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Biomedical subjects

Kenji Hashimoto

Publications and source records attributed to Kenji Hashimoto.

At least 73 records · Page 4Linked to original sources
PubMed2004

Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.

Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

Acetylcysteine↗
PubMed2004

Role of NMDA receptor subtypes in the induction of catalepsy and increase in Fos protein expression after administration of haloperidol.

The increase of Fos expression in the striatum induced by haloperidol, an antagonist of the dopamine D2 receptor, might be related to the activation of glutamatergic neurotransmission, especially that of N-methyl-D-aspartate (NMDA) receptors. In this study, using behavioral and immunohistochemical techniques, we examined the effects of a noncompetitive NMDA antagonist, (+)-MK-801, and an NMDA receptor NR2B subunit antagonist, ifenprodil, on catalepsy, an extrapyramidal symptom; in this context, we also considered the expression of Fos protein in the forebrain after the administration of haloperidol. Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg). Furthermore, pretreatment with (+)-MK-801 (0.2 mg/kg) significantly attenuated the induction of Fos-immunoreactive (IR) cells in the dorsomedial, dorsolateral, and ventrolateral striatum, but not in the shell region of the nucleus accumbens after the administration of haloperidol, whereas pretreatment with ifenprodil (10 mg/kg) significantly attenuated the induction of Fos-IR cells in all of these areas. It is known that ifenprodil binds sigma receptors and alpha-1 adrenergic receptors with high affinity. Pretreatment with the sigma receptor antagonist BD-1407 (3 mg/kg) or the alpha-1 adrenergic receptor antagonist prazosin (3 mg/kg) affected neither catalepsy nor the expression of Fos-IR cells after the administration of haloperidol. However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol. These results suggest that the NMDA receptor antagonists attenuated the induction of catalepsy and Fos-IR cells in forebrain after the administration of haloperidol. It was also suggested that haloperidol-induced expression of Fos-IR cells in the shell region of the nucleus accumbens might be differentially regulated by NMDA receptor subunits. Therefore, it appears that selective antagonists for the NR2B subunit of the NMDA receptor (e.g., CP-101,606) might be useful drugs for the treatment of extrapyramidal side effects (EPS) associated with the chronic use of typical antipsychotics such as haloperidol.

Adrenergic alpha-Antagonists↗
PubMed2004

Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans.

Family and twin studies have indicated that genes influence susceptibility to panic disorder, but the genes involved remain unknown. The neuropeptide angiotensin II has been found to be involved in anxiety and regulation of respiration which are important in the pathophysiology of panic attacks. Assuming that angiotensins may be candidate genes in panic disorder, we analyzed the association between panic disorder and angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism. We recruited 101 patients with panic disorder diagnosed according to DSM-IV criteria, and 184 control subjects in the study. No significant differences in the frequency of the genotype or allele in the polymorphism between patient and control groups were found (genotype, chi(2)=0.56, d.f.=2, P=0.77; allele, chi(2)=0.074, d.f.=1, P=0.78). This study suggests that the ACE I/D gene polymorphism is not directly associated with panic disorder in our Japanese patient group.

Adult↗
PubMed2004

Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders.

Several lines of evidence suggest that genetic factors might contribute to the pathogenesis of eating disorders and that brain-derived neurotrophic factor (BDNF) plays a role in the pathophysiology of eating disorders. To investigate the role of the BDNF gene in the susceptibility to eating disorders, we analyzed the BDNF 196G/A gene polymorphism in female patients with eating disorders and female normal controls. The difference in the genotype frequency between patients (n = 198) and normal controls (n = 222) was statistically significant (P = 0.029). Interestingly, a significant (P = 0.015) difference in the genotype frequency between normal controls and bulimia nervosa patients (n = 101) with binge-purging type was detected. This study suggests that the BDNF 196G/A gene polymorphism might be associated with a susceptibility to eating disorders.

Adolescent↗
PubMed2004

Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers.

Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.

Adult↗
PubMed2004

Association between brain-derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects.

Several lines of evidence suggest that a certain type of personality or temperament is at risk for developing neuropsychiatric diseases, and that brain-derived neurotrophic factor (BDNF) might be involved in pathophysiology of neuropsychiatric diseases such as mood disorders. Considering the role of BDNF and personality traits in the neuropsychiatric diseases, it is of interest to examine the association between BDNF gene polymorphism and personality test scores. In this study, we examined the association between 196 G/A the polymorphism in the coding region of the BDNF gene and personality traits scores (temperament and character inventory (TCI) and NEO personality inventory (NEO-PI)) in Japanese healthy subjects. We found that female, but not male, subjects with BDNF genotype A/A have high scores in reward dependence on TCI and high scores in extraversion on NEO-PI as compared with other genotypes (G/A or G/G), suggesting an association between reward dependence (or extraversion) personality traits and BDNF genotype in female subjects. Our findings suggest that BDNF 196 A/G polymorphism might be associated with personality traits in female, but not male, healthy subjects.

Adult↗
PubMed2004

Effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12- (4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons: an in vivo electrophysiological study.

This study examined the effect of the p.o. administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on the activity of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in anesthetized male Sprague-Dawley rats. This was accomplished using in vivo electrophysiology. The acute p.o. administration of Y-931 did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals. A single p.o. administration of 3 and 10 mg/kg of Y-931 significantly increased and decreased, respectively, the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The acute administration of 3 mg/kg of Y-931 significantly altered the firing pattern parameters for all spontaneously active SNC DA. The 3 and 10 mg/kg doses of Y-931 significantly increased the degree of bursting and irregular activity of spontaneously active VTA and SNC DA neurons firing in a bursting pattern. The repeated p.o. administration (21 days) of 1, 3, or 10 mg/kg of Y-931 significantly decreased the number of spontaneously active VTA DA neurons but had no significant effect on SNC DA neurons compared to vehicle-treated animals. The repeated administration of Y-931 did not significantly alter the firing pattern of all spontaneously active SNC or VTA DA neurons. Our findings indicate that the acute and chronic administration of Y-931 significantly alters the activity of midbrain DA neurons in rats and the electrophysiological profile of chronic Y-931 resembles that of atypical antipsychotic agents.

Action Potentials↗
PubMed2004

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study.

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.

Action Potentials↗
PubMed2004

Critical role of brain-derived neurotrophic factor in mood disorders.

The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders.

Animals↗
PubMed2004

Possible role of D-serine in the pathophysiology of Alzheimer's disease.

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.

Aged↗
PubMed2004

Decreased cell proliferation in the dentate gyrus of alpha 7 nicotinic acetylcholine receptor heterozygous mice.

It is suggested that deficits of alpha 7 nicotinic acetylcholine receptors (nAChRs) might be associated with the cognitive impairments of Alzheimer's disease and schizophrenia, and that agonists for alpha 7 nAChR could be useful for treatment of cognitive dysfunction in these diseases. This study was undertaken to examine the role of alpha 7 nAChRs on hippocampal cellular proliferation of adult mice. The number of 5-bromo-2'-deoxyuridine (BrdU)-immunoreactive cells in the granule cell layer (GCL) and hilus of alpha 7 nAChR heterozygous (+/-) mice was significantly decreased as compared with that of wild-type (+/+) mice. In contrast, the number of BrdU-immunoreactive cells in GCL and hilus of alpha 7 nAChR homozygous (-/-) mice was not different from that of wild-type mice. The results suggest that reduced levels of alpha 7 nAChRs may decrease cell proliferation of adult hippocampus.

Animals↗
PubMed2004

No changes in serum ghrelin levels in female patients with bulimia nervosa.

It has been reported that fasting plasma ghrelin levels may play a role in the pathophysiology of eating disorders. In this study, the authors examined whether serum levels of ghrelin were altered in the patients with bulimia nervosa (BN). We enrolled 18 female patients with BN, and 21 age-matched female controls for this study. Eating-related psychopathology, depressive symptoms were evaluated by using the Bulimic Investigatory Test, Edinburgh (BITE) and the 17-item Hamilton Depression Rating Scale (HDRS). Serum levels of ghrelin were measured by Ghrelin enzyme immunoassay kit. There were no significant differences in serum ghrelin levels between the patients with BN and normal controls. Furthermore, the authors did not found correlation between serum ghrelin levels and clinical parameters in the patients with BN. Our study suggests that serum ghrelin levels in the patients with BN were indistinguishable from normal controls. Therefore, it is unlikely that ghrelin plays a role in the pathophysiology of BN.

Adolescent↗
PubMed2004

Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A(1) receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of dizocilpine. Pretreatment with adenosine A(1) receptor agonists, 2-chloro-N(6)-cyclopentyladenosine (CCPA) (0.1, 0.3, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N(6)-cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p.), attenuated neurotoxicity by dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the dizocilpine-induced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 microM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A(1) receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

Acetylcholine↗
PubMed2004

Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine.

Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]beta-CFT. In contrast, the binding of [11C]SCH 23390 to dopamine D1 receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

Acetylcysteine↗
PubMed2004

Functional analysis of a rice putative voltage-dependent Ca2+ channel, OsTPC1, expressed in yeast cells lacking its homologous gene CCH1.

We isolated a cDNA (OsTPC1) from rice that was homologous to AtTPC1, a putative voltage-dependent Ca(2+) channel (VDCC) gene of Arabidopsis thaliana. The hydropathy profile of its deduced amino acid sequence showed significant structural features of the alpha 1-subunit of animal VDCCs. Functional analysis using a heterologous yeast expression system showed that OsTPC1 facilitates Ca(2+) permeation. The K(m) value for Ca(2+) of OsTPC1, 47.5 micro M, was comparable to that of intrinsic CCH1, a candidate VDCC in yeast. Ca(2+) permeation by OsTPC1 was inhibited by verapamil, a VDCC blocker. These findings indicate for the first time that OsTPC1 is a putative VDCC in rice.

Amino Acid Sequence↗
PubMed2004

Effects of N-acetyl-L-cysteine on the reduction of brain dopamine transporters in monkey treated with methamphetamine.

Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). The present study undertakes to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography (PET) studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]b-CFT (for DAT). In contrast, the binding of [11C]DASB to 5-hydroxytryptamine transporter (5-HTT) in the monkey brain was slightly decreased after the administration of MAP, although the difference was not statistically significant. The binding of [11C]SCH 23390 to dopamine D1 receptors in the striatum was also not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before administration of MAP and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity on dopaminergic nerve terminals related to chronic use of MAP in humans.

Acetylcysteine↗