Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model
| Autor: | Fatimah Alsebaa, Lauren J. Massingham, Diana W. Bianchi, Umadevi Tantravahi, Faycal Guedj, Ashley E Siegel, Jeroen L. A. Pennings |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Vascular Endothelial Growth Factor A PAX6 Transcription Factor Down syndrome medicine.disease_cause Hippocampus Nestin chemistry.chemical_compound Mice 0302 clinical medicine Neurotrophic factors Pregnancy Genetics (clinical) Spatial Memory 0303 health sciences Stem Cells Gene Expression Regulation Developmental 3. Good health trisomy 21 Interleukin 10 In utero Apigenin Female Neurogenesis Primary Cell Culture Prenatal diagnosis prenatal treatment Article Andrology 03 medical and health sciences Fetus Sex Factors In vivo Genetics medicine Animals Humans 030304 developmental biology apigenin business.industry Interleukin-7 SOXB1 Transcription Factors medicine.disease Amniotic Fluid cytokines Disease Models Animal Oxidative Stress 030104 developmental biology Ki-67 Antigen chemistry inflammation Exploratory Behavior Trisomy business transcriptome 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Am J Hum Genet |
| Popis: | Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. Prenatal diagnosis provides a potential opportunity to begin treatment in utero. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with DS and mouse models we can discover novel targets for therapy. Here, we tested the safety and efficacy of apigenin (4’, 5, 7-trihydroxyflavone), identified using this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. The experiments compared treated to untreated results in T21 and euploid cells, as well as in Ts1Cje mice and their wild-type littermate controls. T21 cells cultured with apigenin (2µM) had significantly reduced oxidative stress and improved antioxidant defense response in vitro. Apigenin (333-400 mg/kg/day), mixed with chow, was initiated 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, with males showing significantly more improvement than females. Global gene expression analyses demonstrated that apigenin targets similar signaling pathways through common upstream regulators both in vitro and in vivo. These studies provide proof-of-principle that apigenin has therapeutic effects in preclinical models of Down syndrome.ONE SENTENCE SUMMARYAs a candidate prenatal treatment for Down syndrome, apigenin improved oxidative stress/antioxidant capacity imbalance and reduced pathways associated with inflammation in human cells while improving aspects of behavior in the Ts1Cje mouse model. |
| Databáze: | OpenAIRE |
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