Systemic Radical Scavenger Treatment of a Mouse Model of Rett Syndrome: Merits and Limitations of the Vitamin E Derivative Trolox

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder typically arising from spontaneous mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. The almost exclusively female Rett patients show an apparently normal development during their first 6–18 months of life. Subsequently, cognitive- and motor-impairment, hand stereotypies, loss of learned skills, epilepsy and irregular breathing manifest. Early mitochondrial impairment and oxidative challenge are considered to facilitate disease progression. Along this line, we recently confirmed in vitro that acute treatment with the vitamin E-derivative Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, ameliorates cellular redox balance and improves hypoxia tolerance in male MeCP2-deficient (Mecp2−/y) mouse hippocampus. Pursuing these promising findings, we performed a preclinical study to define the merit of systemic Trolox administration. Blinded, placebo-controlled in vivo treatment of male mice started at postnatal day (PD) 10–11 and continued for ~40 days. Compounds (vehicle only, 10 mg/kg or 40 mg/kg Trolox) were injected intraperitoneally every 48 h. Detailed phenotyping revealed that in Mecp2−/y mice, blood glucose levels, lipid peroxidation, synaptic short-term plasticity, hypoxia tolerance and certain forms of environmental exploration were improved by Trolox. Yet, body weight and size, motor function and the rate and regularity of breathing did not improve. In conclusion, in vivo Trolox treatment partially ameliorated a subset of symptoms of the complex Rett phenotype, thereby confirming a partial merit of the vitamin E-derivative based pharmacotherapy. Yet, it also became evident that frequent animal handling and the route of drug administration are critical issues to be optimized in future trials.

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC‐1 and roGFP1 Fluorescence

“…The conducted redox analyses now confirm for the first time that the oxidative burden in RTT also applies to astrocytes. As we verified earlier, the free-radical scavenger Trolox improved the cellular redox balance in organotypic hippocampal slices [40], dampened neuronal hyperexcitability in adult hippocampal slices of symptomatic Mecp2 −/y mice, and also improved the hypoxia tolerance as well as certain types of synaptic plasticity [66, 67]. In these studies, any adverse impact of Trolox on mitochondrial function could be ruled out, and also here, an overnight incubation of astrocytes with Trolox did not affect mitochondrial shape or ΔΨm.…”

“…Also, we previously confirmed that the vitamin E derivative Trolox improves cellular redox balance as well as synaptic function of the Mecp2 −/y hippocampus in vitro [40, 66], and it ameliorates some RTT symptoms when applied systemically to Mecp2 −/y mice [67]. Therefore, we assessed potential Trolox-mediated effects on mitochondrial function by incubating cell cultures overnight with this free-radical scavenger (100  μ M, 12–14 h).…”

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…Hypoxic conditions are often experienced in the form of intermittent hypoxia. It is a characteristic condition in patients suffering from obstructive sleep apnoea, familial dysautonomia (Weese-Mayer et al 2008a,b;Carroll et al 2012), Rett syndrome (Weese-Mayer et al 2006;Schüle et al 2008;Janc et al 2016), mitochondrial disease (Brown & Squier, 1996;Quintana et al 2012;Herst et al 2017), epilepsy (Cohen-Gadol et al 2004;Farrell et al 2016) and many other disorders characterized as 'dysautonomia' . These disorders are often associated with breathing disturbances, increased heart rate, decreased heart rate variability and other forms of disturbed cardiorespiratory coupling.…”

“…4; Viemari et al 2005). These mice and also human patients are characterized by increased oxidative stress (De Felice et al 2012Janc & Muller, 2014;Ciccoli et al 2015;Filosa et al 2015;Janc et al 2016;Pecorelli et al 2016). It is therefore conceivable that the oxidative stress seen after CIH also contributes to the breathing disturbances in Rett syndrome including the characteristic fluctuations in tidal volume (Fig.…”

Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice

“…The Mecp2 −/y mouse model of RTT shows a prominent respiratory phenotype that develops relatively late during postnatal development. At P40, breathing is more irregular and MeCP2-deficient mice show reduced respiratory rate and an increased number of longer breathing arrests (Janc et al, 2016 ). At this age, 5-ht 5b receptor expression in the medulla of Mecp2 −/y mice is still elevated while it drops to neonatal level in the WT littermates between P21 and P40 (Vogelgesang et al, 2017 ).…”