title: 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome.
abstract: Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene (MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.
authors.affiliation: Department of Surgical Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Johnson
authors.forename: Maxine
authors.initials: M
authors.lastname: Lam
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Punzo
authors.forename: Hongda
authors.initials: H
authors.lastname: Li
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Lin
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Mitchell
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
mesh_terms: D000818:Animals; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D004195:Disease Models, Animal; D047309:Flavones / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D020813:Receptor, trkB / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D015518:Rett Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013990:Tidal Volume / Q000187:drug effects / Q000502:physiology
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D020813:Receptor, trkB