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E Nagata

Publications and source records attributed to E Nagata.

At least 37 records · Page 2Linked to original sources
PubMed1999

Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3.

To evaluate the role in synaptic plasticity of ryanodine receptor type 3 (RyR3), which is normally enriched in hippocampal area CA1, we generated RyR3-deficient mice. Mutant mice exhibited facilitated CA1 long-term potentiation (LTP) induced by short tetanus (100 Hz, 100 ms) stimulation. Unlike LTP in wild-type mice, this LTP was not blocked bythe NMDA receptor antagonist D-AP5 but was partially dependent on L-type voltage-dependent Ca2+ channels (VDCCs) and metabotropic glutamate receptors (mGluRs). Long-term depression (LTD) was not induced in RyR3-deficient mice. RyR3-deficient mice also exhibited improved spatial learning on a Morris water maze task. These results suggest that in wild-type mice, in contrast to the excitatory role of Ca2+ influx, RyR3-mediated intracellular Ca2+ ([Ca2+]i) release from endoplasmic reticulum (ER) may inhibit hippocampal LTP and spatial learning.

Animals↗
PubMed1999

Role of the ryanodine receptor in ischemic brain damage--localized reduction of ryanodine receptor binding during ischemia in hippocampus CA1.

1. The ryanodine receptor has recently been shown to play a pivotal role in the regulation of intracellular Ca2+ concentration via Ca(2+)-induced Ca2+ release (CICR). Effects of ischemia on CICR in the brain tissue, however, remain largely unknown since only a few reports have been published on this subject. In this paper we report on work in this area by our group and review related progress in this field. 2. We examined alterations of ryanodine receptor binding and local cerebral blood flow (LCBF) at 15 min, 30 min, and 2 hr after occlusion of the right common carotid artery in the gerbil brain. A quantitative autoradiographic method permitted simultaneous measurement of these parameters in the same brain. The LCBF was significantly reduced in most of the cerebral regions on the occluded side during each time period of ischemia. In contrast, only in the hippocampus CA1 on the occluded side was a significant reduction in ryanodine binding found at 15 min, 30 min and 2 hr after the occlusion. 3. These findings suggest that suppression of ryanodine binding in the hippocampus CA1 may be attributable to a regionally specific perturbation of CICR and that this perturbation may be closely associated with the pathophysiological mechanism that leads to be selective ischemic vulnerability of this region. 4. Other recent studies have also reported an important role for ryanodine receptors in neuronal injury such as the delayed neuronal death in the hippocampus CA1. These data suggest that derangement of CICR is likely to be involved in acute neuronal necrosis as well as in delayed neuronal death in ischemia. 5. Further studies on clarifying the role of CICR in ischemic brain damage are needed in order to develop new therapeutic strategies for stroke patients.

Animals↗
PubMed1999

Giant cell interstitial pneumonia in two hard metal workers: the role of bronchoalveolar lavage in diagnosis.

Two cases of hard metal lung disease and pathological findings of giant cell interstitial pneumonia are reported. The cases worked in different factories manufacturing hard metal parts from tungsten carbide and cobalt. Pathological specimens were obtained by percutaneous thoracoscopy and transbronchial lung biopsy. X-ray microanalysis detected only tungsten carbide in the lung specimen of one case. Bronchoalveolar lavage showed diagnostic bizarre macrophages in the lavage fluid.

Adult↗
PubMed1999

Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats.

Although interleukin-6 (IL-6) has various neuroprotective effects against cerebral ischemia, the topographic distribution and cellular source of IL-6 after cerebral ischemia remain unclear. In the current study, the localization of IL-6 protein was immunohistochemically examined in rats after 3.5, 12, 24, and 48 hours of reperfusion after 1.5 hours of middle cerebral artery occlusion. Middle cerebral artery occlusion was induced by the intraluminal suture method. The specificity of the anti-IL-6 antibody used in the current study was confirmed by Western blot analysis and an immunoabsorption test. To identify the cellular source, lectin histochemical study and immunohistochemical study with microtubule-associated protein-2, ED1, and glial fibrillary acidic protein also were carried out. The sham group did not show any clear IL-6 immunoreactivity. After 3.5 hours of reperfusion, IL-6 immunoreactivity was first detected on the reperfused side, and it was upregulated, especially in the periinfarct region, after 24 hours of reperfusion. Also, IL-6 was expressed after 3.5 hours of reperfusion in the contralateral cerebral cortex and bilateral hippocampi. Double staining showed that the cells containing IL-6 were neurons and round-type microglia, not astrocytes. The current findings suggest that IL-6 expression in ischemically threatened neurons and reactive microglia is closely associated with brain tissue neuroprotective mechanisms against cerebral ischemia.

Animals↗
PubMed1999

[Alteration of cAMP-mediated signal transduction in cerebral ischemia--binding activity of PKA and phosphorylation of CREB].

Binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) is an essential step for cAMP-mediated signal transduction including phosphorylation of cAMP response element binding protein (CREB). In the present study, binding activity of PKA with cAMP and CREB phosphorylation were examined in rat focal brain ischemia induced by occlusion of the middle cerebral artery for 1.5 hours followed by various time of recirculation. Binding activity of PKA with cAMP was progressively inhibited during the acute phase of ischemia from the ischemic core to peri-ischemia area. Phosphorylated CREB-positive cells in the ischemic core revealed a significant, but transient increase in number at 3.5 hours of recirculation, followed by a rapid decrease below the control level during the subsequent period. On the other hand, in the peri-ischemia area, the number of phosphorylated CREB-positive cells showed a more marked increase as compared to that in the ischemic core, and the increase continued until 48 hours of recirculation with a tendency for gradual decline. Persistent enhancement of CREB phosphorylation may thus be closely related to the neuronal viability and neuroprotective mechanisms, whereas rapid disappearance of CREB phosphorylation following ischemic insult may clearly precede neuronal death.

Animals↗
PubMed1998

Cloning, mapping, expression, function, and mutation analyses of the human ortholog of the hamster putative tumor suppressor gene Doc-1.

doc-1 is a putative tumor suppressor gene isolated and identified from the hamster oral cancer model. Here, we report the molecular cloning and the functional characterization of the human ortholog of the hamster doc-1 gene. Human doc-1 cDNA is 1.6 kilobase pairs in length and encodes for a 115-amino acid polypeptide (12.4 kDa, pI 9. 53). Sequence analysis showed 98% identity between human and hamster doc-1 protein sequences. DOC-1 is expressed in all normal human tissues examined. In oral keratinocytes, expression of DOC-1 is restricted to normal oral keratinocytes. By immunostaining of normal human mucosa, DOC-1 is detected in both the cytoplasm and nuclei of basal oral keratinocytes; while in suprabasilar cells, it is primarily found in the nuclei. Human oral cancers in vivo did not exhibit immunostaining for DOC-1. Like murine DOC-1, human DOC-1 associates with DNA polymerase alpha/primase and mediates the phosphorylation of the large p180 catalytic subunit, suggesting it may be a potential regulator of DNA replication in the S phase of the cell cycle. Using a human doc-1 cosmid as a probe, human doc-1 is mapped to chromosome 12q24. We identified four exons in the entire human doc-1 gene and determined the intron-exon boundaries. By polymerase chain reaction and direct sequencing, we examined premalignant oral lesion and oral cancer cell lines and found no intragenic mutations.

Amino Acid Sequence↗
PubMed1998

Binding capacity of FK506 binding protein after 2-hour hemispheric ischemia in gerbil brain.

The binding capacity of FK506 binding protein (FKBP) was examined after 2-h hemispheric ischemia in the gerbil brain in order to clarify the precise mechanism of the neuroprotective effects of FK506. Firstly, the FK506 binding was evaluated in vitro in the normal gerbil brain using 1 nM [3H]dihydro-FK506 as a specific ligand. FK506 binding sites were distributed in a rather homogeneous manner, although the greatest binding was noted in the hippocampus CA1. Secondly, Scatchard analysis demonstrated that the binding sites of FK506 could be composed of two components in each brain region. Thirdly, 18 Mongolian gerbils were divided into two groups: an ischemia group (n = 12) and a sham group (n = 6). The right common carotid artery was ligated to induce hemispheric ischemia for 2 h in the ischemia group. The local cerebral blood flow was measured at the end of the experiment by the [14C]iodoantipyrine method. The ligated animals with levels of local cerebral blood flow in the lateral nuclei of the thalamus of less than 50 ml/100 g/min were utilized as the ischemia group (n=6) for further data analysis. No significant differences in FK506 binding between the ischemia and sham groups were observed in any regions. The above data indicate that the binding capacity of FKBP tends to remain normal during 2-h ischemia, suggesting that FK506 may exert its neuroprotective effects through its binding to FKBP in the brain during the early phase of cerebral ischemia.

Animals↗
PubMed1998

Partial inhibition of reverse tolerance by a high dose of ritanserin or low dose of haloperidol in methamphetamine-sensitized rat.

To clarify the implication of antagonism of serotonin (5-HT)2 receptors in the treatment of schizophrenia, the effects of ritanserin (RIT) on the development of reverse tolerance in rats repeatedly administered methamphetamine (MAP) were investigated and compared with those of low doses of haloperidol (HPD). RIT administered at a dose of 2 mg/kg and low doses of HPD (0.05, 0.1 mg/kg) shared partial inhibition of the development of reverse tolerance in MAP-sensitized rats; the drugs inhibited sniffing but not head moving and had no effect on locomotion or rearing. A combination of low doses of HPD and RIT resulted in the inhibition of head moving. These results suggested that strong antagonism for 5-HT2 receptors would be useful to some extent to treat MAP-induced psychosis and schizophrenia as well as weak antagonism of dopamine D2 receptors, and that a combination of these two actions would produce better results in these psychoses than that obtained from D2 antagonism alone. In the presence of 0.05 mg/kg of HPD, RIT caused increased locomotion and rearing, whereas it decreased them in the presence of 0.1 mg/kg of HPD. This result suggested that the interactions between 5-HT and dopamine (DA) neurons are complex, and that 5-HT2 antagonism may inhibit or disinhibit DA neurons depending on the level of D2 blockade.

Animals↗
PubMed1998

Effects of washing procedure on platelets pretreated with serotonin uptake inhibitors in vitro: low Ki values predict long-lasting inhibition of serotonin uptake in vivo.

The effect of a washing procedure on serotonin (5-HT) uptake in vitro was investigated using human platelets pretreated with nine 5-HT uptake inhibitors and various Ki values to confirm the assumption that a drug with high affinity for the 5-HT uptake site would be hardly removed and have a long-lasting effect in vivo. Among the drugs tested, those with low Ki values, such as clomipramine, duloxetine and paroxetine, inhibited 5-HT uptake even after removal from the medium, while those with high Ki values such as amitriptyline, desipramine, imipramine, mianserin, trazodone, and zimelidine were easily removed by washing. The results indicated that low Ki values might be proportionally related to the long-lasting binding of drugs to the 5-HT uptake site. The results also suggested that the threshold Ki value which could separate 5-HT uptake inhibitors with a probable long-lasting effect in vivo from those without the effect would be between 5 nM and 42 nM.

Antidepressive Agents↗
PubMed1998

[Convulsion].

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Animals↗
PubMed1997

Immunohistochemical detection of nitrotyrosine in postischemic cerebral cortex in gerbil.

We examined whether or not nitration of tyrosine residues takes place in the ischemic and postischemic reperfused brain. The nitration of tyrosine residues to produce nitrotyrosine is a sensitive marker elicited by peroxynitrite, a powerful oxidant formed by the reaction of nitric oxide (NO) with superoxide. Mongolian gerbils were subjected to 60 min ischemia induced by occlusion of the right common carotid artery (ischemia group), to 30 min recirculation following 60 min ischemia (reperfusion group) or to sham surgery (sham group). Immunohistochemical staining with polyclonal anti-nitrotyrosine antibody revealed the widespread and distinct occurrence of nitrotyrosine in cortical neurons on the reperfused side of the brain in the reperfusion group, while only partial or weak immunoreactivity was noted on the contralateral side. On the other hand, nitrotyrosine was not detected in the brain of the ischemia and sham groups. These findings suggest that nitration of tyrosine residues in various proteins may be closely associated with reperfusion injury of the brain.

Animals↗
PubMed1997

Acute ischemic vulnerability of PKA in the dendritic subfields of the hippocampus CA1.

Alterations of [3H]cyclic AMP (cAMP) binding, an indicator of the binding activity of particulate cyclic AMP-dependent protein kinase (PKA), were examined after 15 and 30 min of ischemia in the gerbil brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. Significant reductions in cAMP binding were noted only in the dendritic subfields of the hippocampus CA1 such as the strata oriens, radiatum and lacunosum-moleculare, on the ischemic side after 15 min of ischemia. After 30 min ischemia cAMP binding was significantly decreased not only in each dendritic subfield of the hippocampus CA1, but also in the layer of pyramidal cell bodies (stratum pyramidale) on the occluded side; other brain regions such as the hippocampus CA3, dentate gyrus and cerebral cortices revealed no significant changes in cAMP binding. These findings suggest that derangement of PKA may begin in the dendritic subfields of the hippocampus CA1 after as little as 15 min of severe ischemia, and proceed centrally to the neuronal cell bodies of the hippocampus CA1.

Animals↗
PubMed1997

A novel neurological mutant mouse, yotari, which exhibits reeler-like phenotype but expresses CR-50 antigen/reelin.

We present yotari, a novel neurological mutant mouse whose mutation is transmitted in an autosomal recessive manner. The phenotype of yotari is very similar to that of reeler. yotari mutants are recognizable by their unstable gait and tremor and by their early deaths at around the time of weaning. The cerebella of homozygous yotari are hypoplastic and have no foliation. A molecular and a granular cell layer can be identified, but Purkinje cells are scattered throughout both the granular layer and white matter. The laminar structure of the cerebral cortex and the hippocampal formation are also distorted. To test whether the mutated gene in yotari is the reeler gene, reelin, yotari heterozygotes were mated with reeler homozygotes or heterozygotes. The absence of abnormal offspring indicated that the yotari gene is distinct from reelin. Furthermore, expression of mRNA and protein of reelin was verified by Northern blotting and immunohistochemistry using a CR-50 monoclonal antibody (mAb) which is specific to Reelin, the reelin gene product. Although the mutation of several genes, including cyclin-dependent kinase 5 (Cdk 5), p35 and LIS1, 45 kDa subunits of platelet-activating factor acetylhydrolase (PAF-AH) Ib, in Miller-Dieker lissencephaly syndrome (MDS) has been reported to cause abnormal laminar structure in the brain, no abnormality was found in yotari by Western blotting with antibodies (Ab's) against these molecules. The close similarity of the phenotypes of yotari and reeler and the expression of reelin in yotari may suggest that the gene mutated in yotari encodes a molecule that is on the same signaling pathway as Reelin, the product of reelin. yotari will provide valuable clues to explore the molecular mechanism of neuronal migration and orderly laminar structure formation of the brain.

Animals↗
PubMed1997

Calcineurin inhibitor, FK506, prevents reduction in the binding capacity of cyclic AMP-dependent protein kinase in ischemic gerbil brain.

We examined the effects of FK506, a specific inhibitor of calcineurin, on the binding capacity of cyclic AMP-dependent protein kinase (cAMP-DPK) in gerbils subjected to 2-h cerebral hemispheric ischemia. FK506 (0.1 mg/kg) was infused intravenously at 15 min prior to the induction of ischemia by common carotid artery occlusion. The binding capacity of cAMP-DPK was evaluated by autoradiographic analysis of the cAMP binding, and cerebral blood flow (CBF) was measured by the [14C] iodoantipyrine method. In the sham-operated gerbils. FK506 significantly increased mean arterial blood pressure and tended to decrease CBF, suggesting that FK506 may constrict systemic blood vessels as well as cerebral blood vessels. On the other hand, cAMP binding was not altered by FK506 in the sham-operated gerbils. In the ischemia group of gerbils, FK506 prevented any significant reduction of cAMP binding in the hippocampus CA1 and cerebral cortices on the ischemic side, whereas it exerted no significant influence on the cAMP binding of the nonischemic side. The values of CBF were comparable between the vehicle-treated gerbils and FK506-treated gerbils in the ischemic regions. Preservation of cAMP binding indicates that intracellular signal transduction via cAMP-DPK can be maintained by FK506 despite ischemia, suggesting that this agent may be beneficial for reducing ischemic tissue damage.

Animals↗
PubMed1997

Rapid reduction in ryanodine binding of hippocampus CA1 in cerebral ischemia.

Ryanodine receptors located on the sarcoplasmic or endoplasmic reticulum, play an important role in the regulation of the intracellular Ca2+ level via the mechanism of Ca(2+)-induced Ca2+ release (CICR). Perturbation of intracellular Ca2+ regulation has been considered to be one of the most important mechanisms underlying acute ischemic neuronal damage. The ryanodine binding, an indicator of intracellular channels of CICR, and local cerebral blood flow (LCBF) were therefore examined at 15 min post-ischemia in the gerbil brain. The autoradiographic method developed in our laboratory enabled us to determine both parameters within the same brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. LCBF was measured at the end of the experiment using [14C]iodoantipyrine method. The ryanodine binding was evaluated autoradiographically in vitro using [3H] ryanodine. A group of gerbils who underwent a sham procedure served as controls. LCBF was found to be significantly decreased in most cerebral regions on the occluded side. In contrast, a significant reduction in ryanodine binding was noted only in the hippocampus CA1 on the occluded side. Taken together, these findings indicate that the CICR in the hippocampus CA1 may be especially susceptible to acute ischemic stress, and be closely associated with the pathophysiological mechanisms of the selective vulnerability of this region.

Animals↗