PubMed Health⌕ Search

Biomedical subjects

Kenji Hashimoto

Publications and source records attributed to Kenji Hashimoto.

At least 37 records · Page 2Linked to original sources
PubMed2006

Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors.

We have previously reported that both transferred microglia and microglia-conditioned medium (MCM) potentiated the N-methyl-D-aspatate (NMDA) receptor-mediated synaptic responses in cortical neurons. To elucidate the mechanism underlying the potentiation of NMDA receptor-mediated responses by microglia, we examined the effects of MCM on NMDA-induced inward currents in mechanically dissociated hippocampal CA1 neurons under whole-cell patch recordings. MCM potentiated the amplitude of NMDA-induced currents up to 10-fold in a dose-dependent manner, and this effect of MCM remained even after boiling or cutting off molecules with a molecular mass more than 3 kDa. In the presence of glycine with a concentration sufficient to saturate the NMDA receptor glycine site, MCM failed to further potentiate the NMDA-induced currents. The glycine site antagonist 5, 7-dichrolokynurenic acid, significantly inhibited the effects of MCM. The effect of MCM was still observed even after treatment with D-amino acid oxidase, a D-serine degrading enzyme. On the other hand, MCM had no significant effect on the voltage-dependent Mg(2+) blockade of NMDA receptors. Furthermore, MCM enhanced the formation of the long-term potentiation in the Schaffer collateral pathway-CA1 pyramidal cell synapses. Using a high performance liquid chromatography system, we found the levels of both glycine and L-serine in MCM to be significantly higher than those in the control medium. It was also noted that an increased glycine productivity of microglia was observed in the hippocampus in the acute phase of neuronal injury. These observations strongly suggest that glycine is a major causative molecule released from microglia that potentiates the NMDA-induced currents.

Animals↗
PubMed2006

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors.

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.

Analysis of Variance↗
PubMed2006

Dopamine selectively induces migration and homing of naive CD8+ T cells via dopamine receptor D3.

The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8+ T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the Galphai class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8+ T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8+ T cells. Dopamine selectively induced adhesion of naive CD8+ T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8+ T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8+ T cells into lymph nodes. Collectively, naive CD8+ T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8+ T cells via D3.

Animals↗
PubMed2006

p16INK4A in oral squamous cell carcinomas--a correlation with biological behaviors: immunohistochemical and FISH analysis.

PURPOSE: The p16(INK4A) gene and Rb gene are key tumor suppressor genes in a cell cycle regulatory pathway that is commonly inactivated in various cancers. The disruption of p16(INK4A) expression has been reported in several types of carcinoma but sparse in the area of oral oncology. MATERIALS AND METHODS: The study included 66 cases who were diagnosed as oral squamous cell carcinoma. Immunohistochemical p16(INK4A) and pRb expression, fluorescence in situ hybridization analysis were performed to the resected materials. RESULTS: p16(INK4A) protein expressions were detected in 14 cases without lymph node metastasis versus in 4 cases with metastasis (P = .04). As to histopathological grading of the effect of chemotherapy, almost all the p16(INK4A)-positive cases (9 cases out of 10) exhibited the histological feature of being rather sensitive to chemotherapy (2B and better response according to Ohboshi and Shimosato's criteria) versus 17 of 33 negative cases (P = .02). Survival curves showed that the survival rate of patients with loss of p16(INK4A) expression was significantly worse than those with amplification and normal genetic dosage of p16(INK4A) (P < .0001). CONCLUSIONS: The expressions of p16(INK4A) were significantly correlated with biological behavior of OSCCs. These results indicate we can use p16(INK4A) as a marker of a prognostic prediction of oral cancer and it is useful for management of OSCCs.

Biomarkers, Tumor↗
PubMed2006

Slow oscillatory activity of rat globus pallidus neurons in vitro.

The neurons in the external segment of the pallidum in the primate develop a characteristic firing pattern consisting of alternately occurring long, 2-20 s, strongly active phases and long completely silent phases when the subthalamo-pallidal excitatory inputs are blocked. The induction of the activity might be a factor in the development of dyskinesias after the loss of subthalamic output. In this study, we used globus pallidus (GPe) slice preparations obtained from juvenile rats to examined the conditions that support the alternatively occurring long depolarized and hyperpolarized phases which we refer to as the slow oscillation (SO). SO was not induced by the blockade of glutamatergic inputs but was induced by treatments that depolarized dendrites and, at the same time, hyperpolarized the somata with current injections. The treatments included elevation of extracellular K(+), application of K-current blockers and the lowering of extracellular Ca(2+). Application of TTX or intracellular BAPTA injection blocked the SO, while the SO could be maintained in hyperpolarization-activated inward current blockers, organic Ca-current blockers and up to 200 microm CdCl(2). These results suggest that Na currents play a major role in the generation of SO in vitro. It can be speculated that Na currents are involved in the development of active phases observed in the GPe after blockade of the glutamatergic inputs in vivo and that the unique property of GPe neurons in maintaining strong activity after the elimination of the glutamatergic driving force contributes to the development of motor disorders such as dyskinesia.

Action Potentials↗
PubMed2006

Dietary restriction changes behaviours in brain-derived neurotrophic factor heterozygous mice: role of serotonergic system.

Accumulating evidence has suggested that brain-derived neurotrophic factor (BDNF) plays a role in eating behaviours, and that BDNF-heterozygous (+/-) mice exhibit abnormal behaviours (e.g. obesity, anxiety and aggression). The present study was undertaken to determine whether or not dietary restriction (DR) alters the behaviours in BDNF(+/-) mice, as DR has been shown to exert a number of beneficial effects on the brain. Eight-week-old male wild-type (+/+) and BDNF(+/-) mice were divided into two groups, ad libitum (AL) diet group and DR group, for 16 weeks. After carrying out a behavioural evaluation, we determined the BDNF mRNA levels, as well as mRNA levels for subtypes (5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C)) of the 5-HT receptor and 5-HT transporter (5-HTT), protein levels of BDNF and concentrations of 5-HT and 5-HIAA in the hypothalamus, hippocampus and frontal cortex. DR significantly ameliorated behaviours including obesity, anxiety and aggression in BDNF(+/-) mice. The concentrations of 5-HT and 5-HIAA in the frontal cortex, and 5-HT in the hippocampus, of BDNF(+/-) mice were significantly lower than those of wild-type mice. Interestingly, DR significantly increased the levels of 5-HT and 5-HIAA in the frontal cortex of BDNF(+/-) mice. These findings suggest that DR may alter the behaviours in BDNF(+/-) mice, and that the 5-HT system may be implicated in the beneficial effects of DR on these behaviours.

Aggression↗
PubMed2006

Optic strut as a radiographic landmark in evaluating neck location of a paraclinoid aneurysm.

OBJECTIVE: The optic strut (OS) is a candidate landmark in computed tomographic (CT) angiographic scans for the discrimination of intradural and extradural/intracavernous aneurysms involving the paraclinoid segment of the internal carotid artery. The goal of this study is to examine and confirm the qualifications of the OS as a landmark in CT angiographic scans for the preoperative evaluation of aneurysms in this region. METHODS: Seventeen consecutive patients with 18 unruptured paraclinoid aneurysms who underwent preoperative CT angiography scans and direct surgery between 1998 and 2005 were evaluated retrospectively. We focused on the relationships of the necks of aneurysms to the OS in CT angiographic scans and that of the necks to proximal dural rings during intraoperative examinations. RESULTS: Direct surgery revealed that 14 aneurysms, the necks of which were distal to the OS on CT angiographic scans, arose distal to the proximal dural rings. All aneurysms were clipped, except one exhibiting calcification of the neck. Three aneurysms, for which the neck was proximal to the OS on CT angiographic scans, revealed only a portion or nothing of their domes instead of their necks through the proximal dural rings after dissection of the distal dural rings. Dome coating with fibrin glue and a piece of muscle tissue or mere exploration was performed. Another aneurysm, of which the neck straddled the OS on CT angiographic scans, was found to arise across the proximal dural ring. Clipping of the neck was performed after dissection of the proximal dural ring. Of the source images of CT angiographic scans, the axial images were the most useful in evaluating the relationship of the neck of an aneurysm to the OS. CONCLUSION: On CT angiographic scans, the OS is a precise identification of the proximal dural ring that forms the superior border of the cavernous sinus. The aneurysms whose necks arise obviously distal to the OS on CT angiographic scans are able to be clipped without dissection of the proximal dural ring.

Adult↗
PubMed2006

Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals.

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

Animals↗
PubMed2005

Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes.

D-Serine is an endogenous coagonist that increases the opening of N-methyl-D-aspartate (NMDA)-type glutamate receptor channels. We previously reported a reduction of D-serine serum levels in schizophrenia, supporting the disease hypothesis of NMDA receptor-mediated hypo-neurotransmission. The serum levels of D-serine are thought to reflect brain d-serine content. It is important to understand whether there is a direct link between the altered D-serine levels and NMDA receptor expression in vivo or whether these are independent processes. Two polymorphisms are known to regulate the expression of NMDA receptor subunit genes: (GT)(n) (rs3219790) in the promoter region of the NR2A subunit gene (GRIN2A) and -200T > G (rs1019385) in the NR2B gene (GRIN2B). These polymorphisms are also reported to be associated with schizophrenia. Therefore, we examined the correlation between these two polymorphisms and d-serine serum levels in mentally healthy controls, schizophrenics and the combined group. We observed no significant genotype-phenotype correlations in any of the sample groups. However, analyses of larger sample numbers and the detection of additional polymorphisms that affect gene expression are needed before we can conclude that NMDA receptor expression and serum levels of d-serine, if involved in schizophrenia pathophysiology, are independent and additive events.

Adult↗
PubMed2005

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.

BACKGROUND: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. METHODS: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined. RESULTS: In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice. CONCLUSIONS: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

Animals↗
PubMed2005

Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of alpha 7 nicotinic acetylcholine receptors.

RATIONALE: Deficient inhibitory processing of the P50 auditory evoked potential is a pathophysiological feature of schizophrenia. Several lines of evidence suggest that alpha 7 nicotinic receptors play a critical role in this phenomenon. Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 auditory evoked potential, which is thought to be a rodent analog of the human P50 auditory evoked potential. OBJECTIVE: The present study was undertaken to examine whether tropisetron, a partial agonist at alpha 7 nicotinic receptors and an antagonist at 5-hydroxytryptamine-3 receptors, improves this deficit in DBA/2 mice. RESULTS: Administration of tropisetron (1 mg/kg i.p.) significantly improved the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. Coadministration of methyllycaconitine (MLA; 3 mg/kg i.p.), a partially selective antagonist at alpha 7 nicotinic receptors, significantly blocked the normalizing effect of tropisetron. Furthermore, MLA alone did not alter the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. CONCLUSIONS: The data suggest that tropisetron improves the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice by effects on alpha 7 and perhaps alpha 4 beta 2 nicotinic receptors. Tropisetron may be useful for the treatment of deficient inhibitory processing in schizophrenia.

Aconitine↗
PubMed2005

Association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and novelty seeking personality in healthy females.

A certain type of personality is at risk for developing psychiatric diseases. Several lines of evidence support the interaction between brain angiotensins and central catecholamine systems, and suggest that angiotensin I-converting enzyme (ACE) may be a reasonable candidate gene for psychiatric disorders. The present study examined the possibility that ACE insertion (I)/deletion (D) functional polymorphism might be associated with particular personality traits. Healthy Japanese subjects (N=184) were administered the Temperament and Character Inventory (TCI) and the NEO Personality Inventory Revised version (NEO-PI-R), and their ACE I/D polymorphisms were determined. There was an ethnic difference in the genetic distribution of ACE I/D between Japanese (D=34.5%) and Caucasians (D=55.2%). We found that the scores of novelty seeking (NS) in the Low-ACE group (II genotype) of healthy female subjects were significantly lower than those in the High-ACE group (ID or DD genotype) (p=0.018). Our findings suggested that the ACE I/D polymorphism might be associated with the NS personality trait in females, but not males. Taking into account the effects of multiple comparisons, this result should be interpreted with caution, and needs confirmation in a larger sample.

Adult↗
PubMed2005

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol.

This study was undertaken to examine the effects of subsequent administration of antipsychotic drugs (clozapine and haloperidol) on cognitive deficits in mice after repeated administration of phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg) significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent subchronic (2 weeks) administration of clozapine (5 mg/kg), but not haloperidol (0.1 mg/kg). These findings suggest that PCP-induced cognitive deficits using the novel object recognition test may be a potential animal model of atypical antipsychotic activity.

Analysis of Variance↗
PubMed2005

Posterior cingulate gyrus metabolic changes in chronic schizophrenia with generalized cognitive deficits.

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.

Adult↗
PubMed2005

Tropisetron improves deficits in auditory P50 suppression in schizophrenia.

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

Adult↗
PubMed2005

No changes in serum epidermal growth factor levels in patients with schizophrenia.

A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits.

Adult↗
PubMed2005

Functional polymorphism of the glutathione peroxidase 1 gene is associated with personality traits in healthy subjects.

BACKGROUND: Several lines of evidence suggest that a certain type of personality or temperament as well as oxidative stress may be implicated in the pathophysiology of neuropsychiatric diseases. Glutathione peroxidase 1 (GPX1) plays a role in the antioxidant defense system. OBJECTIVES: The authors studied the association between the GPX1 gene polymorphism and personality traits in healthy subjects. METHODS: One hundred forty-nine healthy subjects were enrolled. Analysis of the functional polymorphism (Pro198Leu) in the human GPX1 gene was performed. RESULTS: Subjects with Pro198Pro have significantly higher scores in openness to experience on the Revised NEO Personality Inventory (NEO-PI-R) as compared with subjects with other genotypes (Pro198Leu or Leu198Leu). In contrast, we detected no association between other personality dimensions on the NEO-PI-R and scores on the Temperament and Character Inventory. CONCLUSION: This study reports that the functional polymorphism (Pro198Leu) in the GPX1 gene might be associated with openness to experience among the personality traits.

Adult↗