title: 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 confirmedin vitrothat 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-controlledin vivotreatment 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 inMecp2-/ymice, 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 vivoTrolox 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.
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Göttingen, Germany; Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-UniversitätGöttingen, Germany.
authors.forename: Oliwia A
authors.initials: OA
authors.lastname: Janc
authors.affiliation: Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Germany.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Hüser
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Göttingen, Germany; Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-UniversitätGöttingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dietrich
authors.affiliation: Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Germany.
authors.forename: Belinda
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Göttingen, Germany; Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-UniversitätGöttingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Menzfeld
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Göttingen, Germany; Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Georg-August-UniversitätGöttingen, Germany.
authors.forename: Swen
authors.initials: S
authors.lastname: Hülsmann
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Göttingen, Germany; Zentrum Physiologie und Pathophysiologie, Institut für Neuro- und Sinnesphysiologie, Universitätsmedizin Göttingen, Georg-August-UniversitätGöttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
keywords: Rett syndrome; antioxidants; disease progression; oxidative stress; pharmacotherapy; preclinical study; reactive oxygen species (ROS); redox signaling