橋本 謙二

Background: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls. Methods: Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured. Results: Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-I showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects. Conclusions: These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.

The present study was undertaken to examine whether the second generation antibiotic drug minocycline attenuates behavioral changes (eg, acute hyperlocomotion and prepulse inhibition ( PPI) deficits) in mice after the administration of the N-methyl-D-aspartate ( NMDA) receptor antagonist (+)-MK-801 ( dizocilpine). Dizocilpine (0.1 mg/kg)-induced hyperlocomotion was significantly attenuated by pretreatment with minocycline ( 40 mg/kg). Furthermore, the PPI deficits after a single administration of dizocilpine ( 0.1 mg/kg) were attenuated by pretreatment with minocycline ( 10, 20, or 40 mg/kg), in a dose-dependent manner. Moreover, in vivo microdialysis study in the free-moving mice revealed that pretreatment with minocycline ( 40 mg/kg, i.p.) significantly attenuated the increase of extracellular dopamine (DA) levels in the frontal cortex and striatum after administration of dizocilpine ( 0.1 mg/kg), suggesting that the inhibition of dizocilpine-induced DA release by minocycline may, at least in part, be implicated in the mechanism of action of minocycline with respect to dizocilpine-induced behavioral changes in mice. These findings suggest that minocycline could attenuate behavioral changes in mice after the administration of the NMDA receptor antagonist dizocilpine. Therefore, it is possible that minocycline would be a potential therapeutic drug for schizophrenia.

この総説では多様なグリア細胞のうち，アストロサイトに焦点を合わせた研究の成果を中心として医薬品開発への手がかりとしての重要性を解説した．小泉はアストロサイトのP2Y1受容体を制御し正常に維持する薬物が脳虚血等の酸化ストレスによる神経細胞およびアストロサイトの機能障害保護作用を持つ可能性を示唆した．工藤はアストロサイトが保有するグリオトランスミッターやサイトカインを遊離させる薬物の探索によって新しい中枢神経作用薬を発見することが可能であることを示唆した．和田はグリア細胞に存在するGPCRの研究が中枢神経系薬理学的研究に極めて重要な意味を持つことをNtsr2，PAC1およびVPAC2を実例として示した．橋本は統合失調症発症のグルタミン酸仮説の要になるNMDA受容体機能低下の原因がグリア細胞で合成されるD-セリンの減少やキヌレン酸の増加にある可能性を示唆し，統合失調症の新しい治療薬の開発にはグリア細胞に焦点を当てることが重要であることも示唆した．

Kynurenic acid (KYNA), one of the tryptophan metabolites, serves as an endogenous antagonist of N-methyl-D-aspartate and the alpha 7 nicotinic receptors in mammalian brains. In the present study, the column-switching high-performance liquid chromatography (HPLC) method vie developed for plasma KYNA was extended and validated for the determination of brain KYNA. Rat cerebrum, cerebellum and brainstem homogenates were deproteinized with acetone, and the extracts reconstituted with the mobile phase were injected onto the HPLC. In spite of the facile pretreatment, the fluorescence peak of KYNA in the cerebrum, cerebellum and brainstem was clearly observed with no interfering peaks. Intra- and inter-day precisions [relative standard deviation (%)] and accuracies [relative mean error (%)] were satisfactory (< +/- 5.8%). The concentrations of KYNA in rat cerebrum, cerebellum, and brainstem were 224 +/- 65.8, 606 +/- 191, and 323 +/- 114 fmol/mg protein (n = 5), respectively. The proposed HPLC method will be a useful tool for pharmacokinetic and pharmacological researches on brain KYNA. Copyright (c) 2007 John Wiley & Sons, Ltd.

ミドカイン欠損マウスにおけるプレパルス抑制障害が、どのような分子メカニズムにより引き起こされ、定型および非定型の抗精神病薬により改善されるか検討した。ミドカイン欠損マウスにおけるプレパルス抑制(PPI)障害は、haloperidolあるいはclozapine投与によって、野生型と同じレベルに改善した。また、成体ミドカイン欠損マウスでは、グルタミン酸系の神経化学的、行動学的異常は検出しなかった。グルタミン酸伝達系ではなく、すでに報告したドパミン機能低下が、PPI異常を引き起こしている可能性から、ドパミン機能低下が想定される統合失調症サブタイプモデルとしてのミドカイン欠損マウスの有用性が示唆された。

This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N- methyl- D- aspartate receptor antagonist phencyclidine ( PCP). In the novel object recognition test, repeated administration of PCP ( 10 mg/ kg/ day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP- induced cognitive deficits were significantly improved by subsequent subchronic ( 2- week) administration of fluvoxamine ( 20 mg/ kg/ day), but not paroxetine ( 10 mg/ kg/ day). Furthermore, the effect of fluvoxamine on PCP- induced cognitive deficits was antagonized by co- administration of the selective sigma- 1 receptor antagonist NE- 100 ( 1 mg/ kg/ day). Moreover, PCP- induced cognitive deficits were also significantly improved by subsequent subchronic ( 2- week) administration of the selective sigma- 1 receptor agonist SA4503 ( 1 mg/ kg/ day) or neurosteroid dehydroepiandrosterone 3-sulfate ( DHEA- S; 25 mg/ kg/ day). The effects of SA4503 or DHEA- S were also antagonized by co- administration of NE- 100 ( 1 mg/ kg/ day), suggesting the role of sigma- 1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs ( fluvoxamine, paroxetine, SA4503) alone or combination with NE- 100 did not alter PCP- induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma- 1 receptors plays a role in the active mechanisms of fluvoxamine on PCP- induced cognitive deficits in mice. Therefore, sigma- 1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.

Background: Positron emission tomography (PET) studies of methamphetamine (METH) abusers suggest that psychotic symptoms of METH abusers may be attributable to the reduction of dopamine transporters (DAT) in the human brain. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with METH abuse. Methods: Using a PET study in conscious monkeys, we investigated whether the second generation antibiotic minocycline could protect against the reduction of DAT in monkeys treated with METH (2 mg/kg X 3, 3-hour intervals). Results: Pretreatment and subsequent administration of minocycline significantly attenuated the reduction of DAT in the striatum of monkeys treated with METH. Furthermore, posttreatment and subsequent administration of minocycline also significantly attenuated the reduction of DAT. In contrast, repeated administration of minocycline alone did not alter the density of DAT in the striatum of monkeys treated with METH. Conclusions: Our findings suggest that minocycline protects against METH-induced neurotoxicity in the monkey brain. Therefore, minocycline is likely to be a promising therapeutic agent for the treatment of several symptoms associated with METH use in humans.

Background: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. Methods: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. Results: The serum levels (503.5 +/- 160.5 pg/mL (mean +/- SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0,p &lt; 0.001) lower than those (817.6 +/- 232.4 mu g/mL (mean SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. Conclusions: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism. (c) 2006 Elsevier Inc. All rights reserved.

Patients who have not responded to recommended antipsychotic medications should be considered for electroconvulsive therapy (ECT). However, there has been controversy about the standardized methods of continuation and maintenance ECT in the management of treatment-resistant schizophrenia. We describe a patient with a serious case of disorganized schizophrenia who had not responded well with any typical and atypical antipsychotic drug for seven years, but responded remarkably to acute ECT. Continuation ECT was necessary to sustain a positive therapeutic response. The patient showed dramatic improvement from 70 to 20 in the 18-item Brief Psychiatric Rating Scale (BPRS) score (71% reduction) after acute ECT and continuation ECT. Using maintenance ECT, she was able to live in the custody of her parents after 7-years hospitalization. This case report suggests that continuation and maintenance ECT benefits patients with serious cases of refractory schizophrenia. (c) 2006 Elsevier Inc. All rights reserved.

Background: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. Methods: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. Results: The serum levels (503.5 +/- 160.5 pg/mL (mean +/- SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0,p &lt; 0.001) lower than those (817.6 +/- 232.4 mu g/mL (mean SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. Conclusions: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism. (c) 2006 Elsevier Inc. All rights reserved.

Background: Kynurenic acid (KYNA)-a tryptophan metabolite-elicits antagonistic activity against glutaminergic and cholinergic receptors; it has been suggested to have some relationship with neurological disorders. Considering this, serum KYNA may be an important marker in clinical diagnosis. We determined serum KYNA concentration and elucidate its correlation with several amino acids in human serum.Methods: KYNA and amino acids concentrations in human serum of healthy subjects [n=35 (21 males and 14 females)] were determined by HPLC with fluorescence detection; thus, the correlation between KYNA concentration and that of several amino acids was examined in these subjects.Results: Of the amino acids examined in this study, a significant negative correlation was observed between KYNA and glutamine (Gln) concentrations (r=-0.452, p < 0.01) in the healthy subjects, particularly males (r=-0.687, p < 0.01), and age-related changes were not observed. In addition to Gln, Gly and Ala concentrations showed a significant negative correlation with KYNA concentration in the serum of mate subjects (r=-0.440 and -0.456, respectively, p < 0.05).Conclusion: The significant correlation between KYNA and Gln concentrations in vivo may support the previous finding that kynurenine aminotransferase I (KAT I), responsible for the biosynthesis of KYNA, was identical to Gln transaminase K (GTK), which catalyses the transamination of Gln to 2-oxoglutamic acid. Both KYNA and Gln concentrations in vivo might be influenced due to altered KAT I/GTK activity. (c) 2006 Elsevier B.V. All rights reserved.

Brain-derived neurotrophic factor (BDNF) is the most-abundant neurotrophin in the brain. In mammals, it Is synthesized as a precursor called proBDNF, which is proteolytically cleaved to generate mature BDNF. The BDNF gene is located on chromosome 11p13, and a functional single nucleotide polymorphism (SNP) of this gene has been shown to produce a valine (Val)-to-methionine (Met) substitution in the proBDNF protein at codon 66 (Va166Met). Several papers suggest that this SNP is related to decreased hippocampal volume and hippocampus-mediated memory performance in humans. Recently, Chen et al.((1)) generated a variant BDNF mouse (BDNFMet/Met) that reproduces the pheno-typic hallmarks in humans with a variant Met allele. In the behavioral analysis, BDNFMet/Met mice show increased anxiety-related behaviors. This mini-review examines the impact of Met substitution of proBDNF on anxiety-related behaviors. (c) 2007 Wiley Periodicals, Inc.

N-Methyl-D-aspartate (NMDA) receptor antagonists are known to induce schizophrenia-like psychotic symptoms and cognitive deficits in humans, and have been shown to cause neuronal damage in the posterior cingulate gyrus (PCG) of rodents. Patients with chronic schizophrenia exhibit generalized cognitive deficits, but it remains unclear whether or not the PCG is related to their cognitive dysfunction. To determine what biochemical changes may occur in the PCG of patients with chronic schizophrenia, and to ascertain whether or not such abnormalities may be related to the incidence of cognitive deficits, we obtained cognitive scores and proton magnetic resonance spectra (MRS) from the PCG and the left and right medial temporal lobes (MTL) of 19 patients with schizophrenia and 18 age- and sex-matched normal healthy controls. Compared to the normal controls, the patients with chronic schizophrenia showed significantly worse cognitive performance on verbal and visual memory tests, verbal fluency tests, and the Trail Making Test. The ratio of N-acetylaspartate to creatine and phosphocreatine (NAA/Cr) in the PCG of the patients was significantly lower than that of the controls. Moreover, the NAA/Cr in the PCG of the healthy controls exhibited age-related decline, whereas in the patients with schizophrenia, the corresponding values were consistently low, regardless of age. These findings are thus in accord with current speculation about neuronal dysfunction in the PCG based on the NMDA hypofunction hypothesis regarding the pathophysiology of chronic schizophrenia. (c) 2005 Elsevier Ltd. All rights reserved.

Recent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (-1106T &gt; C, -906T &gt; C, -809G &gt; A, -616G &gt; C, -521T &gt; C, -376C &gt; T, -291C &gt; T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) -809G &gt; A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, -809G &gt; A, -616G &gt; C, -291C &gt; T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.

Although preclinical studies suggest that methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propan-1-one) and 5-MeO-MIPT (5methoxy-N-methyl,N-isopropyl tryptamine) may have psychostimulant properties, the scientific reports about the clinical effects of these agents are scant. We describe a 27-year-old male patient with substance intoxication after a single ingestion of the mixture of methylone and 5-MeO-MIPT. Though he bought the drug as pure methylone powder via an internet order, our chemical analyses indicated that the drug was composed of about 60% methylone (120 mg) and 38% 5-MeO-MIPT (76 mg). This case report suggests that clinicians should be alert to the possibility of the emergence of methylone or 5-MeO-MIPT intoxication, and substance-related mental disorder may be complicated by combined use of other psychoactive drugs. (c) 2006 Elsevier Inc. All rights reserved.

Background: The neurobiological basis for autism remains poorly understood. Given the key role of transforming growth factor-beta 1 (TGF-beta 1) in brain development, we hypothesized that TGF-beta 1 plays a role in the pathophysiology of autism. In this study, we studied whether serum levels of TGF-beta 1 are altered in patients with autism. Methods: We measured serum levels of TGF-beta 1 in 19 male adult patients with autism and 21 age-matched male healthy subjects using enzyme-linked immunosorbent assay (ELISA). Results: The serum levels (7.34 +/- 5.21 ng/mL(mean +/- S.D.))of TGF-beta 1 in the patients with autism were significantly (z = -5.106, p &lt; 0.001) lower than those (14.48 +/- 1.64 ng/mL (mean +/- S.D.)) of normal controls. However, there were no marked or significant correlations between serum TGF beta 1 levels and other clinical variables, including Autism Diagnostic Interview-Revised (ADI-R) scores, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), aggression, Theory of Mind, and Intellectual Quotient (IQ) in patients. Conclusions: These findings suggest that decreased levels of TGF+beta 1 may be implicated in the pathophysiology of autism. (c) 2006 Elsevier Inc. All rights reserved.

The effects of minocycline on behavioral changes and neurotoxicity in the dopaminergic neurons induced by the administration of methamphetamine (METH) were studied. Pretreatment with minocycline (40 mg/kg) was found to attenuate hyperlocomotion in mice after a single administration of METH (3 mg/kg). The development of behavioral sensitization after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly attenuated by pretreatment with minocycline (40 mg/kg). A reduction in the level of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenyl acetic acid (DOPAC), in the striatum after the repeated administration of METH (3 mg/kg x 3, 3-h interval) was attenuated in a dose-dependent manner by pretreatment with and the subsequent administration of minocycline (10, 20, or 40 mg/kg). Furthermore, minocycline (40 mg/kg) significantly attenuated a reduction in DA transporter (DAT)-immunoreactivity in the striatum after repeated administration of METH. In vivo microdialysis study demonstrated that pretreatment with minocycline (40 mg/kg) significantly attenuated increased extracellular DA levels in the striatum after the administration of METH (3 mg/kg). In addition, minocycline was not found to alter the concentrations of METH in the plasma or the brain after three injections of METH (3 mg/kg), suggesting that minocycline does not alter the pharmacokinetics of METH in mice. Interestingly, METH-induced neurotoxicity in the striatum was significantly attenuated by the post-treatment and subsequent administration of minocycline (40 mg/kg). These findings suggest that minocycline may be able to ameliorate behavioral changes as well as neurotoxicity in dopaminergic terminals after the administration of METH. Therefore, minocycline could be considered as a useful drug for the treatment of several symptoms associated with METH abuse in humans. (c) 2006 Elsevier Inc. All rights reserved.

Background: Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, D-serme, and L-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism. Methods: We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography. Results: Serum levels (mean=89.2 mu M, S.D.=21.5) of glutamate in the patients with autism were significantly (t=-4.48, df=35,p &lt; 0.001) higher than those (Mean=61.1 mu M, S.D.= 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, D-serine, L-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r=0.523,p=0.026) between serum glutamate levels and Autism Diagnostic Interview-Revised (ADI-R) social scores in patients. Conclusions: The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism. (c) 2006 Elsevier Inc. All rights reserved.