1. Introduction
impaired neurotransmission, ASD, metabolic abnormalities, behavioral deficits, traumatic brain injuries, Autism spectrum disorder, fibrogenesis, neurodevelopmental disorder, psychotic disorders, mitochondrial dysfunction, DSM-5
DISORDER, DISORDERS, PROLIFERATION, NEURODEGENERATIVE DISEASES, DISORDERS, MULTIPLE SCLEROSIS, LACTIC ACIDOSIS, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, CORTEX
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) as observable behavioral deficits in social communication and social interaction across multiple contexts. Oftentimes, patients with ASD present with difficulties relating to others in the form of repetitive patterns of behaviors and limited interests. Although ASD can present at any age, the disorder usually manifests early in childhood and can be reliably diagnosed by age 2 [The cause of ASD is currently unknown and involves a mix of genetics and environmental factors. Based on the current literature, ASD involves many complex biological processes that manifest as physiologic and metabolic abnormalities. Namely, ASD has been reported to be in association with impaired neurotransmission, immune dysregulation in the brain, mitochondrial dysfunction, and increased oxidative stress [The neurodevelopmental nature of ASD is partially explained by the pathophysiologic imbalance of neurochemical signaling in the central nervous system. ASD has been observed to be associated with changes to neurotransmission involving gamma aminobutyric acid (GABA), glutamate, serotonin, dopamine, acetylcholine, N-acetyl aspartate, and endogenous opioids, amongst others [There is growing evidence that supports a role for immune dysregulation in the brain in ASD. Neurobiological studies on children with ASD have demonstrated an excess in neuronal synapses in the cerebral cortex. An impairment in synaptic pruning is observed to lead to social and behavioral dysregulation, as is seen in ASD. On an immunologic level, brain microglia are crucial in the synaptic refinement process [Synaptic transmission is an energy intensive process that requires large amounts of ATP produced by mitochondria. The synthesis of proteins and dendrites for synaptic plasticity is also another energy intensive process. As such, functional mitochondria are crucial to neurodevelopment. An early study in 1985 cited lactic acidosis in a subset of children with ASD, which further paved the way to explore the association between mitochondrial dysfunction in ASD [Lastly, an imbalance in oxidation–reduction (redox) reactions in cells favor pro-oxidant agents, such as free radicals, which promote oxidative stress. More specifically, the generation of ROS outweighs the body’s ability to remove them. In low concentrations, reactive oxygen species act as signaling molecules that induce apoptosis and dysregulates cell proliferation via changes to gene expression [In order to protect itself, the body utilizes an antioxidant defense mechanism that includes both enzymatic and non-enzymatic ways to remove ROS. Enzymatic defense includes the biological action of superoxide dismutase, catalase, peroxiredoxins, glutathione peroxidase, and several enzymes in the ascorbate-glutathione pathway [One of the most studied antioxidants is glutathione due to its ubiquitous nature and its role as the most abundant non-protein thiol antioxidant in mammalian tissue. Glutathione is a naturally occurring cysteine-glutamate-glycine tripeptide that is synthesized primarily in the liver with significant antioxidative action. In addition to its key role in redox signaling, crucial in the detoxification of xenobiotics, glutathione is an important factor in regulating cell proliferation, apoptosis, immune function, and fibrogenesis [NAC has been a target of interest primarily for its antioxidative role in a variety of disorders including neural cell survival, cell signaling, neurodegenerative diseases, multiple sclerosis, traumatic brain injuries, and other psychotic disorders [Further research into anti-oxidative agents for ASD begs the question of whether direct supplementation with glutathione is equally or more efficacious than NAC supplementation due to bypassing the rate-limiting transsulfuration step (cysteine) in glutathione synthesis. Despite its proposed benefits, oral glutathione supplementation failed to show changes to the observed biomarkers of oxidative stress and glutathione status, due to the enzymatic degradation of supplemental glutathione in the intestine [