Abstract
Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders with no drugs treating the core symptoms and no validated biomarkers for clinical use. The multi-functional phytochemical sulforaphane affects many of the biochemical abnormalities associated with ASD. We investigated potential molecular markers from three ASD-associated physiological pathways that can be affected by sulforaphane: redox metabolism/oxidative stress; heat shock response; and immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with ASD. We first analyzed the mRNA levels of selected molecular markers in response to sulforaphane ex vivo treatment in PBMCs from healthy donors by real-time quantitative PCR. All of the tested markers showed quantifiability, accuracy and reproducibility. We then compared the expression levels of those markers in PBMCs taken from ASD patients in response to orally-delivered sulforaphane. The mRNA levels of cytoprotective enzymes (NQO1, HO-1, AKR1C1), and heat shock proteins (HSP27 and HSP70), increased. Conversely, mRNA levels of pro-inflammatory markers (IL-6, IL-1β, COX-2 and TNF-α) decreased. Individually none is sufficiently specific or sensitive, but when grouped by function as two panels, these biomarkers show promise for monitoring pharmacodynamic responses to sulforaphane in both healthy and autistic humans, and providing guidance for biomedical interventions.
Highlights
Since Autism Spectrum Disorder (ASD) is multi-factorial and multiple genes have been implicated with no specific drug targets, strategies using multi-functional phytochemicals are highly attractive
In search for biomarkers for monitoring responses to SF treatment in ASD, we investigated several potential molecular markers from three ASD-associated basic physiological pathways that can be affected by SF (Fig. 1a–c): (1) redox metabolism/oxidative stress, (2) heat shock response, and (3) immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs)
We examined a subset of www.nature.com/scientificreports these markers in PBMCs from blood taken from subjects with ASD before and after 14 d of daily ingestion of a SF-providing nutritional supplement, calculated to deliver approximately the same daily dose of SF as was provided in our previous study[18]
Summary
Since ASD is multi-factorial and multiple genes have been implicated with no specific drug targets, strategies using multi-functional phytochemicals are highly attractive. Nrf[2] activation is increasingly understood to play a significant role in ameliorating many diseases, including neurological disorders[28] This is in part a consequence of the recognized role of oxidative stress and chronic inflammation as causative factors for these disorders, and Nrf[2] is the master regulator of cellular redox homeostasis and an inhibitor of inflammation, both of which are critical factors in the neuropathology of ASD29,30. In search for biomarkers for monitoring responses to SF treatment in ASD, we investigated several potential molecular markers from three ASD-associated basic physiological pathways that can be affected by SF (Fig. 1a–c): (1) redox metabolism/oxidative stress, (2) heat shock response, and (3) immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs). Criteria evaluated for the biomarkers in these PBMCs included quantifiability, accuracy and reproducibility of the assay methods, as well as sensitivity and responsiveness to both ex vivo and in vivo SF treatments
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