ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats

Abstract

RationaleAttention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders with morphological and functional brain abnormalities. However, there is a growing body of evidence that abnormalities in the immune and endocrine systems may also account for the ADHD pathogenesis.ObjectivesTo test ADHD pathogenesis in neurological, immune and endocrine systems, this study examined the concentrations of cytokines, chemokines, oxidative stress markers, metabolic parameters, steroid hormones and steroidogenic enzymes in the serum and/or tissues of spontaneously hypertensive rats (SHRs, animal model of ADHD) and Wistar Kyoto rats (WKYs, control animals). Moreover, the volume of the medial prefrontal cortex (mPFC) as well as the density of dopamine 2 (D2) receptor-expressing cells and tyrosine hydroxylase (TH)-positive nerve fibres in it was also elucidated.MethodsPeripheral blood, spleen and adrenal gland samples, as well as brain sections collected on day 35 (juvenile) and day 70 (maturating) from SHRs and WKYs, were processed by ELISA and immunohistochemistry, respectively.ResultsThe results show significant increases of serum and/or tissue concentrations of cytokines, chemokines and oxidative stress markers in juvenile SHRs when compared to the age-matched WKYs. These increases were accompanied by a lowered volume of the mPFC and up-regulation of D2 in this brain region. In maturating SHRs, the levels of inflammatory and oxidative stress markers were normalised and accompanied by elevated contents of steroid hormones.ConclusionsSignificant elevations of serum and/or tissue contents of cytokines, chemokines and oxidative stress markers as well as volumetric and neurochemical alterations in the mPFC of juvenile SHRs may suggest the cooperation of neurological and immune systems in the ADHD pathogenesis. Elevated levels of steroid hormones in maturating SHRs may be a compensatory effect involved in reducing inflammation and ADHD symptoms.

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

“…In an animal model of ADHD, using spontaneously hypertensive rats (SHR), the serum levels of IL-1α, MCP-1, RANTES, and IP-10 were elevated in five-week-old compared to control rats. Interestingly, serum levels of IL-6 were similar in five-week-old animals of both strains, with elevated levels in 10-week-old SHR, which correlates with that found in children with ADHD [34]. The association between the dysregulation of the inflammatory response and the pathophysiology of ADHD is possible as a result of the role of inflammation in neurogenesis, differentiation, and neuronal function [30,[35][36][37].…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…This model is limited by the presence of hypertension. However, the results of this rat model coincide with those of other studies on other older rodent models, used well earlier than the 1990s [ 73 ]. This highlights the need for a more suitable ADHD animal model and that research should be conducted in relation to the mechanism of ADHD.…”

Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder

“…Moreover, in children with ADHD, increases in plasma MDA and urinary 8-OHdG levels were found [ 65 ]. Finally, the levels of MDA and free sulphydryl groups in the spleen were higher in 5-week-old SHR than in control rats [ 66 ]. Recently, evaluation of serum levels of hydroperoxide, an oxidative stress marker, was shown to be higher in preschool children with ADHD [ 67 ].…”