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      Torin 1 partially corrects vigabatrin-induced mitochondrial increase in mouse

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          Abstract

          Recent findings in mice with targeted deletion of the GABA-metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4-aminobutyric acid) in the activation of the mechanistic target of rapamycin (mTOR) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short-term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death.

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          Most cited references31

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          Cues, context, and long-term memory: the role of the retrosplenial cortex in spatial cognition

          Spatial navigation requires memory representations of landmarks and other navigation cues. The retrosplenial cortex (RSC) is anatomically positioned between limbic areas important for memory formation, such as the hippocampus (HPC) and the anterior thalamus, and cortical regions along the dorsal stream known to contribute importantly to long-term spatial representation, such as the posterior parietal cortex. Damage to the RSC severely impairs allocentric representations of the environment, including the ability to derive navigational information from landmarks. The specific deficits seen in tests of human and rodent navigation suggest that the RSC supports allocentric representation by processing the stable features of the environment and the spatial relationships among them. In addition to spatial cognition, the RSC plays a key role in contextual and episodic memory. The RSC also contributes importantly to the acquisition and consolidation of long-term spatial and contextual memory through its interactions with the HPC. Within this framework, the RSC plays a dual role as part of the feedforward network providing sensory and mnemonic input to the HPC and as a target of the hippocampal-dependent systems consolidation of long-term memory.
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            Taurine: the comeback of a neutraceutical in the prevention of retinal degenerations.

            Taurine is the most abundant amino acid in the retina. In the 1970s, it was thought to be involved in retinal diseases with photoreceptor degeneration, because cats on a taurine-free diet presented photoreceptor loss. However, with the exception of its introduction into baby milk and parenteral nutrition, taurine has not yet been incorporated into any commercial treatment with the aim of slowing photoreceptor degeneration. Our recent discovery that taurine depletion is involved in the retinal toxicity of the antiepileptic drug vigabatrin has returned taurine to the limelight in the field of neuroprotection. However, although the retinal toxicity of vigabatrin principally involves a deleterious effect on photoreceptors, retinal ganglion cells (RGCs) are also affected. These findings led us to investigate the possible role of taurine depletion in retinal diseases with RGC degeneration, such as glaucoma and diabetic retinopathy. The major antioxidant properties of taurine may influence disease processes. In addition, the efficacy of taurine is dependent on its uptake into retinal cells, microvascular endothelial cells and the retinal pigment epithelium. Disturbances of retinal vascular perfusion in these retinal diseases may therefore affect the retinal uptake of taurine, resulting in local depletion. The low plasma taurine concentrations observed in diabetic patients may further enhance such local decreases in taurine concentration. We here review the evidence for a role of taurine in retinal ganglion cell survival and studies suggesting that this compound may be involved in the pathophysiology of glaucoma or diabetic retinopathy. Along with other antioxidant molecules, taurine should therefore be seriously reconsidered as a potential treatment for such retinal diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Magnetic resonance spectroscopy of neurotransmitters in human brain.

              Magnetic resonance spectroscopy (MRS) is a noninvasive method that permits measurement of the concentration of specific biochemical compounds in the brain and other organ systems in precisely defined regions guided by MR imaging (MRI). Recently, MRS methods have been developed to measure specific neurotransmitters in the brain. More advanced MRS methods have been developed to measure the synthesis rates and turnover of specific neurotransmitters. These turnover rates can provide measures of brain metabolism similar to radioisotope techniques. Also, investigations of the relationship of brain metabolism and specific neurotransmitter systems are now possible using MRS. Here, we review the MRS techniques and studies of neurotransmitters in the human brain. A discussion of the potential use of these techniques in the context of certain pediatric neurotransmitter disorders will be presented.
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                Author and article information

                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                acn3
                Annals of Clinical and Translational Neurology
                John Wiley & Sons, Ltd (Chichester, UK )
                2328-9503
                2328-9503
                June 2015
                17 April 2015
                : 2
                : 6
                : 699-706
                Affiliations
                [1 ]Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University Spokane, Washington
                [2 ]Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Neuroscience Campus, Amsterdam, The Netherlands
                Author notes
                Correspondence K. M. Gibson, Experimental and Systems Pharmacology (ESP), WSU College of Pharmacy, PBS Building Room 347, 412 E. Spokane Falls Blvd, Spokane, WA 99202-2131. Tel: 509 358 7954; Fax: 509 368 6673; E-mail: mike.gibson@ 123456wsu.edu

                Funding Information Supported in part by National Institutes of Health R21 NS 85369 (K. M. G.).

                Article
                10.1002/acn3.200
                4479529
                4db04e7b-d140-46ec-8d32-a551fe32dd64
                © 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 07 January 2015
                : 09 March 2015
                : 11 March 2015
                Categories
                Brief Communications

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