“Jing-Ning Granules” Can Alleviate Attention Deficit Hyperactivity Disorder in Rats by Modulating Dopaminergic D2/D1-Like Receptor-Mediated Signaling Pathways

Abstract

Background. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attention deficit, hyperactivity, and impulsivity. Jing-Ning Granules (JNG) is a traditional Chinese medicine (TCM) that can alleviate ADHD. Although JNG is commonly used for the effective treatment of ADHD and has obtained the national invention patent, the exact mechanism of action remains unclear. Objective. In this study, we examined the effect and mechanism of JNG in spontaneously hypertensive rats (SHRs). We hypothesized that JNG affects dopaminergic D2/D1-like receptors and related pathways. Materials and Methods. Six rat groups were used in the experiment: Wistar-Kyoto rats (WKY, control group) and five SHR groups, including a model group; atomoxetine (ATX, positive control) group; and low, medium, and high-dose JNG groups. The corresponding treatments were daily administered to each group for 6 weeks. A behavioral test, including a step-down test and open field test (OFT), was carried out at the end of treatment. After the behavioral test, all animals were sacrificed, and the brain tissue was collected and analyzed ex vivo; histopathological analysis was performed to assess the pathological changes of the hippocampus; expression of D1-like and D2-like receptors, sensor protein calmodulin (CaM), protein kinase A (PKA), and calcium/calmodulin-dependent serine/threonine protein kinase (CaMKII) in the striatum and hippocampus was measured by western blot and real-time quantitative PCR (RT-PCR); cyclic adenosine monophosphate (cAMP) levels in the striatum were analyzed using an enzyme-linked immunosorbent assay (ELISA), while the level of Ca2+ in the striatum was analyzed by a calcium kit. Results. Our results showed that ATX or JNG could ameliorate the hyperactive/impulsive behavior and cognitive function of ADHD by promoting neuroprotection. Mechanistically, ATX or JNG could prompt the expressions of Dl-like and D2-like receptors and improve the mRNA and protein levels of cAMP/PKA and Ca2+/CAM/CAMKII signaling pathways. Conclusion. These results indicate that JNG can produce therapeutic effects by regulating the balance of D2/D1-like receptor-mediated cAMP/PKA and Ca2+/CaM/CaMKII signaling pathways.

Identifying candidate genes associated with hippocampal dysfunction in a hemiparkinsonian rat model by transcriptomic profiling

“…Additionally, the calcium (Ca 2+ ) and cAMP signaling pathways play pivotal roles in intracellular signal transduction, which is crucial for mediating the physiological functions of the DAergic receptors. These functions include voluntary movement, working memory, attention, and learning (Ding et al 2022 ). A substantial portion of Ca 2+ -mediated signal transduction occurs through the Ca 2+ /calmodulin-dependent protein kinase pathway, which influences various physiological functions, including the regulation of neurotransmitter synthesis and synaptic plasticity (Feng et al 2022 ).…”

Network pharmacology, molecular docking, and experimental validation to explore the potential mechanism of Long Mu Qing Xin mixture for the treatment of attention deficit hyperactivity disorder

“…DAT-CI mice have hyperactive symptoms, and amphetamine enhances striatal DAergic neurotransmission and inhibits paradoxical movements in DAT-CI mice by a mechanism related to DRD1/cAMP/PKA/ DARPP32 pathway activation (Napolitano et al, 2010). In addition, a significant DRD1/DRD2 imbalance was found in the brain tissue of SHRs, and the cAMP/PKA signaling pathway was in a downregulated state; tomoxetine (a non-neuroleptic stimulant for ADHD) or Jingning granules (an herbal prescription) rescued the DRD1/DRD2 imbalance by activating the cAMP/PKA signaling pathway, thereby improving behavioral and cognitive function in SHRs (Ding et al, 2022). In the present study, we measured the expression of DA, cAMP, DRD1, DRD2, and PKA in rat PFC and striatum.…”