Attention-Deficit/Hyperactivity Disorder Animal Model Presents Retinal Alterations and Methylphenidate Has a Differential Effect in ADHD versus Control Conditions

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. Interestingly, children with ADHD seem to experience more ophthalmologic abnormalities, and the impact of methylphenidate (MPH) use on retinal physiology remains unclear. Thus, we aimed to unravel the retina’s structural, functional, and cellular alterations and the impact of MPH in ADHD versus the control conditions. For that, spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were used as animal models of ADHD and the controls, respectively. Animals were divided into four experimental groups as follows: WKY vehicle (Veh; tap water), WKY MPH (1.5 mg/kg/day), SHR Veh, SHR MPH. Individual administration was performed by gavage between P28-P55. Retinal physiology and structure were evaluated at P56 followed by tissue collection and analysis. The ADHD animal model presents the retinal structural, functional, and neuronal deficits, as well as the microglial reactivity, astrogliosis, blood-retinal barrier (BRB) hyperpermeability and a pro-inflammatory status. In this model, MPH had a beneficial effect on reducing microgliosis, BRB dysfunction, and inflammatory response, but did not correct the neuronal and functional alterations in the retina. Curiously, in the control animals, MPH showed an opposite effect since it impaired the retinal function, neuronal cells, and BRB integrity, and also promoted both microglia reactivity and upregulation of pro-inflammatory mediators. This study unveils the retinal alterations in ADHD and the opposite effects induced by MPH in the retina of ADHD and the control animal models.

Changes in Cortisol and in Oxidative/Nitrosative Stress Indicators after ADHD Treatment

“…Similarly, chronic use of methylphenidate in rats had different effects depending on the clinical context: under therapeutic conditions, i.e., rats with ADHD, methylphenidate showed benefits by increasing antioxidant capacity and reducing LPO in the hippocampus and prefrontal cortex, whereas under non-therapeutic conditions, i.e., healthy rats, methylphenidate had detrimental consequences, in terms of oxidative and nitrosative stress, astrocytic reactivity and antioxidant capacity [43]. Comparable results were observed in other study on rats where methylphenidate treatment improved the proinflammatory profile in the ADHD model while in control conditions it induced a proinflammatory state [44].…”

Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases

“…Both ASD and ADHD are believed to be caused by a combination of genetics (e.g., ASD risk genes including FMR1, SHANK3, MECP2, CUL3 and CDKL5) and environmental factors [11]. The principal pathophysiology of ASD involves abnormalities in brain structure and connectivity [12] and in ADHD, there is a significant dysregulation of the monoaminergic neurotransmitter systems [13].…”

“…We closely examined seven recent studies [11][12][13][14][15][16][17], which tested a causal link between microglial dysfunction and pathogenesis in neurodevelopmental disorders; five of these studies employed the targeted genetic manipulation of microglial proteins in mice to test its consequence on synaptic integrity (structure and function), brain connectivity, neuroinflammation and social behavior with relevance to ASD or ADHD; one study used a murine model of ADHD to examine the therapeutic action of a clinically approved methylphenidate (MPH) via microglial pathways; one study conducted a functional analysis of microglial activation in an ADHD patient cohort (see summary in Figure 1 and Table 1). NLR family pyrin domain-containing 3 (Nlrp3).…”

“…Sanches et al ( 2023), explored microglial involvement in ADHD-related retinal dysfunction using a rat model for ADHD [13]. Retinal changes and vision problems (color vision deficiency, monocular vision loss and strabismus) have been linked with ADHD [13].…”

“…Sanches et al ( 2023), explored microglial involvement in ADHD-related retinal dysfunction using a rat model for ADHD [13]. Retinal changes and vision problems (color vision deficiency, monocular vision loss and strabismus) have been linked with ADHD [13]. They noted an increased percentage of activated microglia (CD68+ Iba-1+ cells) and a concurrent decrease in CX3CR1 levels, likely present in a variety of retinal cells (photoreceptors, bipolar cells, ganglion cells, horizontal cells and amacrine cells).…”