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.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder that causes hyperactivity, impulsive behaviour and attention problems (Nagui 2009)
All the findings presented above suggest that the immune, endocrine and nervous systems may cooperate in ADHD pathogenesis
Splenic levels of cytokines (Fig. 2c–f) The splenic levels of IL1β, IL-6, TNF-α and TGF-β were significantly higher in 5week-old spontaneously hypertensive rats (SHRs) than in 5-week-old Wistar Kyoto rats (WKYs) (p < 0.001)
Summary
Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder that causes hyperactivity, impulsive behaviour and attention problems (Nagui 2009). Detectable levels of various cytokines, including IL-2, IL-5, IL-10 and TNF-β, were reported in the cerebrospinal fluid of children with ADHD (Mittleman et al 1997) All this information coincides well with the fact that cytokines might regulate the basal ganglia and play a pivotal role in the dopamine synthesis in the brain, which is, as was described above, implicated in ADHD (Oades et al 2010a; Felger and Miller 2012). Administration of IL1β, IL-2 and IL-6 in rodents reduced dopamine levels in the brain (Zalcman et al 1994; Anisman et al 1996), similar to ADHD patients (Blum et al 2008) Both glucocorticoids and cytokines might increase oxidative stress (Almeida et al 2011) which was recently reported in children with ADHD (Joseph et al 2015; Sezen et al 2016)
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