Verlaet, Annelies

Abstract: Studies report increased levels of oxidative damage markers and decreased activity of antioxidant enzymes in attention deficit hyperactivity disorder (ADHD). Moreover, ADHD has a high comorbidity with cell-mediated disorders. Though results are not consistent, both oxidative and immune dysbalance may contribute to ADHD by injuring neuronal cells. Hence, due to their antioxidant and immunoregulatory effects, polyphenols appear appropriate in ADHD therapy. One example is Pycnogenol\uae, an extract from French maritime pine (Pinus pinaster Ait.) bark, but more research is required. Oxidative stress and immune biomarkers were compared between 57 untreated paediatric ADHD patients and 69 controls: erythrocyte reduced glutathione and plasma lipid soluble antioxidants as markers of antioxidant status, urinary 8-hydroxy-2\u2019-deoxyguanosine and plasma malondialdehyde as oxidative damage markers and plasma cytokines and antibodies as markers of immune status. Though only slightly elevated, an indication of more oxidative damage was found in ADHD. Antioxidant levels however did not differ or were even higher in patients than in the control group, possibly pointing at a compensation mechanism. Slightly higher IgE levels were supported by a trend for more diagnosed allergies in patients than in controls and might point at an immune dysbalance. However, due to the nature of this study, it is unknown whether redox and immune dysbalance play a causative role in ADHD. Using the Human Embryonic Kidney (HEK) and human monocytic leukaemia (THP-1) cell lines, Pycnogenol\uae was shown to act as Toll-like receptor (TLR)1/2 and TLR2/6 agonist and TLR5 partial agonist, stimulating pro-inflammatory cytokine secretion and NF-?B activation. Lipopolysaccharide (LPS)-Pycnogenol\uae complex formation was required to stimulate TLR4. In vitro metabolism of Pycnogenol\uae caused immuno-suppressive potential against TLR1/2 and TLR2/6, secretion of anti-inflammatory IL-10 and alteration of gut microbial composition, stressing the effect of metabolism on Pycnogenol\uae\u2019s biological activity. Finally, a randomised double-blind placebo and active product controlled clinical trial was set up to investigate the efficacy, mechanism of action and value of Pycnogenol\uae in paediatric ADHD therapy as compared to methylphenidate treatment and placebo, including effects on immunity, oxidative stress and comorbid complaints. Results of this trial, which is currently ongoing, are not available yet. This thesis indicates that redox and immune dysbalance play a potential role in ADHD aetiology, but decisive evidence remains to be reported. Polyphenol-rich extracts may have a positive impact on ADHD-related behaviour. The ongoing clinical trial will provide further understanding of the pathogenesis and treatment options of ADHD

Oxidative stress and immunity in attention deficit hyperactivity disorder

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