Ansari Mushtaq A, Attia Sabry M, Nadeem Ahmed, Bakheet Saleh A, Raish Mohammad, Khan Tajdar H, Al-Shabanah Othman A, Ahmad Sheikh F
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Mol Cell Neurosci. 2017 Jul;82:76-87. doi: 10.1016/j.mcn.2017.04.012. Epub 2017 Apr 30.
Autism spectrum disorder (ASD) is neurodevelopmental disorders characterized by stereotypical repetitive behavior, impaired social interaction, and deficits in communication. The BTBR T Itpr3/J (BTBR) mice have been extensively used as an animal model of the ASD-like phenotype. Adenosine A2A receptors (A2ARs) are considered potential targets in the treatment of neurodegenerative diseases. In this study, we used the A2AR antagonist SCH 5826 (SCH) and the A2AR agonist CGS 21680 (CGS) to investigate the activation of A2AR signaling in immune cells. Further, we examined the effects of A2ARs on the expression of the cytokines interleukin 2 (IL-2), IL-6, IL-9, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and transforming growth factor β (TGF-β) in the spleen and in splenic CD4 T cells. In addition, we assessed the mRNA and protein expression levels of these cytokines in the brain tissue. Our results showed that the levels of IL-2, IL-6, IL-9, IFN-γ, and TNF-α were significantly lower, whereas the levels of TGF-β in the spleen and in splenic CD4 T cells were significantly higher in the CGS-treated mice than in the BTBR control and SCH-treated mice. In addition, reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed a decrease in the mRNA and protein expression levels of IL-2, IL-6, IL-9, IFN-γ, and TNF-α and an increase in the mRNA and protein expression levels of TGF-β in the CGS-treated mice, while treatment with BTBR alone and SCH resulted in increased Th1 levels and decreased Th2 levels in the brain tissue. Our results suggest that treatment the A2AR agonist CGS may be a promising therapeutic option for neuroimmune dysfunction.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征为刻板重复行为、社交互动受损和沟通缺陷。BTBR T Itpr3/J（BTBR）小鼠已被广泛用作类自闭症谱系障碍表型的动物模型。腺苷A2A受体（A2ARs）被认为是神经退行性疾病治疗的潜在靶点。在本研究中，我们使用A2AR拮抗剂SCH 5826（SCH）和A2AR激动剂CGS 21680（CGS）来研究免疫细胞中A2AR信号的激活。此外，我们检测了A2ARs对脾脏和脾脏CD4 T细胞中细胞因子白细胞介素2（IL-2）、IL-6、IL-9、干扰素γ（IFN-γ）、肿瘤坏死因子α（TNF-α）和转化生长因子β（TGF-β）表达的影响。另外，我们评估了这些细胞因子在脑组织中的mRNA和蛋白质表达水平。我们的结果表明，与BTBR对照组和SCH处理组小鼠相比，CGS处理组小鼠脾脏和脾脏CD4 T细胞中IL-2、IL-6、IL-9、IFN-γ和TNF-α的水平显著降低，而TGF-β的水平显著升高。此外，逆转录聚合酶链反应（RT-PCR）和蛋白质印迹分析表明，CGS处理组小鼠中IL-2、IL-6、IL-9、IFN-γ和TNF-α的mRNA和蛋白质表达水平降低，而TGF-β的mRNA和蛋白质表达水平升高，而单独使用BTBR和SCH处理导致脑组织中Th1水平升高和Th2水平降低。我们的结果表明，用A2AR激动剂CGS治疗可能是神经免疫功能障碍的一种有前景的治疗选择。
