期刊
ANTIOXIDANTS
卷 11, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/antiox11010062
关键词
Down syndrome; Ts65Dn mice; brain mitochondria; oxidative phosphorylation; mitochondrial respiratory chain; 7; 8-dihydroxyflavone
资金
- Associazione A.M.A.R. Down-Onlus, Martina Franca, Italy [DSB.AD006.203, DSB.AD006.245]
- Fondazione Generali e Assicurazione Generali, Italy
- Associations Progetto AVVENTUNO, Lugano, Switzerland
- Circolo ARCI alle rive del Reno, Bologna, Italy
This study found that brain mitochondrial bioenergetic defects are present in Ts65Dn pups and early treatment with 7,8-DHF can positively impact mitochondrial function. These findings suggest the potential of 7,8-DHF as a translational treatment for neurodevelopmental alterations in Down syndrome.
Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3-P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3-P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1 alpha. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.
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