Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice

Oxidative stress and reduced brain glutathione (GSH) levels have been reported in psychiatric illnesses including schizophrenia and bipolar disorder. However the role of GSH in cognitive impairment in the illness remains unclear. Treatment of Sprague-Dawley rats and C57Bl/6 mice with 2-cyclohexene-1-one (CHX) dose-dependently reduced striatal and frontal cortical GSH levels similar to those in schizophrenia. In both species, GSH depletion resulted in disruption of short-term spatial recognition memory in a Y-maze test. In conclusion, GSH depletion induces cognitive impairment, which may be relevant to the role of GSH in psychiatric illnesses.

[1]  O. Pastoris,et al.  Age‐related acute depletion of cerebral glutathione by peroxidative stress , 1991, Journal of neuroscience research.

[2]  M. Cuénod,et al.  N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial , 2008, Biological Psychiatry.

[3]  G. Koob,et al.  Genetic Differences in Response to Novelty and Spatial Memory Using a Two-Trial Recognition Task in Mice , 2000, Neurobiology of Learning and Memory.

[4]  S. Mukherjee,et al.  Free radical pathology and antioxidant defense in schizophrenia: a review , 1996, Schizophrenia Research.

[5]  D. Butterfield,et al.  Effect of 2-cyclohexene-1-one-induced glutathione diminution on ischemia/reperfusion-induced alterations in the physical state of brain synaptosomal membrane proteins and lipids , 1997, Neuroscience.

[6]  S. Manabe,et al.  A novel model of continuous depletion of glutathione in mice treated with L-buthionine (S,R)-sulfoximine. , 2003, The Journal of toxicological sciences.

[7]  S. Oja,et al.  Modulation of glutamate receptor functions by glutathione , 2000, Neurochemistry International.

[8]  P Boesiger,et al.  Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo , 2000, The European journal of neuroscience.

[9]  P. Sonsalla.  The role of N-methyl-D-aspartate receptors in dopaminergic neuropathology produced by the amphetamines. , 1995, Drug and alcohol dependence.

[10]  M. Berk,et al.  N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial , 2008, Biological Psychiatry.

[11]  Jeffrey K. Yao,et al.  Oxidative Damage and Schizophrenia , 2001, CNS drugs.

[12]  M. Altschule,et al.  Effect of injections of placebos on blood glutathione level and eosinophil counts in chronic schizophrenia. , 1960, Comprehensive psychiatry.

[13]  W. Almaguer-Melian,et al.  Behavioral and biochemical effects of glutathione depletion in the rat brain , 2001, Brain Research Bulletin.

[14]  Yuan-Ye Ma,et al.  Improved spatial recognition memory in mice lacking adenosine A2A receptors , 2006, Experimental Neurology.

[15]  M. Le Moal,et al.  A two-trial memory task with automated recording: study in young and aged rats , 1992, Brain Research.

[16]  M. Berk,et al.  Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. , 2008, The international journal of neuropsychopharmacology.

[17]  B. Frey,et al.  Changes in Antioxidant Defense Enzymes after d-amphetamine Exposure: Implications as an Animal Model of Mania , 2006, Neurochemical Research.

[18]  T. Hastings,et al.  Role of oxidative changes in the degeneration of dopamine terminals after injection of neurotoxic levels of dopamine , 2000, Neuroscience.

[19]  M. Le Moal,et al.  Extension of a New Two-Trial Memory Task in the Rat: Influence of Environmental Context on Recognition Processes , 1997, Neurobiology of Learning and Memory.

[20]  R. Schiestl,et al.  Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice. , 2006, Carcinogenesis.

[21]  E. Pileblad,et al.  Intracerebroventricular Administration of l‐Buthionine Sulfoximine: A Method for Depleting Brain Glutathione , 1989, Journal of neurochemistry.

[22]  August G. Wang,et al.  Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. , 2006, American journal of human genetics.

[23]  G. Cerniglia,et al.  Microtiter plate assay for the measurement of glutathione and glutathione disulfide in large numbers of biological samples. , 1990, Analytical biochemistry.

[24]  R. Sandhir,et al.  Carbofuran-induced neurochemical and neurobehavioral alterations in rats: attenuation by N-acetylcysteine , 2006, Experimental Brain Research.

[25]  E. Pileblad,et al.  Effective depletion of glutathione in rat striatum and substantia nigra by L-buthionine sulfoximine in combination with 2-cyclohexene-1-one. , 1990, Life sciences.

[26]  J. Franco,et al.  Differential susceptibility following β-amyloid peptide-(1–40) administration in C57BL/6 and Swiss albino mice: Evidence for a dissociation between cognitive deficits and the glutathione system response , 2007, Behavioural Brain Research.

[27]  Y. Tochino,et al.  Methods for depleting brain glutathione. , 1989, Life sciences.

[28]  F. Holsboer,et al.  γ‐Glutamylglutamine and Taurine Concentrations Are Decreased in the Cerebrospinal Fluid of Drug‐Naive Patients with Schizophrenic Disorders , 1995, Journal of neurochemistry.

[29]  M. Cuénod,et al.  Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia , 2004, Neurobiology of Disease.

[30]  M. Cuénod,et al.  An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development , 2004, Neuroscience.

[31]  G. Réus,et al.  Effect of N-acetylcysteine and/or deferoxamine on oxidative stress and hyperactivity in an animal model of mania , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[32]  Wendy K. Adams,et al.  Serotonin depletion in the dorsal and ventral hippocampus: Effects on locomotor hyperactivity, prepulse inhibition and learning and memory , 2008, Neuropharmacology.

[33]  Ravinder Reddy,et al.  Altered Glutathione Redox State in Schizophrenia , 2005, Disease markers.

[34]  P. Mitchell,et al.  Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia. , 2007, Bipolar disorders.

[35]  I. Ferrier,et al.  Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. , 2006, Bipolar disorders.

[36]  Benicio N Frey,et al.  Oxidative stress markers in bipolar disorder: a meta-analysis. , 2008, Journal of affective disorders.

[37]  H. Wedner,et al.  Inhibition of human polymorphonuclear leukocyte function by 2-cyclohexene-1-one. A role for glutathione in cell activation. , 1981, The Journal of clinical investigation.

[38]  D. D. Hoff,et al.  Effect of inhibition of γ-glutamyltranspeptidase by AT-125 (Acivicin) on glutathione and cysteine levels in rat brain and plasma , 2004, Investigational New Drugs.

[39]  S. Oja,et al.  Release of [3H]GABA evoked by glutamate agonists from hippocampal slices: effects of dithiothreitol and glutathione , 1994, Neurochemistry International.

[40]  Trevor R. Norman,et al.  Behavioural studies of spatial working memory dysfunction in schizophrenia: A quantitative literature review , 2007, Psychiatry Research.

[41]  R. Agarwal,et al.  Potential Role of Cerebral Glutathione in the Maintenance of Blood-Brain Barrier Integrity in Rat , 1999, Neurochemical Research.

[42]  F. Schenk,et al.  Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: Relevance to schizophrenia , 2007, Neurobiology of Disease.