Biomedical subjects

Tetsuro Kikuchi

Publications and source records attributed to Tetsuro Kikuchi.

29 records · Page 2Linked to original sources

PubMed2002

Intratumoral injection of dendritic and irradiated glioma cells induces anti-tumor effects in a mouse brain tumor model.

Malignant astrocytoma is the most common primary brain tumor in adults. The median survival of patients with malignant astrocytomas (high-grade astrocytomas) is about 1-2 years, despite aggressive treatment that includes surgical resection, radiotherapy and cytotoxic chemotherapy. Therefore, novel therapeutic approaches are needed to prolong survival. We investigated antitumor immunity conferred by the intratumoral injection of dendritic (DC) and irradiated glioma cells (IR-GC) in a mouse brain tumor model. Intratumorally injected DC migrated to the lymph nodes and elicited systemic immunity against autologous glioma cells. In a treatment model, intratumoral injection of DC and IR-GC prolonged the survival of brain tumor-bearing mice. Efficacy was reduced when studies were performed in mice depleted of CD8(+) T cells. Administration of DC or IR-GC alone had no effect on survival of brain tumor-bearing mice. CTL activity against glioma cells from immunized mice was also stimulated by coadministration of DC and IR-GC compared with the controls. These results support the therapeutic efficacy of intratumoral injection of DC and IR-GC.

Animals↗

PubMed2002

Effects of antioxidant, OPC-14117, on secondary cellular damage and behavioral deficits following cortical contusion in the rat.

In the present study, we examined the effects of OPC-14117, a superoxide radical scavenger, on the secondary cellular damage and cognitive dysfunction occurring in a rat model of cerebral contusion induced by a controlled cortical impact (CCI). Histological examinations revealed that the contusion necrosis volume reached 13.6+/-5.3 mm(3) in non-treated animals and declined to 1.9+/-0.6 mm(3) in OPC-14117-treated animals (P<0.01). The cell number of the CA3 region was 120.0+/-12.4 cells/mm in the normal controls, 73.6+/-9.9 cells/mm in the non-treated animals, and 111.2+/-10.2 cells/mm in the OPC-14117-treated animals, indicating that CCI-induced selective neuronal cell death in the CA3 region was attenuated by the OPC-14117 administration (P<0.01). The tissue osmolality, as determined with a vapor pressure osmometer, was 314.5+/-15.4 mmol/kg in the normal brain and increased to 426.0+/-20.1 mmol/kg at 12 h following CCI. The increase in tissue osmolality was significantly attenuated by OPC-14117 administration (P<0.01). The OPC-14117 administration also attenuated the CCI-induced cognitive deficits. The OPC-14117-treated animals showed a tendency to improve on the Morris water maze performance test. The impairment of the habituation of exploratory activity elicited by CCI was significantly attenuated by OPC-14117 administration (P<0.05). In conclusion, OPC-14117 may have a potential for decreasing secondary cellular damage due to traumatic brain injury since it is as efficacious as any other compound tested in this model.

Animals↗

PubMed2002

The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor.

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer.

Animals↗

PubMed2002

Maturation of dendritic cells induced by Candida beta-D-glucan.

We investigated whether Candida beta-D-glucan (CSBG) alters the maturation of dendritic cells (DCs). DC phenotypes were analyzed using FACScan. The expression of surface molecules, including major histocompatibility complex (MHC) classes I and II, as well as CD80 and CD86, increased on DCs that were stimulated with lipopolysaccaride (DCs/LPS), in comparison with unstimulated bone marrow-derived DCs (BM-DCs). Furthermore, the level of surface molecule expression on DCs stimulated with CSBG (DCs/CSBG) was between that of DCs and DCs/LPS. Phagocytosis was assessed by the uptake of FITC-dextran. There were no differences in the uptake of dextran among DCs/LPS and DCs/CSBG. The ability of BM-DCs to uptake dextran was higher than that of DCs/LPS and DCs/CSBG. We analyzed the concentration of IL-12 secreted by DCs using ELISA. BM-DCs secreted a low concentration of IL-12, while DCs/LPS and DCs/CSBG secreted higher levels of IL-12 than BM-DCs. There were no remarkable differences in the concentrations of IL-12 produced by DCs/LPS and DCs/CSBG. This data suggests that CSBG may augment DC maturation.

Animals↗

PubMed2002

Effects of glioma cells on maturation of dendritic cells.

We investigated whether glioma cells affected the maturation of dendritic cells (DCs). First, DCs phenotypes were analyzed using FACScan. Incubation of both human and mouse immature DCs with glioma cells altered their expression of cell surface molecules, whereas expression of cell surface molecules by mature mouse and human DCs was not affected by exposure to glioma cells. Subsequently, phagositosis was assessed by uptake of FITC-dextran. Coculture with glioma cells did not inhibit phagositosis of either mature or immature DCs relative to the controls. We also analyzed the concentration of IL-12 secreted by mature DCs using enzyme-linked immunoabsorbent assay (ELISA). IL- 12 production by DCs was inhibited by coculture with glioma cells. However, stimulation with lipopolysaccharide restored the production of IL- 12 by both human and mouse DCs. These data suggest that glioma cells suppress the maturation of DCs.

Animals↗

PubMed2002

Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors.

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.

1-Methyl-3-isobutylxanthine↗

PubMed2002

Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate).

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.

Acetylcholine↗

PubMed2002

Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats.

Second Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan In order to elucidate the role of adenosine in brain ischemia, the possible protective effects of adenosine on ischemic brain injury were investigated in a rat model of brain ischemia both in vitro and in vivo. Exogenous adenosine dose-dependently rescued cortical neuronal cells from injury after glucose deprivation in vitro. Adenosine (1 mM) also significantly reduced hypoglycemia/hypoxia-induced glutamate release from the hippocampal slice. In a rat model of transient middle cerebral artery occlusion (MCAO), extracellular adenosine concentration was increased immediately after occlusion, and then returned to the baseline by 30 min after reperfusion. Adenosine infusion through a microdialysis probe into the ipsilateral striatum (1 mM adenosine, 2 microl min(-1), total 4.5 h from the occlusion to 3 h after reperfusion) showed a significant improvement in the neurological outcome, and about 25% reduction of infarct volume, although the effect did not reach statistical significance, compared with the vehicle-treated group at 20 h after 90 min of MCAO. These results demonstrated the neuroprotective effect of adenosine against ischemic brain injury both in vitro and in vivo, suggesting the possible therapeutic application of adenosine regulating agents, which inhibit adenosine uptake or metabolism to enhance or maintain extracellular endogenous adenosine levels, for stroke treatment.

Adenosine↗

PubMed2001

Antitumor Effect of Immunizations With Fusions of Dendritic and Glioma Cells in a Mouse Brain Tumor Model.

SUMMARY: The authors studied antitumor immunity conferred by fusions of dendritic and glioma cells in a mouse brain tumor model. Previous immunization with fusion cells (FCs) prevented tumor formation on challenge with glioma cells in the flank or in the brain. Efficacy was decreased when studies were performed in mice depleted of CD8+ cells. In a treatment model, FCs were injected subcutaneously after tumor development in the brain. The administration of FCs alone had limited effects on survival of mice bearing brain tumors. Importantly, however, administration of FCs and recombinant interleukin-12 (rIL-12) remarkably prolonged the survival of mice with brain tumors. Cytotoxic T lymphocyte activity against glioma cells from immunized mice was also stimulated by coadministration of FCs and rIL-12 compared with that obtained with FCs or rIL-12 alone. These data support the therapeutic efficacy of combining FC-based vaccine therapy and rIL-12.

Journal Article↗

PubMedDate not supplied

Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12.

Despite aggressive treatment, the median survival of patients with high-grade malignant astrocytoma is about 1 year. The authors investigated the safety and clinical response to immunotherapy using fusions of dendritic and glioma cells combined with recombinant human interleukin 12 (rhIL-12) for the treatment of malignant glioma. Fifteen patients with malignant glioma participated in this study. Dendritic cells were generated from peripheral blood. Cultured autologous glioma cells were established from surgical specimens in each case. Fusion cells were prepared from dendritic and glioma cells using polyethylene glycol. All patients received fusion cells intradermally on day 1. rhIL-12 was injected subcutaneously at the same site on days 3 and 7. Response to the treatment was evaluated by clinical observations and radiologic findings. No serious adverse effects were observed. In four patients, magnetic resonance imaging showed a greater than 50% reduction in tumor size. One patient had a mixed response. These results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma.

Adult↗

PubMedDate not supplied

Effects of glucocorticoids on antitumor effects of immunizations with fusions of dendritic and tumor cells.

BACKGROUND: A pitfall of immunotherapy with dendritic cells (DCs) for patients with malignant tumor is that certain patients have already been treated with Dexamethasone (DEX) prior to vaccination. Therefore, it is important to investigate whether DEX has negative effects on induction of antitumor immune response in dendritic cell-therapy. MATERIALS AND METHODS: We analyzed surface phenotypes and phagocytosis of DCs incubated with or without DEX. We also investigated the effects of DEX on in vivo antitumor effects of immunization with fusions of dendritic and glioma cells. RESULTS: Treatment with DEX did not affect the expression of surface markers, including H-2Kk, I-Kk, CD80 and CD86, on DCs. Likewise, DEX did not affect phagocytosis. Immunization with FCs inhibited tumor growth in vivo, and DEX did not suppress antitumor effects induced by FCs. CONCLUSION: These data suggest that vaccination with FCs can be used to treat cancer patients receiving DEX.

Animals↗