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Zürich, Switzerland

Ralvenius W.T.,University of Zurich | Ralvenius W.T.,Center for Neuroscience Zurich | Benke D.,University of Zurich | Benke D.,Center for Neuroscience Zurich | And 7 more authors.
Nature Communications | Year: 2015

Agonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAA R). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAA R point-mutated mice, which express only one benzodiazepine-sensitive GABAA R subtype at a time, to show that targeting only α2GABAA Rs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Hu L.,University of Zurich | Hu L.,Center for Neuroscience Zurich | Ibrahim K.,Hamad Medical Corporation | Stucki M.,University of Zurich | And 11 more authors.
Journal of Inherited Metabolic Disease | Year: 2015

Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD+) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD+ depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD+ depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD+ depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder. © 2015, SSIEM. Source


Traber G.L.,University of Zurich | Traber G.L.,Zurich Center for Integrative Human Physiology | Chen C.-C.,University of Zurich | Chen C.-C.,Zurich Center for Integrative Human Physiology | And 11 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. Individuals with oculocutaneous albinism are predisposed to visual system abnormalities affecting the retina and retinofugal projections, which may lead to reduced visual acuity and Infantile Nystagmus Syndrome (INS). Due to absence of an established mammalian animal model, mechanisms underlying INS remain elusive. In this study, we screened wild-type mice of varying pigmentation for ocular motor abnormalities in order to identify a possible mouse model for INS. METHODS. Three albino mouse strains (CD1, BALB/c, DBA/1), and two normally pigmented strains (129S6, C57BL/6) were screened using infrared oculography. Varying visual stimuli (black or white background, stationary pattern, optokinetic, i.e., horizontally rotating pattern) were displayed to the full (fVF) or anterior visual field (aVF) of the restrained mouse. RESULTS. We found spontaneous nystagmus, specifically jerks and oscillations, in albino mice under all experimental conditions. Median eye velocity was between 0.8 and 3.4 deg/s, depending on the strain. In contrast, the eyes in pigmented mice were nearly stable with a median absolute eye velocity of below 0.4 deg/s. In albino mice, fVF optokinetic stimuli elicited an optokinetic response (OKR) in the correct direction, albeit with superimposed oscillations. However, aVF optokinetic stimuli evoked reversed OKR in these strains, a well known feature of INS. CONCLUSIONS. Based on our results, we endorse the investigated albino mouse strains as new animal models for INS. © 2012 The Association for Research in Vision and Ophthalmology, Inc. Source

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