Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone

• Prif Awduron: Daniela Valenti (Awdur), Fiorenza Stagni (Awdur), Marco Emili (Awdur), Sandra Guidi (Awdur), Renata Bartesaghi (Awdur), Rosa Anna Vacca (Awdur)
• Fformat: Llyfr
• Cyhoeddwyd: MDPI AG, 2021-12-01T00:00:00Z.
• Pynciau: article
• Mynediad Ar-lein: Connect to this object online.
• Notes: 10.3390/antiox11010062; 2076-3921
• Keywords: Down syndrome; Ts65Dn mice; brain mitochondria; oxidative phosphorylation; mitochondrial respiratory chain; 7,8-dihydroxyflavone; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 11, Iss 1, p 62 (2021)

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-1α. 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.