Autism spectrum disorder (ASD) comprises a broad range of neurodevelopmental disorders that are associated with deficits in social interaction and communication. The tyrosine kinase inhibitor tyrphostin AG126 represents a promising therapeutic agent for several neuroinflammatory disorders. There are currently no treatments available that can improve ASD and we previously showed that AG126 treatment exerts beneficial effects on BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism that shows the core features of ASD; however, the immunological mechanisms and molecular targets associated with this effect were previously unclear. This study was undertaken to delineate the neuroprotective effect of AG126 on BTBR mice. Here, using this mouse model, we investigated the effects of AG126 administration on IL-21R, IL-21, IL-22, TNF-α, NOS2, STAT3, IL-27, and Foxp3 production by CD8+ T cells in the spleen by flow cytometry. We further explored the mRNA and protein expression of IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, STAT3, IL-27, and Foxp3 in brain tissue by RT-PCR, and western blotting. We found that BTBR mice treated with AG126 exhibited significant decreases in IL-21R-, IL-21-, IL-22-, TNF-α-, NOS2-, STAT3-producing, and increases in IL-27- and Foxp3-producing, CD8+ T cells. Our results further demonstrated that AG126 treatment effectively decreased IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, and STAT3, and increased IL-27 and Foxp3 mRNA and protein expression in brain tissues. Our findings suggest that AG126 elicits a neuroprotective response through downregulation of the IL-21/IL-21R and JAK/STAT pathway in BTBR mice, which could represent a promising novel therapeutic target for ASD treatment.

中文翻译：

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tyrphostin AG126对酪氨酸激酶信号的抑制下调了BTBR孤独症小鼠模型中的IL-21 / IL-21R和JAK / STAT通路。

自闭症谱系障碍（ASD）包括广泛的神经发育障碍，这些障碍与社交互动和沟通不足有关。酪氨酸激酶抑制剂tyrphostin AG126代表了几种神经炎性疾病的有前途的治疗剂。目前尚无可改善ASD的治疗方法，并且我们先前已证明AG126治疗可对BTBR T + Itpr3tf / J（BTBR）小鼠发挥有益作用，BTBR T + Itpr3tf / J（BTBR）小鼠显示了ASD的核心特征，是一种自闭症模型。然而，与这种作用有关的免疫机制和分子靶标以前尚不清楚。进行了这项研究以描绘AG126对BTBR小鼠的神经保护作用。在这里，我们使用这种小鼠模型研究了AG126给药对IL-21R，IL-21，IL-22，TNF-α，NOS2，STAT3，IL-27，流式细胞术检测脾脏中CD8 + T细胞产生Foxp3和Foxp3。我们进一步通过RT-PCR和Western印迹研究了脑组织中IL-21，IL-22，IL-1β，TNF-α，NOS2，JAK1，STAT3，IL-27和Foxp3的mRNA和蛋白表达。我们发现用AG126处理的BTBR小鼠在产生IL-21R-，IL-21-，IL-22-，TNF-α-，NOS2-，STAT3的过程中表现出显着降低，而在产生IL-27-和Foxp3的过程中则显着增加CD8 + T细胞。我们的结果进一步证明，AG126治疗可有效降低脑组织中的IL-21，IL-22，IL-1β，TNF-α，NOS2，JAK1和STAT3，并增加IL-27和Foxp3 mRNA和蛋白质表达。我们的发现表明，AG126通过下调BTBR小鼠中的IL-21 / IL-21R和JAK / STAT途径引起神经保护反应，这可能代表ASD治疗的有希望的新型治疗靶点。