Oxidative stress leads to mitochondria impairment and diminished levels of protective glutathione
Autism, is a a group of neuro-developmental disorders that manifest as repetitive behavior, restricted communication and impaired social interaction.
At present, ASD Autism is the fastest growing developmental disability in the United States. Typically signs include difficulty with relationships, repetitive verbal, behavior and motor patterns, hyporeaction responses to stimulation. ASD classically arise during childhood. The cause of autism is not agreed upon and most treatments are limited to managing behavioral abnormalities; pharmaceutical medicines given to treat the symptoms are ineffective in curing the condition. A major reason for that is there are few to no medicines that improve biochemistry of mitochondria dysfunction, glutathione deficiency and DNA transcription.
Mitochondria are organelles primarily responsible for aerobic energy production in vertebrate eukaryotic cells . In addition, they also play an important role in calcium homeostasis and signaling, regulation of apoptosis, and reactive oxygen species (ROS) formation.
To counterbalance ROS toxicity and to provide cytoprotection, cells are equipped with a variety of antioxidants such as glutathione (GSH), SOD, glutathione peroxidase, catalase, ascorbic acid, α-tocopherol, and β-carotene .
Decreased levels of other antioxidant enzymes, such as erythrocyte SOD, erythrocyte and plasma glutathione peroxidase, serum transferrin, and serum ceruloplasmin have also been described in autism [78, 79]. Importantly, a correlation between such reduced levels and loss of language skills has been established in children with ASD .
A number of studies have found that individuals with ASD display hallmarks of increased oxidative stress or abnormalities in redox regulation, supporting the notion of a mechanistic role for ROS in the manifestation of the autistic phenotype [7, 14, 62]. Such evidence of increased oxidative damage to DNA, proteins and lipids has been identified in blood, urine, and post-mortem brain samples from autistic individuals . For example, markers of impaired capacity for methylation and enhanced oxidative stress, such as lower S-adenosylmethionine-to-S-adenosylhomocysteine ratios and lower redox ratios of reduced glutathione-to-oxidized glutathione (GSH/GSSG), have been found in the plasma of children with ASD [73, 74].
Gu et al. found decreased activity of glutathione peroxidase, glutathione-Stransferase, and glutamate cysteine ligase in the ASD cerebellum. In other work, supplementation with antioxidants such as N-acetyl-L-cysteine (a precursor to glutathione), coenzyme Q10, ubiquinol, ascorbic acid, α-tocopherol, methylcobalamin, and carnosine also improved behavioral symptoms associated with autism [122–129]. In a randomized doubleblind placebo controlled trial, a formulation of multivitamins combined with mineral supplements (containing multiple mitochondrial cofactors, vitamins, and antioxidants) improved plasma or erythrocyte levels of methylation, glutathione, oxidative stress, sulfation, ATP, nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH) and improved overall behavior, hyperactivity, tantrums, and receptive language in children and adults with ASD [126, 127]. Trials involving other antioxidants such as the phytochemical sulforaphane and the flavonoid luteolin also improved ASD symptoms, however no metrics of oxidative stress were examined [130, 131].
Other Metabolic Targets. Folic acid is important for redox metabolism, methylation, and mitochondrial homeostasis [132, 133]. Disruption of folate receptor α activity occurs in autism due to autoantibodies and mitochondrial dysfunction and results in CNS folate deficiency . Severe reductions in cerebral folate levels can lead to neurodevelopmental regression and the autism phenotype . Importantly, targeted
treatment with folinic acid has been shown to partially or completely improve communication, social interaction, attention, and stereotypical ASD behavior in patients with autoantibodies to folate receptor α [135–137]. Thus, targeting various causes and effects of mitochondrial dysfunction in autism may rescue behavior and minimize the clinical manifestations of ASD.