Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.

具有21三体性（T21）的人类胎儿具有非典型的大脑发育，这在妊娠中期的超声检查中很明显。我们假设通过分析和整合失调的基因表达和唐氏综合症（DS）的人类和小鼠模型常见的途径，我们可以发现产前治疗的新目标。在这里，我们测试了用这种方法鉴定的芹菜素在来自T21胎儿的人羊膜细胞和Ts1Cje小鼠模型中的安全性和有效性。在体外，用芹菜素培养的T21细胞具有明显降低的氧化应激和改善的抗氧化防御反应。体内，将芹菜素与松饼混合处理是在产前对大坝进行管理，并在幼崽的一生中喂食。产前芹菜素治疗不会导致出生缺陷或幼仔死亡的显着增加。芹菜素显着改善了Ts1Cje新生儿的几个发育里程碑和空间嗅觉记忆。此外，我们注意到成年小鼠对探索行为和长期海马记忆的性别特异性影响，雄性比雌性表现出显着改善。我们证明芹菜素的治疗作用是多效的，可降低氧化应激，激活促增殖和促神经原性基因（KI67，Nestin，Sox2和PAX6）），通过抑制NFκB信号传导减少促炎性细胞因子INFG，IL1A和IL12P70，增加抗炎性细胞因子IL10和IL12P40以及增加血管生成和神经营养因子VEGFA和IL7的表达。这些研究提供了原理证明，芹菜素在DS的临床前模型中具有多个治疗靶点。