Ameliorative effect of betanin on monosodium glutamate-induced mouse ADHD and modulation of Nrf2 and TLR4/NFκB/p53 interplay

Abstract Background Attention-deficit hyperactivity disorder (ADHD) is a state of poor attention and hyperactivity. Neuroinflammation and oxidative stress are complicated in the pathology of ADHD. Betanin is a potent water-soluble nitrogen-containing antioxidant and anti-inflammatory molecule not tested before in ADHD models. The current study aimed to test the ability of betanin to mitigate ADHD in mice in terms of cognitive and motor dysfunction, in addition to brain histopathology, neurotransmitter levels and inflammatory protein levels; the molecular study was supported by a bioinformatic investigation. Male albino mice were allotted to three experimental groups: (i): normal, (ii): ADHD group, (iii) ADHD + betanin 50 mg/kg. We induced ADHD by including monosodium glutamate (SGLU) in the diet for 8 weeks. Cognitive and motor dysfunction were evaluated using the open field test (OF-T) for locomotor alterations, the marble burying test (MB-T) for attention and compulsive behavior, and the rope crawling test. Results The ADHD control group (fed with SGLU) showed increased activities in the OF-T and high compulsive behavior in the MB-T. Further, high brain glutamate and low dopamine levels were observed in the ADHD control group along with high levels of malondialdehyde and inflammatory parameters such as toll-like receptors (TLRs), tumor necrosis factor-α (TNF-α), nuclear transcription factor-κB (NFκB), interleukin-1β (IL-1β), and IL6. Conversely, brain Nrf2 and total antioxidants were reduced in the ADHD group. Microscopic investigation showed pathological alterations in the brain. Western blot analysis and immunostaining showed greater levels of p-53 in the ADHD group versus the normal group. Conclusions Orally administered betanin improved most neurobehavioral, biochemical, and histopathological findings in the ADHD model in mice. Hence, betanin can be considered for further investigation as a useful food component in children for mitigating ADHD symptoms. Graphical abstract