6-7-dihydroxyflavone and Down-Syndrome

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52-60 days (P52-60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52-60 mice showed no difference between treated and untreated Ts65Dn mice. At P52-60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.

Topics: Animals; Animals, Newborn; Brain; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Down Syndrome; Female; Flavones; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitosis; Neurogenesis; Neurons; Pregnancy; Prenatal Care; Treatment Outcome

Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Reduced neurogenesis and impaired neuron maturation are considered major determinants of altered brain function in DS. Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and neuron maturation should take place as soon as possible. The brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain development by specifically binding to tropomyosin-related kinase receptor B (TrkB). Systemic BDNF administration is impracticable because BDNF has a poor blood-brain barrier penetration. Recent screening of a chemical library has identified a flavone derivative, 7,8-dihydroxyflavone (7,8-DHF), a small-molecule that crosses the blood-brain barrier and binds with high affinity and specificity to the TrkB receptor. The therapeutic potential of TrkB agonists for neurogenesis improvement in DS has never been examined. The goal of our study was to establish whether it is possible to restore brain development in the Ts65Dn mouse model of DS by targeting the TrkB receptor with 7,8-DHF. Ts65Dn mice subcutaneously injected with 7,8-DHF in the neonatal period P3-P15 exhibited a large increase in the number of neural precursor cells in the dentate gyrus and restoration of granule cell number, density of dendritic spines and levels of the presynaptic protein synaptophysin. In order to establish the functional outcome of treatment, mice were treated with 7,8-DHF from P3 to adolescence (P45-50) and were tested with the Morris Water Maze. Treated Ts65Dn mice exhibited improvement of learning and memory, indicating that the recovery of the hippocampal anatomy translated into a functional rescue. Our study in a mouse model of DS provides novel evidence that treatment with 7,8-DHF during the early postnatal period restores the major trisomy-linked neurodevelopmental defects, suggesting that therapy with 7,8-DHF may represent a possible breakthrough for Down syndrome.

Topics: Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor; Cells, Cultured; Disease Models, Animal; Down Syndrome; Female; Flavones; Flavonoids; Hippocampus; Male; Memory; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Pilot Projects; Receptor, trkB

Down syndrome (DS) is caused by the triplication of human chromosome 21 and represents the most frequent genetic cause of intellectual disability. The trisomic Ts65Dn mouse model of DS shows synaptic deficits and reproduces the essential cognitive disabilities of the human syndrome. Aerobic exercise improved various neurophysiological dysfunctions in Ts65Dn mice, including hippocampal synaptic deficits, by promoting synaptogenesis and neurotransmission at glutamatergic terminals. Most importantly, the same intervention also prompted the recovery of hippocampal adult neurogenesis and synaptic plasticity and restored cognitive performance in trisomic mice. Additionally, the expression of brain-derived neurotrophic factor (BDNF) was markedly decreased in the hippocampus of patients with DS. Since the positive effect of exercise was paralleled by increased BDNF expression in trisomic mice, we investigated the effectiveness of a BDNF-mimetic treatment with 7,8-dihydroxyflavone at alleviating intellectual disabilities in the DS model. Pharmacological stimulation of BDNF signaling rescued synaptic plasticity and memory deficits in Ts65Dn mice. Based on our findings, Ts65Dn mice benefit from interventions aimed at promoting brain plasticity, and we provide evidence that BDNF signaling represents a potentially new pharmacological target for treatments aimed at rescuing cognitive disabilities in patients with DS.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Down Syndrome; Excitatory Postsynaptic Potentials; Female; Flavones; Hippocampus; Humans; Learning; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Neuronal Plasticity; Physical Conditioning, Animal; Signal Transduction