Mokhtar Hatem I, Zaitone Sawsan A, El-Sayed Karima, Lashine Rehab M, Ahmed Nada, Moursi Suzan M M, Shehata Shaimaa A, Aldahish Afaf A, Helal Mohamed A, El-Kherbetawy Mohamed K, Fawzy Manal S, Abd El-Fadeal Noha M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University-Kantara Branch, Ismailia 41636, Egypt.
Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 47713, Saudi Arabia.
Pharmaceuticals (Basel). 2024 Oct 26;17(11):1436. doi: 10.3390/ph17111436.
One of the most abundant and growing neurodevelopmental disorders in recent decades is attention deficit hyperactivity disorder (ADHD). Many trials have been performed on using drugs for the improvement of ADHD signs. This study aimed to detect the possible interaction of naringin with Wnt/β-catenin signaling and its putative anti-inflammatory and protective effects in the mouse ADHD model based on bioinformatic, behavioral, and molecular investigations. Furthermore, molecular docking was applied to investigate possible interactions with the GSK-3β and HSP90 proteins. : Male Swiss albino mice were divided into four groups, a normal control group, monosodium glutamate (SGL) control, SGL + naringin 50 mg/kg, and SGL + naringin 100 mg/kg. The psychomotor activity of the mice was assessed using the self-grooming test, rope crawling test, and attentional set-shifting task (ASST). In addition, biochemical analyses were performed using brain samples. : The results of the SGL group showed prolonged grooming time (2.47-folds), a lower percentage of mice with successful crawling on the rope (only 16.6%), and a higher number of trials for compound discrimination testing in the ASST (12.83 ± 2.04 trials versus 5.5 ± 1.88 trials in the normal group). Treatment with naringin (50 or 100 mg per kg) produced significant shortening in the grooming time (31% and 27% reductions), as well as a higher percentage of mice succeeding in crawling with the rope (50% and 83%, respectively). Moreover, the ELISA assays indicated decreased dopamine levels (0.36-fold) and increased TNF-α (2.85-fold) in the SGL control group compared to the normal mice, but an improvement in dopamine level was observed in the naringin (50 or 100 mg per kg)-treated groups (1.58-fold and 1.97-fold). Similarly, the PCR test showed significant declines in the expression of the Wnt (0.36), and β-catenin (0.33) genes, but increased caspase-3 (3.54-fold) and BAX (5.36-fold) genes in the SGL group; all these parameters were improved in the naringin 50 or 100 mg/kg groups. Furthermore, molecular docking indicated possible inhibition for HSP90 and GSK-3β. : Overall, we can conclude that naringin is a promising agent for alleviating ADHD symptoms, and further investigations are required to elucidate its mechanism of action.
注意缺陷多动障碍（ADHD）是近几十年来最为常见且发病率不断上升的神经发育障碍之一。已经进行了许多使用药物改善ADHD症状的试验。本研究旨在基于生物信息学、行为学和分子研究，检测柚皮苷与Wnt/β-连环蛋白信号传导之间可能的相互作用及其在小鼠ADHD模型中的假定抗炎和保护作用。此外，应用分子对接研究与GSK-3β和HSP90蛋白的可能相互作用。：雄性瑞士白化小鼠分为四组，正常对照组、谷氨酸钠（SGL）对照组、SGL + 50 mg/kg柚皮苷组和SGL + 100 mg/kg柚皮苷组。使用自我梳理试验、绳索爬行试验和注意力转换任务（ASST）评估小鼠的精神运动活动。此外，使用脑样本进行生化分析。：SGL组的结果显示梳理时间延长（2.47倍），成功在绳索上爬行的小鼠百分比降低（仅16.6%），并且在ASST中进行复合辨别测试的试验次数增加（12.83±2.04次试验，而正常组为5.5±1.88次试验）。用柚皮苷（每千克50或100毫克）治疗可显著缩短梳理时间（分别减少31%和27%），以及成功用绳索爬行的小鼠百分比更高（分别为50%和83%）。此外，ELISA分析表明，与正常小鼠相比，SGL对照组中的多巴胺水平降低（0.36倍），TNF-α升高（2.85倍），但在柚皮苷（每千克50或100毫克）治疗组中观察到多巴胺水平有所改善（1.58倍和1.97倍）。同样，PCR测试显示SGL组中Wnt（0.36）和β-连环蛋白（0.33）基因的表达显著下降，但caspase-3（3.54倍）和BAX（5.36倍）基因增加；在50或100毫克/千克柚皮苷组中所有这些参数均得到改善。此外，分子对接表明对HSP90和GSK-3β可能有抑制作用。：总体而言，我们可以得出结论，柚皮苷是一种有望缓解ADHD症状的药物，需要进一步研究以阐明其作用机制。
