Eissa Nermin, Venkatachalam Karthikkumar, Jayaprakash Petrilla, Yuvaraju Priya, Falkenstein Markus, Stark Holger, Sadek Bassem
Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates.
Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates.
Pharmaceuticals (Basel). 2022 Jul 27;15(8):929. doi: 10.3390/ph15080929.
Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H3R/D2R/D3R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H3R/D2R/D3R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.
神经递质调节异常可能导致包括自闭症谱系障碍（ASD）在内的脑部疾病出现许多病理生理变化。鉴于目前尚无FDA批准的有效治疗ASD社交缺陷的方法，本研究确定了新型多靶点H3R/D2R/D3R受体拮抗剂ST-2223慢性全身治疗对雄性黑褐短尾（BTBR）小鼠ASD相关社交缺陷的影响。与阿立哌唑（1mg/kg，腹腔注射）相比，ST-2223（2.5、5和10mg/kg，腹腔注射）能显著且剂量依赖性地减轻BTBR小鼠的社交缺陷并改善焦虑水平（p<0.05）。此外，通过LC-MS/MS对前额叶皮质、小脑、纹状体和海马体四个脑区的单胺能神经递质水平进行定量分析发现，ST-2223（5mg/kg）给药后，小脑和纹状体中的组胺（HA）、前额叶皮质和纹状体中的多巴胺（DA）以及前额叶皮质、纹状体和海马体中的乙酰胆碱（ACh）水平均显著升高（均p<0.05）。这些体内研究结果表明，多靶点H3R/D2R/D3R拮抗剂对评估的BTBR小鼠的社交缺陷具有缓解作用，这表明其在挽救ASD相关核心行为和改变单胺能神经递质方面具有药理学潜力。进一步研究ASD中的神经化学变化对于阐明ASD核心症状和异质性背后的早期神经发育变异至关重要，有望为ASD未来的治疗管理带来新方法。
