Oxidative and nitrosative stress in ADHD: possible causes and the potential of antioxidant-targeted therapies

Abstract

Attention deficit hyperactivity disorder (ADHD) has a complex etiology although theories associated with disturbances in dopaminergic and noradrenergic activity are most commonly cited.The importance of these catecholamines in ADHD is supported by its effective treatment utilising stimulant and non-stimulant medications that modify their activity. Recently there has been interest in oxidative and nitrosative stress (O&NS) in ADHD and its potential to contribute to this condition. In this article, research investigating O&NS in ADHD is reviewed and its impact on catecholaminergic activity and neurological structure is discussed. Lifestyle, environmental, ADHD is most commonly treated with stimulant medications such as methylphenidate and amphetamines, non-stimulants such as atomoxetine, and alpha2-adrenergic agonists such as clonidine and guanfacine. Through their effects on dopamine and noradrenaline transporters, stimulants inhibit the reuptake of dopamine and noradrenaline, thereby increasing the extracellular levels of these neurotransmitters. These stimulants also inhibit monoamine oxidase, the enzyme that metabolises these catecholamines (Wilens et al. 2011). Atomoxetine works as a selective reuptake inhibitor of noradrenaline leading to its increased extracellular concentration (Garnock- Jones and Keating 2009).While effective, these medications are associated with several adverse effects. These include loss of appetite, growth delay and sleep disturbances (Cortese et al. 2013). It is important to note that despite their widely accepted short-term efficacy, the long-term effectiveness of pharmacological treatments on social, educational and occupational functioning in people with ADHD continues to be debated (Huang and Tsai 2011;Langberg and Becker 2012;Nijmeijer et al. 2008). On a positive note, recent analyses using the Swedish national registrar suggests that long-term stimulant use in people with ADHD is associated with reduced rates of substance use, criminality, and serious traffic accidents (Chang et al. 2014a;Chang et al. 2014b;Lichtenstein et al. 2012).Despite wide appreciation of catecholaminergic theories associated with ADHD, there has been increased research into other biological mechanisms associated with ADHD. For example, in psychiatry there has been interest in immune-inflammatory pathways and oxidative and nitrosative stress (O&NS). In particular, it has been confirmed through recent meta-analyses that depression is Increased O&NS has also been found in bipolar disorder (Andreazza et al. 2008;Brown et al. 2014),

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

“…Although there are inconsistent results regarding the relationship of oxidative stress and ADHD, in a meta-analysis it was confirmed that ADHD is associated with increased oxidative stress in ADHD patients [16]. Taken together, the data suggest that both oxidative and nitrosative stress in ADHD have the potential to contribute to this condition [15].…”

“…Moreover, increasing evidence indicates a critical role for neuroinflammation [13,14]. Also, the involvement of oxidative stress is highlighted as a pathophysiological cause of ADHD [15,16].…”

“…There is increasing evidence for the involvement of oxidative stress in the pathophysiology of ADHD [15,16], but some studies have shown low levels of malondialdehyde (MDA) and the DNA damage indicator 8-hydroxy-2 -deoxyguanosine (8-OHdG) in ADHD children [112,113]. MDA is the degradation product of the main chain reactions that lead to the oxidation of polyunsaturated fatty acids, and therefore serves as an oxidative stress marker.…”

Abordagem nutrológica do transtorno do déficit de atenção e hiperatividade em crianças

“…Deficiências de minerais, como zinco, ferro, magnésio, e de vitaminas, como a vitamina D, têm sido reportadas em crianças com TDAH 16,17,20,22,23,24 , bem como têm sido observados níveis elevados de estresse oxidativo 14,25,26,27,28,29 . Caso a criança possua alguma deficiência/insuficiência nutricional suspeitada/documentada, esta deve ser tratada/ corrigida.…”

Rationale for Dietary Antioxidant Treatment of ADHD

“…In addition, an overall dysfunction in the dopaminergic and noradrenergic system is involved in ADHD [ 9 , 10 , 11 ]. These catecholamines are active in brain areas involved in the regulation of attention and behavior [ 12 ]. Indeed, destruction of dopamine pathways in the prefrontal cortex resulted in hyperactivity [ 13 ], while concentrations of catecholamines are higher in the urine of ADHD patients compared to controls [ 14 , 15 ].…”