Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates; Zayed Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates; Zayed Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates; Department of Applied Sciences, College of Arts and Sciences, Abu Dhabi University, P.O. Box 59911, Abu Dhabi, United Arab Emirates.
Biomed Pharmacother. 2021 Jun;138:111517. doi: 10.1016/j.biopha.2021.111517. Epub 2021 Mar 24.
Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
几种脑神经递质，包括组胺（HA）、乙酰胆碱（ACh）和多巴胺（DA），被认为与几种脑疾病有关，包括认知障碍、抑郁症、精神分裂症、焦虑症和嗜睡症，所有这些都与自闭症谱系障碍（ASD）共病。因此，评估了新型多活性化合物 ST-713 对雄性 BTBR T+tf/J 小鼠模型 ASD 样行为的改善作用，该化合物对组胺 H3 受体（H3R）、多巴胺 D2sR 和 D3R 具有高亲和力。ST-713（3-（2-氯-10H-吩噻嗪-10-基）-N-甲基-N-（4-（3-（哌啶-1-基）丙氧基）苄基）丙-1-胺；2.5、5 和 10 mg/kg，ip）剂量依赖性地改善了社交缺陷，并显著减轻了 BTBR 小鼠的重复/强迫行为（均 P<0.05）。此外，ST-713 调节了失调的焦虑水平，但未能消除测试小鼠的活动过度增加。此外，ST-713（5 mg/kg）减弱了 BTBR 小鼠海马和小脑 NF-κB p65、COX-2 和 iNOS 蛋白表达水平的升高（均 P<0.05）。H3R 激动剂（R）-α-甲基组氨酸或抗胆碱能药物东莨菪碱的共同给药完全逆转了 ST-713 对社会参数的改善作用。这些结果表明，多活性化合物具有治疗神经精神疾病的潜力，例如 ASD。
