RESEARCH

There are two ADHD subtypes: hyperactivity ADHD type (ADHD-PHI) and attention-deficit ADHD type (ADHD-PI). Compared to previous research on traditional literature, a newer and more efficient methodology of selecting herbal medicines was developed in this process. (1) In a study by Park et al., (2004) it considered hyperactivity ADHD type (ADHD-PHI) and attention-deficit ADHD type (ADHD-PI) as two separate disease symptoms. DSM is the most typical diagnostic method of ADHD, which classifies ADHD into three subtypes: predominantly inattentive (ADHD-PI), predominantly hyperactive-impulsive (ADHD-PHI), and combined type (ADHD-C). (2)

According to the results of the latest meta-analysis, the global prevalence of ADHD in children and adults was 7.2% and 6.76%, respectively, (3) indicating persistent lifetime symptoms in most ADHD patients. Additionally, ADHD is often accompanied by other psychiatric conditions, such as depression disorder, severe anxiety, and oppositional defiant disorder. With the rising incidence in recent years, ADHD has become a global public health concern. (4) Patients with attention-deficit/hyperactivity disorder (ADHD) present with symptoms such as lack of concentration, impulsiveness, and excessive activity, and ADHD is one of the neurobehavioral disorders commonly occurring in childhood. (5) Both genetic and environmental factors affect the occurrence of ADHD, but the exact cause has not yet been elucidated. However, some researchers have found that symptoms of impulsiveness and attention-deficiency tend to be present when the function of the frontal lobe of controlling thought and concentration decreases.

Another possible reason could be a problem in metabolizing neurotransmitters such as catecholamine, norepinephrine, and dopamine. (6) Controlled studies support the elimination of artificial food dyes to reduce ADHD symptoms, but this treatment may be more applicable to the general pediatric population than to children with diagnosed ADHD. Mineral supplementation is indicated for those with documented deficiencies but is not supported for others with ADHD. Carnitine may have a role for inattention, but the evidence is limited. Dimethylaminoethanol probably has a small effect. (7)

The enrichment analysis results indicated that 16 potential targets were involved in 25 biological processes (e.g., dopamine (DA) transport) and 22 molecular functions (e.g., postsynaptic neurotransmitter receptor activity), which were mainly localized at excitatory synapses. The neuroactive ligand- receptor interaction, cholinergic synapse, and dopaminergic synapse might be the core pathways of gastrodin in ADHD treatment. Through molecular docking, it was preliminarily verified that gastrodin showed good binding activity to seven important targets and formed stable binding conformations.

Gastrodin may exert an anti-ADHD effect by upgrading the dopaminergic system and central cholinergic system, inhibiting the inflammatory response and GIRK channel, and exerting a synergistic effect with other drugs on ADHD. For this reason, gastrodin should be considered a multitarget drug for ADHD treatment.
The main targets of gastrodin for ADHD treatment might be DRD2, DRD4, CHRNA3, CYP1A1, TNF, IL6, and KCNJ3, which were preliminarily verified by molecular docking. Gastrodin might exert an anti-ADHD effect by enhancing the function of the dopaminergic system and central cholinergic system, inhibiting the inflammatory response and GIRK channel, and exerting a synergistic effect with other drugs on ADHD. Among them, gastrodin might promote the release and transport of DA through various mechanisms, which deserves the most attention. Gastrodin should be considered a multitarget drug for ADHD treatment. (3)

Modern pharmacological studies have revealed that gastrodin has the properties of the regulation of monoamine neurotransmitters, (8) anti-inflammation, (9) antioxidation, (10) antianxiety, (11) neuron protection, (12) etc., closely related to the known ADHD pathogenesis. Moreover, gastrodin exhibits excellent oral bioavailability, rapid penetration of the blood-brain barrier, and almost nontoxicity. (13)

Figure 1: Flowchart of the study on the molecular mechanism of gastrodin in attention-deficit/hyperactivity disorder (ADHD) treatment (3).

A study indicates that basic TCM prescriptions for treating ADHD were principally composed of apoptogenic (‘nourishing Liver and Kidney’, ‘invigorating Heart and Spleen’) and calming/stabilising with herbs and calming ‘Liver’, clearing ‘Heat’, promoting qi-circulation, promoting blood-circulation, reducing ‘Phlegm’ and calming endogenous ‘Wind’.

Liriope platyphylla: The isolate Methylphenidate improves clinical symptoms and brain activity in ADHD patients through the attention-regulation network's dopamine system. Additionally, water-soluble extracts of Gastrodia elata and Liriope platyphylla showed a greater improvement in total attention and inattention scores. (14)

Paeonia lactiflora (PL) has been considered by traditional Chinese medicine as a drug that can improve mental or emotional disorders, including depression, anxiety, and affective disorders. A significant antidepressant effect on the symptoms of CORT-induced depression in mice, and significantly down-regulated the levels of CRH, ACTH and cortisol in the brain tissues of mice. (15)

Coptis chinensis: Berberine, the major constituent alkaloid in Coptis chinensis, has been shown to exert antidepressant-like effects. The elevation of hippocampal pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, as well as the activation of microglia were decreased by berberine. It prevents depressive-like behaviours in CUMS mice by suppressing neuro-inflammation in the hippocampus. (16)

Polygala tenuifolia: Anxiolytic and sedative-hypnotic activities of polygalasaponins extracted from Polygala tenuifolia and results suggest that polygalasaponin possesses evident anxiolytic and sedative-hypnotic activities. (17) Polygala tenuifolia and its active components have multiplex neuroprotective potential associated with AD, such as anti-Aβaggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing central cholinergic system and promote neuronal proliferation. (18)

Phellodendron amurense: Phellodendron amurense and Coptis chinensis were combined. Oral administration at a dose of 200 mg/kg showed in vivo anti-inflammatory activity as potent as the effects associated with 100 mg/mL of celecoxib or 1 mg/kg of dexamethasone. These effects were seen in both acute and chronic inflammation models, suggesting that this combination may be effective in controlling some inflammation-related diseases. (19)

Anemone altaica: Isolate ferulic acid shown a significant amelioration in correct alteration behaviour and motor learning with reduction of anxiety-like behaviours. (20) Isolate chlorogenic acid (CGA ) dose-dependently mitigated cerebral ischemia-reperfusion (CI/R)-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins. (21)

References

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Wang X, Yan S, Wang A, Li Y, Zhang F. Gastrodin ameliorates memory deficits in 3,3'-iminodipropionitrile-induced rats: possible involvement of dopaminergic system. 2014;39(8):1458-66.

Wang XL, Xing GH, Hong B, Li XM, Zou Y, Zhang XJ, et al. Gastrodin prevents motor deficits and oxidative stress in the MPTP mouse model of Parkinson's disease: involvement of ERK1/2-Nrf2 signaling pathway. 2014;114(2):77-85.

Peng Z, Wang H, Zhang R, Chen Y, Xue F, Nie H, et al. Gastrodin ameliorates anxiety-like behaviors and inhibits IL-1beta level and p38 MAPK phosphorylation of hippocampus in the rat model of posttraumatic stress disorder. 2013;62(5):537-45.

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Cai Z, Huang J, Luo H, Lei X, Yang Z, Mai Y, et al. Role of glucose transporters in the intestinal absorption of gastrodin, a highly water-soluble drug with good oral bioavailability. 2013;21(6):574-80.

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Sun JY, Liu YT, Jiang SN, Guo PM, Wu XY, Yu J. Essential oil from the roots of Paeonia lactiflora pall. has protective effect against corticosterone-induced depression in mice via modulation of PI3K/Akt signaling pathway. 2022;13:999712.

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