Evaluierung einer oralen Antioxidantien-Therapie in einem Mausmodell für das Rett-Syndrom

Evaluation of an oral antioxidant therapy in a mouse model of Rett syndrome

by Lena Rinne
Doctoral thesis
Date of Examination:2021-09-07
Date of issue:2021-09-06
Advisor:Prof. Dr. Michael Müller
Referee:Prof. Dr. Michael Müller
Referee:Prof. Dr. Thomas Dresbach
Persistent Address: https://dx.doi.org/10.53846/goediss-8812

 

 

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Abstract

English

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by spontaneous mutations in the X-chromosomal gene MECP2 encoding methyl-CpG binding protein 2 (MeCP2). Affecting almost exclusively females, it causes reduced head and brain growth, loss of speech, cognitive and motor impairment, epilepsy and breathing disturbances. MECP2 aberrations are associated with mitochondrial impairment and increased generation of reactive oxygen species. At the same time, the activity and serum levels of antioxidants seem reduced, leading to redox imbalance and oxidative burden. Accordingly, treatment with radical scavengers represents a promising therapeutic approach. The aim of this work was to evaluate an oral antioxidant therapy in a mouse model of RTT. It was recently confirmed that intraperitoneal injection of vitamin E-derivative Trolox improves cellular redox balance in male MeCP2-deficient mice. However, there was no amelioration in phenotypic symptoms like body weight and size, breathing and motor function. Due to suspected handling effects, this work investigates the less-invasive oral supplementation of antioxidants and a synergistic substance combination of vitamin E, α-lipoic acid and N-acetylcysteine. Analysing phenotypic parameters, Nissl-stained brain slices and H2O2 release by isolated cortical mitochondria in a coupled reaction of Amplex UltraRed and horseradish peroxidase, several improvements related to oral antioxidant treatment could be registered. In particular, the antioxidant diet (AOF) led to a significant increase in cortical layer thickness and the size of pyramidal neurons in male MeCP2-deficient mice at postnatal day (PD) 50. In MeCP2-deficient females at PD 50 AOF caused a significant increase in body size and brain weight. In addition, they developed significantly larger hemispherical areas and pyramidal cell somata compared to untreated Rett mice. At PD 400 Rett females showed enlarged hippocampal areas. However, they also developed an obese phenotype. Measuring H2O2 release by isolated cortical mitochondria of untreated Rett males at PD 50 showed exaggerated H2O2 releases compared to wild type (WT) mice. Even the AOF could not make this difference disappear. In addition, the AOF had unexpected effects on WT mice whose mitochondria produced significantly higher amounts of H2O2 related to AOF. Therefore, the exact individual dosage of antioxidants and restoration of cellular redox balance deserve further detailed evaluation.
Keywords: Rett syndrome; redox imbalance; radical scavengers; vitamin E; α-lipoic acid; N-acetylcysteine; Amplex UltraRed
 
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