Nrf2 Activators as Dietary Phytochemicals Against Oxidative Stress, Inflammation, and Mitochondrial Dysfunction in Autism Spectrum Disorders: A Systematic Review

Abstract

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder with limited available treatments and diverse causes. In ASD patients, numerous researches demonstrated various alterations in inflammation/immune, oxidative stress, and mitochondrial dysfunction, and these alterations could be regulated by Nrf2. Hence, we aimed to systematically review the current evidence about the effects of Nrf2 activator supplementation on ASD objects from in vitro studies, animal studies, and clinical studies. Relevant articles were retrieved through searching for the Cochrane Library, PubMed, Web of Science, Scope, Embase, and CNKI databases (through September 23, 2020). Ultimately, we identified 22 preclinical studies, one cell culture study, and seven clinical studies, covering a total of five Nrf2 activators. For each Nrf2 activator, we focused on its definition, potential therapeutic mechanisms, latest research progress, research limitations, and future development directions. Our systematic review provided suggestive evidence that Nrf2 activators have a potentially beneficial role in improving autism-like behaviors and abnormal molecular alterations through oxidant stress, inflammation, and mitochondrial dysfunction. These dietary phytochemicals are considered to be relatively safer and effective for ASD treatment. However, there are few clinical studies to support the Nrf2 activators as dietary phytochemicals in ASD, even though several preclinical studies. Therefore, caution should be warranted in attempting to extrapolate their effects in human studies, and better design and more rigorous research are required before they can be determined as a therapeutic option.

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

“…Although resveratrol plays a beneficial role in the treatment of ASD animal model, its clinical study was still in its infancy. Currently, it has only one clinical study and the result is negative ( 252 ). Interestingly, a systematic review of treatments based on antioxidants reported that NAC appears to be the most effective antioxidant therapy of ASD currently ( 253 ).…”

“…Therefore, the Nrf2 system is one of the important ways of antioxidant therapy. A systematic review of treatments based on the Nrf2 system shows a potentially beneficial result, but also explains that these treatments still lack sufficient evidence for their efficacy and safety ( 252 ). Better design and more rigorous research are needed before the treatments can be used.…”

Plant food bioactives and its effects on gut microbiota profile modulation for better brain health and functioning in Autism Spectrum Disorder individuals: A review

“…Plant food bioactives, such as resveratrol, curcumin, naringenin, and many others, present in fruits and vegetables help in promoting the activity of Nrf2, a transcription factor that is involved in oxidative stress responses at exceptionally low concentrations, whereas high doses could be toxic (Yang et al., 2020). Resveratrol, a phytoalexin stilbenoid, commonly found in the skin of berries and grapes, is an Nrf2 antagonist that helped in increasing the Nrf2 levels, their nuclear translocation, and other processes leading to a series of neuroprotective functions (Yang et al., 2020). In Sprague–Dawley rat models, resveratrol dramatically improved the major symptoms of ASD, prevented oxidative stress, and expressed anti‐inflammatory characteristics.…”

“…Plant food bioactives, such as resveratrol, curcumin, naringenin, and many others, present in fruits and vegetables help in promoting the activity of Nrf2, a transcription factor that is involved in oxidative stress responses at exceptionally low concentrations, whereas high doses could be toxic (Yang et al, 2020). Resveratrol, a phytoalexin stilbenoid, commonly found in the skin of berries and grapes, is an TA B L E 1 List of plant food bioactives with their effect on gut microbiota that improves mood, behavior, cognition, and memory depression-like behavior (Parasram, 2017).…”

A Role of Stress Sensor Nrf2 in Stimulating Thermogenesis and Energy Expenditure

“…To show Nrf2 effects in energy metabolism and obesity, Nrf2 can be pharmacologically regulated by its activators or inhibitors. Recently, dietary phytochemicals and small molecules targeting Nrf2 have been extensively reviewed elsewhere [ 75 , 76 , 77 , 78 ]. Genetic loss of Nrf2 or Keap1 can lead to constitutive inhibition or activation of Nrf2, respectively.…”