Plant Compound Improves Cognitive Deficits in Mouse Model of Down Syndrome

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A natural compound that is found in plants such as parsley, celery, peppermint, citrus fruits, and chamomile flowers, has been shown to improve cognitive and memory deficits that are seen in a mouse model of Down syndrome (DS). A research team headed by Diana Bianchi, MD, a senior investigator at the National Human Genome Research Institute (NHGRI), added the compound—which is called apigenin—to the normal diets of pregnant mice that were carrying fetuses with Down syndrome characteristics. The offspring then continued to receive dietary apigenin over their lifespan.

The in vivo mouse studies indicated that apigenin improved several developmental milestones, and was linked with decreased oxidative stress, the activation of pro-proliferative and pro-neurogenic genes, and reduction of the pro-inflammatory cytokines. The combined findings from the experiments in mice, and from in vitro studies, indicate that it may one day possible to offer pregnant women who are carrying fetuses with Down syndrome, diagnosed through prenatal testing, a treatment that could lessen the cognitive deficits seen in the genetic disorder.

Reporting their findings in the American Journal of Human Genetics (“Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model”), Bianchi, together with first author Faycal Guedj, PhD, a staff scientist at the NHGRI, and colleagues, concluded, “These in vitro and in vivo studies provide proof of principle that apigenin has therapeutic effects in preclinical models of DS.”

Down syndrome is a set of symptoms that result from an extra copy or piece of chromosome 21; trisomy 21 (T21). The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain. Screening for T21 is now universally offered as part of routine obstetric care in most developed countries, the authors noted. “Our laboratory has suggested consideration of prenatal diagnosis as a potential opportunity to treat the fetus in utero. However, they continued, “… this concept does have many “unique challenges.” Treatment must be safe for both the pregnant woman and her fetus, and any therapeutic agent must be able to cross both the placental and blood-brain barriers, and lead to improved postnatal outcomes in the baby.

The investigators reasoned that by analyzing and integrating dysregulated gene expression, and pathways that are characteristic of human T21 and mouse models of Down syndrome, they might be able to identify targets for prenatal therapy. “In our previous studies, we integrated gene expression data from nine different cellular and tissue sources in both humans with DS and mouse models to identify common dysregulated signaling pathways and cellular processes,” they explained. “We demonstrated that pathway abnormalities associated with DS were the result of gene-dosage-specific effects and the consequence of a global stress response with activation of compensatory mechanisms.”

For their newly reported studies, the team used the Connectivity Map database to discover compounds that might be used to “rescue the transcriptome” and “promote more typical brain development in individuals with DS.” One of the molecules identified that showed the most promise was apigenin (4’,5,7-trihydroxyflavone), and the team hypothesized that prenatal treatment with apigenin might at least in part “… rescue the global gene expression dysregulation to improve neurogenesis and postnatal cognitive outcomes in DS.”

Apigenin is not known to have any toxic effects, and previous studies had shown that the compound exhibits antioxidant activity that reduces inflammation, and that it can be absorbed through the placenta and through the blood-brain barrier. “It has potent antioxidant, anti-inflammatory, and anti-apoptotic properties,” the authors noted. For their reported studies, the team tested the effects of apigenin both in vitro, on human amniocytes from fetuses with T21, and in vivo in the Ts1Cje mouse model of DS.

Results from the in vitro experiments showed that the human T21 cells cultured with apigenin demonstrated significantly reduced oxidative stress and improved antioxidant defense responses. “We demonstrated that apigenin is a safe treatment that can rescue oxidative stress and total antioxidant capacity imbalance in human amniocytes from fetuses with T21,” the scientists wrote.

For the in vivo tests, pregnant mouse mothers carrying pups with DS characteristics were fed apigenin in their normal chow diets, and the compound was then added to the diets of the offspring over their lifetimes. Results from the in vivo experiments showed that in comparison to DS-symptomatic mice whose mothers had not been fed apigenin, those that were exposed to the plant compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Interestingly, male mice demonstrated greater benefits. “… the results indicated that an apigenin-containing diet resulted in sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, with males showing significantly more improvement than females.”

The team said the overall results indicated that apigenin may impact brain development through multiple mechanisms. “Our in vitro and in vivo data suggest that apigenin might improve Ts1Cje embryonic brain development through its synergistic anti-inflammatory, pro-angiogenic, and neurotrophic actions,” they stated.

Evaluation of gene activity and protein levels showed that the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth. “We also showed that apigenin achieves its therapeutic action by triggering the expression of neurogenic genes, suppressing inflammation via inhibiting NFkB, and reducing the production of pro-inflammatory cytokines while promoting the production of anti-inflammatory cytokines and angiogenic and neurotrophic factors.”

The team concluded, “Combining an integrated human/murine approach and the Connectivity Map database, we identified apigenin as a candidate prenatal treatment for DS … In summary, our in vitro and in vivo gene and protein expression studies suggest that apigenin has significant anti-inflammatory effects that might play a key role in improving brain development and post-natal cognitive outcome in DS.”

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