Daisuke Matsuzawa

Negative correlation between brain glutathione level and negative symptoms in schizophrenia: A 3T 1H-MRS study

Background Glutathione (GSH), a major intracellular antioxidant, plays a role in NMDA receptor-mediated neurotransmission, which is involved in the pathophysiology of schizophrenia. In the present study, we aimed to investigate whether GSH levels are altered in the posterior medial frontal cortex of schizophrenic patients. Furthermore, we examined correlations between GSH levels and clinical variables in patients. Methods and Findings Twenty schizophrenia patients and 16 age- and gender-matched normal controls were enrolled to examine the levels of GSH in the posterior medial frontal cortex by using 3T SIGNA EXCITE 1H-MRS with the spectral editing technique, MEGA-PRESS. Clinical variables of patients were assessed by the Global Assessment of Functioning (GAF), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), and five cognitive performance tests (Word Fluency Test, Stroop Test, Trail Making Test, Wisconsin Card Sorting Test and Digit Span Distractibility Test). Levels of GSH in the posterior medial frontal cortex of schizophrenic patients were not different from those of normal controls. However, we found a significant negative correlation between GSH levels and the severity of negative symptoms (SANS total score and negative symptom subscore on BPRS) in patients. There were no correlations between brain GSH levels and scores on any cognitive performance test except Trail Making Test part A. Conclusion These results suggest that GSH levels in the posterior medial frontal cortex may be related to negative symptoms in schizophrenic patients. Therefore, agents that increase GSH levels in the brain could be potential therapeutic drugs for negative symptoms in schizophrenia.

Enhanced carbonyl stress in a subpopulation of schizophrenia.

CONTEXT Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B(6) is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. OBJECTIVES To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. DESIGN An observational biochemical and genetic analysis study. SETTING Multiple centers in Japan. PARTICIPANTS One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. MAIN OUTCOME MEASURES Pentosidine and vitamin B(6) concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. RESULTS We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. CONCLUSIONS Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes.

Specific metabolites in the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia: A preliminary study

We measured brain metabolites in the medial prefrontal cortex of 19 schizophrenic patients and 18 healthy controls by 3 T proton magnetic resonance spectroscopy ((1)H MRS), and examined the relationship between prefrontal cortex-related neurocognitive functions and brain metabolites in the medial prefrontal cortex. The patients with schizophrenia exhibited deficits on the verbal fluency, Wisconsin card sorting test (WCST), trail making test, Stroop test and digit span distraction test (DSDT), but not on the Iowa gambling test. The patients showed statistical significant changes in the ratio of glutamine/glutamate, the ratio of N-acetyl-l-aspartate (NAA)/glycerophosphorylcholine plus phosphorylcholine (GPC+PC) and the levels of taurine in the medial prefrontal cortex compared with normal controls. Furthermore, we found significant correlations of the ratio of glutamine/glutamate with WCST and DSDT scores, the ratio of NAA/(GPC+PC) with verbal fluency and WCST scores, and the levels of taurine with scores on the Stroop test and Trail making test A among the participants. The ratios of NAA/(GPC+PC) and (GPC+PC)/(Cr+PCr) had significant relationships with the duration of untreated psychosis of the schizophrenic patients. The glutamine/glutamate ratio and levels of taurine were significantly related to the duration of illness of the patients. These data suggest that specific metabolites of the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia.

Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: as a biological predictor of response to group cognitive behavioral therapy.

Little is known about biological predictors of treatment response in panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common etiologies of depression and anxiety, the authors examined serum BDNF levels of the patients with panic disorder, and its correlation with therapeutic response to group cognitive behavioral therapy (CBT). Group CBT (10 consecutive 1 h weekly sessions) was administered to the patients with panic disorder after consulting the panic outpatient special service. Before treatment, serum concentrations of BDNF and total cholesterol were measured. After treatment, we defined response to therapy as a 40% reduction from baseline on Panic Disorder Severity Scale (PDSS) score as described by [Barlow, D.H., Gorman, J.M., Shear, M.K., Woods, S.W., 2000. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA. 283, 2529-2536]. There were 26 good responders and 16 poor responders. 31 age- and sex-matched healthy normal control subjects were also recruited in this study. The serum BDNF levels of the patients with poor response (25.9 ng/ml [S.D. 8.7]) were significantly lower than those of the patients with good response (33.7 ng/ml [S.D. 7.5]). However, there were no significant differences in both groups of the patients, compared to the normal controls (29.1 ng/ml [S.D. 7.1]). No significant differences of other variables including total cholesterol levels before treatment were detected between good responders and poor responders. These results suggested that BDNF might contribute to therapeutic response of panic disorder. A potential link between an increased risk of secondary depression and BDNF remains to be investigated in the future.

Magnetic Resonance Spectroscopy Study of the Antioxidant Defense System in Schizophrenia

Accumulating evidence suggests that oxidative stress associated with impaired metabolism of the antioxidant glutathione (GSH) plays a key role in the pathophysiology of schizophrenia. Magnetic resonance spectroscopy (MRS) is one of the brain-imaging techniques that can quantitatively measure bioactive substances such as GSH in the intact human brain. Four different measurement sequences including double quantum coherence (DQC) filtering, MEscher-GArwood Point-RESolved Spectroscopy (MEGA-PRESS), Stimulated Echo Acquisition Mode (STEAM), and PRESS have been used to evaluate the (1)H-MRS measurement of GSH in the brains of patients with schizophrenia. Although the results of these studies were somewhat diverse, a negative correlation between brain GSH levels and the severity of negative symptoms in schizophrenia patients suggests that increasing the brain GSH levels might be beneficial for schizophrenia patients with negative symptoms. Moreover, a recent double-blind, placebo-controlled study demonstrated that add-on of N-acetyl-l-cysteine (NAC), a precursor of GSH, to antipsychotics improved the negative symptoms and reduced the side effects (akathisia) in patients with chronic schizophrenia. MRS study of the antioxidant defense system in schizophrenia still remains in the infantile stage; future studies are needed to examine the brain GSH level before and after NAC treatment, and thereby to provide direct evidence of the induced production of GSH in the living brain.

Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain

Bisphenol A (BPA), an endocrine-disrupting chemical, is widely present in the environment. It has been reported that perinatal exposure to low doses of BPA that are less than the tolerable daily intake level (50μg/kg/day) affects anxiety-like behavior and dopamine levels in the brain. Although the dopaminergic system in the brain is considered to be related to anxiety, no study has reported the effects of low-dose BPA exposure on the dopaminergic system in the brain and on anxiety-like behavior using the same methods of BPA exposure. To investigate the relationship between alterations in anxiety-like behavior and changes in the dopaminergic system in the brain induced by BPA, we examined the effects of BPA on anxiety-like behavior using an open field test in juvenile and adult mice and measured DA and DOPAC levels and the DOPAC/DA ratio in the dorsal hippocampus (HIP), amygdala (AMY), and medulla oblongata (MED) using high-performance liquid chromatography (HPLC) in adult mice. In males, BPA decreased the time spent in the center area of the open field in both juveniles and adults. In addition, BPA increased DA levels in the dorsal HIP and MED and decreased the DOPAC/DA ratio in the dorsal HIP, AMY, and MED in adults. The activity of monoamine oxidase (MAO)-B, the enzyme that metabolizes DA into DOPAC, was reduced in the MED. In females, those changes were not observed. These results suggest that an increase in anxiety-like behavior induced by perinatal exposure to BPA may be related to decreases in DA metabolites in the brain, and there are sex differences in those BPA effects.

d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice

Several lines of evidence suggest that the N-methyl-D-aspartate (NMDA) receptor plays a significant role in fear conditioning and extinction. However, our knowledge of the role of D-serine, an endogenous ligand for the glycine site of the NMDA receptor, in fear extinction is quite limited compared to that of D-cycloserine, an exogenous partial agonist for the same site. In the current study, we examined the effects of D-serine on fear extinction and phosphorylation of extracellular signal-regulated kinase (ERK) in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) during the process of fear extinction. Systemic administrations of D-serine (2.7 g/kg, i.p.) with or without the ERK inhibitor SL327 (30 mg/kg, i.p.) to C57BL/6J mice were performed before fear extinction in a cued fear conditioning and extinction paradigm. Cytosolic and nuclear ERK 1/2 phosphorylation in the hippocampus, BLA, and mPFC were measured 1h after extinction (E1h), 24h after extinction (E24h), and 1h after recall (R1h) by Western blotting. We found that D-serine enhanced the extinction of fear memory, and the effects of D-serine were reduced by the ERK phosphorylation inhibitor SL327. The Western blot analyses showed that D-serine significantly increased cytosolic ERK 2 phosphorylation at E1h in the hippocampus and cytosolic ERK 1/2 phosphorylation at R1h in the BLA. The present study suggested that D-serine might enhance fear extinction through NMDA receptor-induced ERK signaling in mice, and that D-serine has potential clinical importance for the treatment of anxiety disorders.

Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.

Quadri-pulse stimulation (QPS) induced LTP/LTD was not affected by Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene

It has been reported that the brain derived neurotrophic factor (BDNF) has some functional roles in inducing plasticity in the adult human brain and the Val66Met BDNF polymorphism affects the plasticity induction. In contrast, some long lasting effects were not fully induced in subjects with non-Val-Val polymorphism. In this communication, we retrospectively investigated whether this polymorphism affects the plastic changes induced by a newly developed stimulation method (quadripulse stimulation (QPS)) in 12 subjects. Both long-term potentiation (LTP) and long-term depression (LTD) like effects were induced by QPS for 30min in any types of BDNF Val66Met polymorphisms. This finding presents a striking contrast to the previous results, which showed reduced long-term effects elicited by some other induction methods in subjects with non-Val-Val polymorphism. Although we are not able to make a final conclusion about the effect of Val66Met BDNF polymorphism on QPS because of the small number of subjects studied, QPS may be less affected by the BDNF polymorphism than several other protocols for inducing LTP/LTD-like effects in humans. Several possibilities may explain this difference. One candidate possibility is that QPS may be long enough for inducing the late LTP/LTD like effect whereas the other stimulation methods may be long enough for early but not enough for late LTP/LTD like effect. It is conspicuous that the QPS for 30min does elicit stable bidirectional long-term effects even in subjects with non-Val-Val polymorphism of BDNF.

A functional glutathione S‐transferase P1 gene polymorphism is associated with methamphetamine‐induced psychosis in Japanese population

Several lines of evidence suggest that oxidative stress plays a role in the mechanisms of action of methamphetamine (MAP) in the human brain. Given the role of glutathione S‐transferases (GSTs) in the protection against oxidative stress, genes encoding the GSTs have been considered as candidates for association studies of MAP abuse. This study was undertaken to investigate the role of the functional polymorphism of GSTP1 gene exon 5 (Ile105Val) in the pathogenesis of MAP abuse. Genotyping for GSTP1 gene polymorphism exon 5 (Ile105Val) in 189 MAP abusers and 199 normal controls was performed by polymerase chain reaction (PCR)‐restriction fragment length polymorphism (RFLP). Association between GSTP1 gene polymorphism and clinical features (prognosis of psychosis (transient‐type and prolonged‐type), spontaneous relapse (positive and negative), and poly‐substance abuse) of MAP abusers was evaluated. Significant differences in the frequency of both alleles (P = 0.026, odds ratio: 1.70, 95% confidence intervals (CI) 1.06–2.72) and genotypes (P = 0.029) between MAP abusers and controls were detected. In particular, a significant difference in both genotype frequency (P = 0.013) and allele frequency (P = 0.014, odds ratio: 1.84, 95% CI 1.13–2.97) between MAP abusers with psychosis (transient‐type and prolonged‐type) and controls was detected. Our findings suggest that the polymorphism (Ile105Val) on exon 5 of the GSTP1 gene may contribute to a vulnerability to psychosis associated with MAP abuse in Japanese population.