Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder with a prevalence in children of approximately 7.2% globally(Anand et al., 2017). The core symptoms of ADHD are age-appropriate inattention and impulsivity, which may affect social functions across the lifespan of the child(Aparicio et al., 2019). The common symptoms of ADHD in childhood may vary from hyperactivity and impulsivity to inattention, inability to sit still, learning difficulties, all these behavior may result in impaired academic and work performance, economic underachievement and emotional and behavioral management disorders(Archer, 1973). ADHD is a heterogeneous disease with complex pathogenesis, whose cause and pathogenesis has not yet been well elucidated, and lacks neurobiological diagnostic markers(Corona, 2020). Risk factors for ADHD include biological factors such as environmental toxins, illnesses or drugs during pregnancy or perinatal period, alcohol consumption, smoking, and stress, and psychosocial factors such as emotional trauma, and abuse. Dopaminergic, noradrenergic, and serotonergic neurotransmission may all have a role in ADHD, according to studies based on animal models(Darwish et al., 2019).
Recently, there has been a lot of research focusing on the role of inflammatory factors in the pathogenesis of ADHD. Increasing evidence suggests that inflammation, especially the neuro-inflammation, plays a crucial role in neuropsychiatric disorders, with inflammatory disorders being implicated in the pathogenesis of depression, schizophrenia, bipolar disorder, and post-traumatic stress disorders(Dunn et al., 2019). Neuro-inflammation, particularly chronic neuro-inflammation, plays a key role in central nervous system (CNS) disorders, such as stroke, depression, autism spectrum disorders, schizophrenia, and chronic pain, as well as in neuro-immune diseases, neurodegenerative diseases, and other neuropsychiatric disorders. For example, CNS disorders have been associated with an increase in peripheral blood leukocytes, neutrophils, acute inflammatory proteins, complement, and coagulation factors; and the release of inflammatory mediators such as PGF2a, PGE2, TNF, arginine precursor, norepinephrine, and epinephrine in the blood. Abnormal thalamic-pituitary-thyroid or adrenal target gland regulation. Abnormalities of the autophagy-immune inflammatory system, etc(Archer, 1973, Ferguson and Cada, 2004, Feng et al., 2017). Researchers believe that ADHD and inflammatory processes are closely linked. ADHD patients have been reported to have abnormal blood oxidative stress and inflammation when compared to the healthy individuals(Hendriksen et al., 2017). Some studies have shown that patients with ADHD had aberrant blood pro-inflammatory cytokine concentrations compared with healthy individuals(Kempuraj et al., 2017, Kozłowska et al., 2019). Chronic immunological dysregulation has been implicated in the onset of ADHD(Leffa et al., 2018). In addition, developmental or prenatal exposure to inflammation has been found to play a role in the development of ADHD(Majdak et al., 2014), with evidence implicating the involvement of peripheral inflammation and neuro-inflammation(Miller, 2020), and the connection between microglia, astrocytes, and mast cells are aided by CNS immune-related cytokines(Pape et al., 2019). Neuro-inflammation can be caused by a variety of pro-inflammatory and neurotoxic mediators produced by peripheral inflammation(Thapar and Cooper, 2016), as well as immune cell activity in the brain(Rivera et al., 2015).
Dysregulation of the hippocampal formation has been observed in ADHD patients and animal models(Thapar and Cooper, 2016). The etiology, biochemistry, symptomatology and treatment of spontaneously hypertensive rats (SHR) is well studied, making it a good ADHD model(Aparicio et al., 2019). Candidate gene studies, neurotransmitter dysfunction, neuropathology, and pharmacology studies validate the use of SHR as a ADHD model (Rivera et al., 2015, Leffa et al., 2018). Furthermore, the SHR prototype shows a significant level of predictive relevance for hitherto unknown behavioral, genetic, and neurobiological features of ADHD. In contrast, the white House Rats (SHR) are a biological model that have been produced from natural rats(Majdak et al., 2014).
Based on the theory of neurotransmitter abnormalities, there are two main types of drugs used to treat ADHD: methylphenidate (MPH), a psychostimulant II, and atomoxetine (ATX), a norepinephrine reuptake inhibitor, which are commonly used in combination with non-pharmacological therapies such as psycho-behavioral therapy (Russell, 2011). Long-term use of MPH and ATX may produce adverse effects such as loss of appetite, drowsiness, headache, dizziness, sleep disturbance and growth inhibition, while the use of MPH may also induce obsessive-compulsive symptoms and substance abuse problems(Hendriksen et al., 2017). It is difficult to avoid the side effects, which makes drug selection and administration difficult. Therefore, further studies are looking forward to explore new possibilities in the etiology and pathogenesis of ADHD, and to identify new treatment strategies that may bring about significant changes in the future understanding and clinical management of the disease(Kozłowska et al., 2019). Natural compounds have been shown to possess anti-oxidative stress, anti-inflammatory, immune-modulation effects, which may be with beneficial in regulating the neurological disease(Leffa et al., 2018). Therefore, the use of natural compounds to attenuate ADHD is currently attracting interest(Skaper et al., 2018).
Polygonum multiflorum is a traditional used herb medicine in China, which has the functions of enhancing immunity and improving DNA repair ability(Lin et al., 2018, Liu et al., 2021). The main component in Polygonum multiflorum is stilbene glycosides, which can protect nerve cells from damage by inhibiting apoptosis(Zhang and Chen, 2018). Stilbene glucoside (2,3,5,4༇-Tetrahydroxy stilbene-2-Ο-β-D-glucoside) is a subcategory of polyphenols found in many plant species that is able to induce cellular senescence(Wu et al., 2017). Stilbene glucoside compounds have good safety profiles in humans and have been suggested for use in chemotherapy and adjuvant therapy for tumors. In this study, we investigated the role of inflammation in ADHD and the effect of stilbene glucoside on neuro-inflammation using SHR as a model for ADHD and the Wistar-Kyoto (WKY) rats as controls. We also analyzed the effect of stilbene glucoside on the levels of DHA, BDNF, TrkB, and CNS immune-related cytokines in prefrontal, striatum and hippocampus tissues using immunostaining, real-time PCR and western blot analysis.