autism because it contains cysteine and other sulfurated amino acids.
Methods: A 6-week open-label trial was conducted, supplementing 10 children with autism or autism spectrum disorder (ASD), 3-15 years of age, with NWPI (Immunocal®). To measure possible side effects, procedures that examined the frequency, intensity, and types of side effects, as well as behavioral measures, were completed at baseline, and at days 3, 14, 30, and 45.
Results: Seven of the ten children took the supplement over the six-week trial and tolerated it well. Two children discontinued after two weeks due to possible side effects: one due to gastrointestinal disturbance and one due to being less responsive to parents. Another child discontinued due to difficulty of administering the product.
Conclusion: This study suggests that NWPI can be used as a supplement for this small population of children with autism without high rates of side effects, which means that further studies to determine its safety and efficacy in larger populations might yield the same promising result. Larger studies are planned to determine its efficacy in raising glutathione levels.
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M.
Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, NY 10314, New York, USA. firstname.lastname@example.org
This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. Conclusion: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.
PMID: 19157572 [PubMed - indexed for MEDLINE]
Note: Glutathione precursors impact inflammation. Oxidative stress is fuel for the inflammatory process. Reduce oxidative stress and you reduce inflammation. Our bio-active protein does just that. Proven to reduce oxidation. It also has a medical patent proving it will “Improve the active systemic immune response”. Immunocal regulates and modulates the immune system to bring it back into balance.
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