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Toshitaka Nabeshima

Publications and source records attributed to Toshitaka Nabeshima.

At least 109 records · Page 6Linked to original sources
PubMed2002

Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress.

A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

Aging↗
PubMed2002

Involvement of kappa-opioid and sigma receptors in short-term memory in mice.

Kappa-opioid receptor agonists, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate (U-50,488H) and dynorphin A-(1-13), improve impairments of learning and memory in mice and rats. sigma Receptor agonists, (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), also reverse learning and memory impairment in various animal models. However, the mechanisms underlying these effects are not well understood. In the present study, the effect of coadministration of U-50,488H and (+)-SKF10,047 on scopolamine-induced memory impairment was investigated in mice using spontaneous alternation performance in a Y-maze. U-50,488H (0.21-2.15 micromol/kg, subcutaneously (s.c.)) and (+)-SKF10,047 (0.10-1.02 micromol/kg, s.c.) 25 min before the Y-maze test improved the impairment of spontaneous alternation induced by scopolamine (1.65 micromol/kg, s.c.). When U-50,488H and (+)-SKF10,047 were coadministered, no additive effect was observed. Furthermore, the ameliorating effects of U-50,488H and (+)-SKF10,047 were not antagonized by a selective sigma receptor antagonist, N,N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride (NE-100), and a selective kappa-opioid receptor antagonist, nor-binaltorphimine, respectively. These results suggest that the mechanisms underlying the ameliorating effects on memory impairment are independent and no direct modulation exists in kappa-opioid and sigma receptors-mediated mechanisms.

Analgesics, Opioid↗
PubMed2002

Learning and memory in two different reward tasks in a radial arm maze in rats.

In an eight-arm radial maze, working and reference memory can be assessed simultaneously in the fixed position of reward task (FPRT) in which half of the arms are baited and their positions are fixed throughout the training trails. We characterized performance of rats in the variable position of reward task (VPRT), in which four out of eight arms were baited, but the positions were varied in every training trial. In the VPRT, the rats learned to choose all arms without any discrimination between baited and non-baited arms and the memory retention was time-dependent. The performance of rats in the FPRT was impaired by altering the spatial organization of the extramaze cues while it was not affected in the VPRT. The number of Fos-positive cells transiently increased in the cerebral cortex and hippocampus of both groups of animals during the training. Finally, bilateral lesions of the dorsal hippocampus resulted in an impairment of working memory in the FPRT and the performance of the rats in the VPRT. These results suggest that different strategies are used between the FPRT and VPRT but the hippocampus plays an important role in performance of rats trained for the VPRT as well as FPRT.

Animals↗
PubMed2002

CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning.

Regulation of gene transcription via the cyclic adenosine 3',5'-monophosphate (cAMP)-mediated second messenger pathway has been implicated in learning and memory. Although the cAMP response element-binding protein (CREB) is an important transcription factor involved in long-term memory, it remains to be determined whether the CREB-dependent events are attributed to spatial learning and memory in a radial arm maze. Here we demonstrate that cAMP-dependent protein kinase A (PKA) and CREB are activated in the course of spatial learning. The radial maze training in rats resulted in a significant increase in PKA and CREB phosphorylation in the hippocampus in the course of spatial learning, which was followed by spatial memory formation. On the other hand, neither the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) nor the mRNA level of brain-derived neurotrophic factor was significantly affected. These results suggest that activation of the PKA/CREB signaling pathway in the hippocampus plays an important role in spatial memory formation.

Animals↗
PubMed2002

Interleukin-6 protects PC12 cells from 4-hydroxynonenal-induced cytotoxicity by increasing intracellular glutathione levels.

Oxidative stress plays an important role in neuronal cell death associated with many different neurodegenerative conditions, and it is reported that 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, is a key mediator of neuronal cell death induced by oxidative stress. Previously, we have demonstrated that interleukin-6 (IL-6) protects PC12 cells from serum deprivation and 6-hydroxydopamine-induced toxicity. Therefore, in the present study, we examined the effects of interleukins on HNE toxicity in PC12 cells. Exposure of PC12 cells to HNE resulted in a decrease in levels of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, which was due to necrotic and apoptotic cell death. Addition of IL-6 24 h before HNE treatment provided a concentration-dependent protection against HNE toxicity, whereas neither IL-1beta nor IL-2 had any effect. Addition of glutathione (GSH)-ethyl ester, but not superoxide dismutase or catalase, before HNE treatment to the culture medium protected PC12 cells from HNE toxicity. We found that IL-6 increases intracellular GSH levels and the activity of gamma-glutamylcysteine synthetase (gamma-GCS) in PC12 cells. Buthionine sulfoximine (BSO), an inhibitor of gamma-GCS, reversed the protective effect of IL-6 against HNE toxicity. These results suggest that IL-6 protects PC12 cells from HNE-induced cytotoxicity by increasing intracellular levels of GSH.

Aldehydes↗
PubMed2002

Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit.

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs), play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. They are composed of the GluRzeta subunit (NR1) combined with any one of four GluRepsilon subunits (GluRepsilon1-GluRepsilon4; NR2A-NR2D). Although the GluRzeta subunit exists in the majority of the CNS throughout all stages of development, the GluRepsilon subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluRepsilon4 subunit. GluRepsilon4 mutant mice exhibited reductions of [(3)H]MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] binding and (45)Ca(2+) uptake through the NMDA receptors. The expression of GluRzeta subunit protein, but not GluRepsilon1 and GluRepsilon2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluRepsilon4 mutant mice revealed that tissue contents of norepinephrine, dopamine, serotonin, and their metabolites were reduced in the hippocampus and that dopamine, as well as serotonin, metabolism was upregulated in the frontal cortex, striatum, hippocampus, and thalamus. To clarify the phenotypical influences of the alteration in neuronal functions, performances in various behavioral tests were examined. GluRepsilon4 mutant mice showed reduced spontaneous locomotor activity in a novel environment and less sensitivity to stress induced by the elevated plus-maze, light-dark box, and forced swimming tests. These findings suggest that GluRepsilon4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.

Animals↗
PubMed2002

Role for brain-derived neurotrophic factor in learning and memory.

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.

Animals↗
PubMed2002

Involvement of dopaminergic system in the nucleus accumbens in the discriminative stimulus effects of phencyclidine.

The effects of microinjection of phencyclidine (PCP) and dizocilpine, non-competitive NMDA receptor antagonists, and dopamine into the nucleus accumbens were examined in rats trained to discriminate PCP (1.5 mg/kg i.p.) from saline under a two-lever fixed ratio 20 schedule of food reinforcement. Microinjection of PCP (2-40 microg) and dizocilpine (2-12 microg) into the bilateral nucleus accumbens produced a dose-dependent increase in PCP-appropriate responding and fully substituted for systemically administered PCP, whereas microinjection of dopamine (1-4 microg) did not produce PCP-like discriminative stimulus effects. The performance of PCP discrimination was assessed after bilateral destruction of the dopaminergic nerve neurons in the nucleus accumbens with dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA, 4 microg/1 microl/side). The destruction of dopaminergic nerve neurons in the nucleus accumbens failed to prevent the performance of PCP discrimination. There was no difference in the average percentages of PCP-appropriate responding between vehicle and 6-OHDA-treated rats in the dose-response tests. These results suggest that the dopaminergic system in the nucleus accumbens does not play a critical role in the discriminative stimulus effects of PCP.

Adrenergic Agents↗
PubMed2002

Amyloid beta-peptide induces cholinergic dysfunction and cognitive deficits: a minireview.

Amyloid beta-peptide (Abeta) plays a critical role in the development of Alzheimer's disease (AD). Much progress has been made in understanding this age-related neurodegenerative disorder, thus an insight into the cellular actions of Abeta and resulting functional consequences may contribute to preventive and therapeutic approaches for AD. In this review, recent evidence of Abeta-induced brain dysfunction, particularly of cholinergic impairment and memory deficits is summarized. Moreover, proposed mechanisms for Abeta-induced neurotoxicity such as oxidative stress, ion-channel formation, and Abeta-receptor interaction are discussed.

Amino Acid Sequence↗
PubMed2002

A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats.

Activity-dependent plastic changes in the strength of synaptic connections are considered to underlie learning and memory. Activation of neurons by a variety of stimuli influences the level of expression of the immediate-early gene c-fos, and the heterodimer of the gene product, Fos, regulates transcription of other genes. Therefore, Fos is regarded as a mediator by which brief stimuli trigger long-term changes in the synaptic connections. Here we show that Fos expression in the CA3 region of the hippocampus may be obligatory for spatial memory formation in a radial arm maze test. Fos-positive cells increased in the cerebral cortices and the CA3 region of the dorsal hippocampus during the course of radial arm maze training in rats. Inhibition of Fos expression in this region of the hippocampus, but not the cingulate and motor cortex, by means of antisense oligonucleotide treatment resulted in an impairment of spatial memory formation. Our results support the hypothesis that the inducible transcription factor c-fos is essential for encoding spatial memory.

Animals↗
PubMed2002

Usefulness of soluble dietary fiber for the treatment of diarrhea during enteral nutrition in elderly patients.

OBJECTIVES: We investigated the clinical usefulness of soluble dietary fiber (SDF) for the treatment of diarrhea during enteral nutrition in elderly patients. METHODS: This study included 10 men and 10 women (mean age +/- standard deviation: 79.3 +/- 5.1 y) who had diarrhea during long-term nutrition management. When administering SDF, the initial dose was 7 g and thereafter gradually increased at 1-wk intervals. After 4 wk, the administration was discontinued for 2 wk to confirm the effects of SDF. RESULTS: After the administration of SDF, serum diamine oxidase activity significantly increased (P < 0.001): The water content of the feces decreased significantly after the administration of fiber (P < 0.01). The frequency of daily bowel movements also decreased significantly (P < 0.05). Simultaneously, the fecal features improved. Concerning intestinal flora, there were no significant changes in the total number of bacteria or the number of anaerobic bacteria. The fecal pH decreased significantly 4 wk after the administration of fiber (P < 0.05). The total level of short-chain fatty acids increased significantly 4 wk after the administration of fiber (P < 0.05). There were no significant changes in the various nutritional indices. CONCLUSIONS: The administration of SDF is useful for controlling spontaneous, favorable bowel movement by improving symptoms of small intestinal mucosal atrophy and normalizing the intestinal flora.

Aged↗
PubMed2002

Valproic acid increases biliary copper excretion in the rat.

The effect of valproic acid (VPA) on the copper absorption and disposition in rat small intestine was investigated using an in situ recirculating perfusion method. Following addition of VPA (20 mg) to the perfusion of 30 ml of 0.9% sodium chloride solution (2 microg/ml copper as CuSO(4)) there were no significant differences in copper decline during the perfusion. The absorption rate constant of copper (k(a)) which was estimated from the copper decline in the perfusion was unchanged without and with VPA (0.19+/-0.02 vs. 0.17+/-0.03 1/h). These results indicate that VPA does not have an effect on copper absorption from the intestine. We also assessed biliary copper excretion by measuring bile flow and biliary copper concentrations. Addition of VPA markedly increased bile flow by 47% for the first hour of bile collection and 91% for the second hour and the biliary copper excretion closely followed the increase in bile flow (without VPA: 0.93+/-0.15 vs. with VPA: 1.44+/-0.21 mg for the first and without VPA: 0.98+/-0.13 mg vs. with VPA: 1.98+/-0.22 mg for the second hour of bile collection). The total mean value for the biliary copper excretion was increased by 79%. The serum VPA concentration after the perfusion was 31.1+/-3.2 microg/ml. This high excretion of copper induced by VPA into the bile may upset the homeostatic balance of copper and cause the abnormalities of serum copper concentration. Based on the present studies, we should pay attention to copper levels in patients with VPA treatment.

Analysis of Variance↗
PubMed2002

Interference of hematocrit in the tacrolimus II microparticle enzyme immunoassay.

The authors studied the effect of hematocrit, bilirubin, and alkaline phosphatase on microparticle enzyme immunoassay for tacrolimus II (MEIA II) using specimens of whole blood obtained from 33 patients undergoing cyclosporine treatment. Tacrolimus was added to these samples at a final concentration of 7.5 microg/L and 15 microg/L. Both coefficients of variation were over 20% (21% at 7.5 macrog/L of tacrolimus and 22% at 15 microg/L of tacrolimus). No correlation was found between bilirubin and tacrolimus concentrations or between alkaline phosphatase and tacrolimus concentrations. On the other hand, negative correlations were found between hematocrit values and tacrolimus concentrations (r2 = 0.47; P < 0.0001 at 7.5 microg/L tacrolimus, r2 = 0.54; P < 0.0001 at 15 microg/L tacrolimus). Negative correlations were also found between hematocrit and the tacrolimus concentration using normal human red blood cells diluted with physiological saline solution (r2 = 0.93; P < 0.0001 at 7.5 microg/L tacrolimus, r2 = 0.91; P < 0.0001 at 15 microg/L tacrolimus). The results showed that the hematocrit interferes with the MEIA II for tacrolimus, and the magnitude of the interference is clinically significant. Beyond the normal range of hematocrit values, caution should be exercised in interpreting results as one may need to compensate for the levels of tacrolimus.

Adolescent↗
PubMed2002

Comparative absorption of 5-aminosalicylic acid (5-ASA) after administration of a 5-ASA enema and salazosulfapyridine (SASP) after an SASP suppository in Japanese volunteers.

Salazosulfapyridine (SASP) is widely used orally and rectally in the treatment of ulcerative colitis. SASP is mainly metabolized by hydrolysis and the main active metabolite, 5-aminosalicylic acid (5-ASA), has an antiinflammatory effect. In the present study, we prepared suppositories containing 6.5 mmol of SASP and an enema containing 6.5 mmol of 5-ASA. We measured the concentrations of SASP and its various metabolites, 5-ASA, sulfapyridine (SP), acetylated metabolite of SP (Ac-SP), and N-acetyl-5-ASA (Ac-5-ASA), in the serum and urine after a single administration of each preparation to healthy male volunteers. When the SASP suppository was administered, the maximum concentration (Cmax) of SASP and Ac-5-ASA was 2.5+/-0.4 and 0.5+/-0.2 microM and the time to Cmax (Tmax) was 5 and 12 h, respectively. The Cmax value of SP, which causes side effects, was one-half of that of the parent compound. No 5-ASA in the serum was observed. When the 5-ASA enema was administered, Cmax and Tmax values of 5-ASA and Ac-5-ASA were 5.8+/-2.0 and 13.3+/-3.6 microM and 1 and 7 h, respectively. The area under the serum concentration-time curve (AUC) of SASP was 27.4+/-4.8 microM x h, a finding similar to that of 5-ASA after the administration of the 5-ASA enema (29.4+/-11.1 microM x h). The percentage of urinary recovery of SASP 24 h after administration of the SASP suppository was approximately 0.2%. These results indicate that SASP administered rectally is almost completely hydrolyzed in the colon and that 5-ASA is partially absorbed from the small intestine in unchanged form. On the other hand, approximately 0.3% of 5-ASA was recovered in the urine in unchanged form after the administration of the 5-ASA enema, whereas the urinary recovery of Ac-5-ASA was more than 10%. The present findings suggest that 5-ASA has favorable absorptive properties and can be expected to have systemic action after rectal administration of a 5-ASA enema.

Absorption↗
PubMed2002

[Learning/memory and drug dependence].

We investigated the possible mechanisms of development of latent learning and morphine dependence by the methods of behavioral pharmacology and confirmed them by using mutant mice. The heterozygous mice for the tyrosine hydroxylase (TH) gene and for the cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP) gene showed the impairment of latent learning in the water finding task, and these mice did not develop morphine dependence. The spatial learning and hippocampal long-term potentiation (LTP) were normal in the both mutants. TH heterozygous mice showed a reduction of high K(+)-evoked noradrenaline release in the frontal cortex measured by the microdialysis technique and of cAMP content in the brain. In conclusion, the results of mutant mice suggest that the alternation of catecholamine biosynthesis and cAMP signal pathways may play a key role in development of latent learning and morphine dependence, and they furthermore show that the expression of genes mediated by phosphorylated CREB may be involved in the development of latent learning and morphine dependence.

Animals↗
PubMed2002

[Analysis of neuronal functions in mice lacking the NMDA receptor epsilon 1 subunit].

The NMDA subtype of glutamate receptor (GluR) plays an important role in excitatory neurotransmission, synaptic plasticity, brain development, and neurodegeneration. NMDA receptors are inherent high Ca(2+)-permeable channels, which are formed by heteromeric assembly of the GluR zeta 1 subunit (NR1) and any one of four GluR epsilon subunits (GluR epsilon 1-4; NR2A-D). Mice lacking the GluR epsilon 1 subunit exhibited a malfunction of NMDA receptors, as evidenced by reduction of NMDA receptor channel current, hippocampal long-term potentiation, [3H]MK-801 binding, and NMDA-stimulated 45Ca2+ uptake. A biochemical analysis revealed a hyperfunction of dopaminergic and serotonergic neuronal systems in the frontal cortex and striatum of GluR epsilon 1 mutant mice. The enhancement of dopaminergic neuronal activity in the striatum, at least, due to the disinhibition of inhibitory GABAergic neuronal input. GluR epsilon 1 mutant mice showed an increase of locomotor activity in a novel environment attributed to the hyperfunction of the dopaminergic neuronal system, and an impairment of spatial, contextual, and latent learning. These findings provide evidence that NMDA receptors regulate behavior through the modulation of not only glutamatergic but also GABAergic and dopaminergic neuronal systems. Moreover, it is suggested that GluR epsilon 1 mutant mice are useful as an animal model, which is associated with the malfunction of NMDA receptors and hyperfunction of the dopaminergic neuronal system.

Animals↗
PubMed2002

Effect of dietary fiber on morphine-induced constipation in rats.

Morphine is used to alleviate chronic cancer pain. However, constipation is a major adverse effect that often detracts from the patient's quality of life. In this study, we investigated the effectiveness of dietary fiber on morphine-induced constipation. Rats were fed on a normal diet or one containing either 10% or 20% apple fiber for two weeks before morphine was administered. In the control diet group, the fecal number and dry weight were decreased by treating with morphine in a dose-dependent manner. Moreover, the motility of the small and large intestines was reduced. The fecal number and weight were increased and the colon motility was promoted by dietary fiber, regardless of whether morphine was being administered. The dietary fiber increased the concentration of short-chain fatty acids (SCFAs) in the cecum. These results suggest that dietary fiber has a preventative effect on morphine-induced constipation by increasing SCFAs in the cecum, and thereby promoting colon motility in rats.

Animals↗