Pharmacotreatment of a mouse model of Rett syndrome with the radical scavenger Trolox: Detailed assessment of potential merits in vitro and in vivo
von Oliwia Alicja Janc
Datum der mündl. Prüfung:2015-04-16
Betreuer:Prof. Dr. Michael Müller
Gutachter:Prof. Dr. Michael Müller
Gutachter:Dr. Dr. Oliver Schlüter
EnglischRett syndrome is a severe neurodevelopmental disorder, with an incidence of ~1/1000 female births, in which most patients carry mutations in the methyl-CpG binding protein 2 gene. No cure exists so far. Rett girls are born after a normal pregnancy and have an apparently normal development throughout the first 6-18 months of life. Subsequently, they start to show symptoms including severe cognitive impairment, stereotypic hand movements, loss of already learned skills, epilepsy, intermittent systemic hypoxia, breathing disturbances and impaired mitochondrial function. It has been reported that a subunit of complex III of the mitochondrial respiratory chain is among the potentially dysregulated genes, the inner mitochondrial membrane is leaking protons, and also brain ATP levels seem to be affected. In the present work, it could be clearly shown by FAD/NADH autofluorescence imaging that increased oxidative burden appears already after the first postnatal week in the hippocampus of Rett mice. Furthermore, it has been confirmed that the hippocampal synaptic plasticity and the susceptibility to hypoxia are impaired. To evaluate whether free radical scavengers are capable of improving neuronal and mitochondrial dysfunction, Trolox – a water soluble vitamin E derivative – was applied to acute brain slices in vitro. Also chronic in vivo treatment was performed by bidaily intraperitoneal injections of Trolox. In vitro experiments verified that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, ameliorates cellular redox balance, and improves hypoxia tolerance in Mecp2-/y hippocampus. Adverse side effects of Trolox on mitochondrial function and seizure susceptibility can be excluded. In contrast, chronic in vivo Trolox-treatment did not show any beneficial outcome on body weight and/or size, motor function and learning, exploratory behavior, breathing function, mitochondria, or neuronal network function. The blood glucose level, the hypoxia tolerance as well as the short-term potentiation were significantly improved in Mecp2-/y mice by low dose Trolox treatment. Taken together, these findings demonstrate that the scavenger treatment in vitro is very promising for the treatment of various aspects of the neuronal dysfunction in Rett syndrome. However, the in vivo study identifies the route of drug administration and frequent animal handling as critical issues to be thoughtfully considered in study design.
Keywords: Rett syndrome; oxidative stress; mitochondrial metabolism; synaptic dysfunction; vitamin E treatment