Biomedical subjects

S Okuyama

Publications and source records attributed to S Okuyama.

At least 73 records · Page 4Linked to original sources

PubMed1996

VA-045, a novel apovincamic acid derivative attenuates neuronal injury induced by hypoxia or by excitatory amino acids in cultures of rat cortices.

Effects of VA-045, a novel apovincaminic acid derivative, on neuronal damage induced by hypoxia or by excitatory amino acids (glutamate (Glu), N-methyl-D-aspartate and kainate) were examined in cultures of the rat cortices. The extent of cell injury was quantified by measuring lactic dehydrogenase activity released from the damaged cells into the culture medium. VA-045 at concentrations between 1 microM and 30 microM significantly attenuated this neuronal damage and exceeded those of vinpocetine. VA-045 had no significant binding affinity to Glu receptor subtypes. The cytoprotection of VA-045 does not seem to be the result of antagonism at Glu receptors. VA-045 inhibited lipid peroxide production in brain homogenates. Vitamin E also had this antioxidant effect, but did not attenuate the hypoxia-induced neuronal damage. A cAMP analogue and a phosphodiesterase (PDE) inhibitor also attenuated the hypoxia-induced neuronal damage. As VA-045 inhibits the activity of PDE, the effect of VA-045 may possibly relate to cAMP cascade. VA-045 may prove to be efficacious for the treatment of disorders related to cerebral neuronal injury.

Animals↗

PubMed1996

Behavioral evidence for modulation by sigma ligands of (+)MK-801-induced hyperlocomotion in monoamine-depleted mice.

The selective non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine maleate ((+)MK-801) led to a dose-dependent increase in locomotor activity in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine (alpha-MT). A selective and potent sigma receptor "antagonist" NE-100 (N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride), which did not per se affect spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. Sulpiride, a dopamine D2 receptor antagonist, and clozapine, a dopamine D4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801. The sigma receptor "agonists" (+)N-allynormetazocine [(+)SKF10,047], (+)pentazocine and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)3-PPP], which did not per se affect spontaneous locomotor activity, did dose-dependently enhance the hyperlocomotion induced by (+)MK-801. The enhancement of (+)MK-801-induced the hyperlocomotion by (+)SKF10,047, (+)pentazocine and (+)3-PPP was completely blocked by NE-100. The enhancement of (+)MK-801-induced hyperlocomotion by (+)pentazocine was not affected by treatment with sulpiride and clozapine. As sigma ligands can markedly attenuate NMDA antagonist-induced behavior, the major physiological role of sigma receptors in vivo might be to modulate functions of the NMDA receptor ion channel complex.

Animals↗

PubMed1996

Effect of VA-045 on central noradrenergic neuronal system in rats.

1. Administration of VA-045 [2-(nitrooxy)ethyl apovincaminate] and thyrotropin-releasing hormone (TRH) led to improvement in the closed head injury (CHI)-induced neuronal dysfunction such as the loss of righting reflex and disruption of spontaneous movement in rats. 2. The improvement seen with effect of VA-045, but not TRH, was abolished in rats pretreated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a selective noradrenaline (NA) neurotoxin. DSP4 reduced endogenous NA levels in all central nervous system (CNS) regions analyzed. 3. The extracellular concentrations of NA in the frontal cortex (FC) and in the locus coeruleus (LC) of urethane-anesthetized rats were measured using in vivo microdialysis coupled with high-performance liquid chromatography (HPLC) with electrochemical detection. VA-045 had no effect on extracellular concentrations of NA, in both FC and LC. Perfusion with clonidine, and alpha 2 adrenoceptor agonist, led to inhibition in NA output in both FC and LC, and VA-045 antagonized the effect of clonidine. 4. These findings indicate that the mode of action of VA-045 may be, at least in part, related to central NA neuronal systems.

Animals↗

PubMed1996

Neuroprotective effect of 4'-(4-methylphenyl)-2,2':6',2-terpyridine trihydrochloride, a novel inducer of nerve growth factor.

We have identified 4'-(4-methylphenyl)-2,2':6',2-terpyridine: trihydrochloride (SS701), which belongs to a family of a small unique neuroprotective agents. SS701 accelerated the production of nerve growth factor (NGF) in cultured astroglial cells, dose- and time-dependently. In in vivo studies, SS701, when administered 30 min after induced cerebral ischemia, neuroprotective effects on delayed neuronal death in Mongolian gerbils were evident. The neuroprotective effects of SS701 against ischemia-induced delayed neuronal death are attributed to stimulation of the production of NGF.

2,2'-Dipyridyl↗

PubMed1996

Evolution of Hodgkin's disease.

Hodgkin's disease is an oncogenic core disorder characterized by both mitotic and amitotic neoplastic multiplication, and is associated with collateral disorders such as lacunar formation and leukocytic infiltration. Research has demonstrated that Hodgkin's disease progresses stepwise, beginning with a reversible, biological stage during which Hodgkin and Reed-Sternberg cells are formed, followed by constitutive, but reversible Hodgkinogenic medical stage that leads to an irreversible, systemic and fatal proto-oncogenic stage. This disease results from collateral activation of cytokine and archaic oncogenes, suppression of DNA repair genes in multiple chromosomes. The variability of Hodgkin's disease manifestations has required antisynthetic (antimetabolites, radiotherapy), anti-viral (acyclovir) and anti-mitotic (vincristine, vinblastine) for different loci minores of treatment. Continued molecular biological research of the ancestral and prokaryotic oncogenes is recommended.

Biological Evolution↗

PubMed1996

Pirarubicin pasting for radiotherapy of inoperable colorectal cancers.

Three cases of inoperable primary or recurrent colorectal cancer were subjected to pirarubicin pasting during radiotherapy. The tumor masses dissolved or greatly regressed, and the patients resumed their activity. The technique is simple, safe, and effective, and it may also be applicable to other approachable cancers, with or without the concurrent radiotherapy. Other anticancer chemotherapeutics, which do not harm normal tissue, may also be used.

Aged↗

PubMed1996

[Social factors related to awareness of public health care services among elderly adults].

This article presents findings on the association between social ties and the awareness in elderly of seven services. A total of 1,200 persons aged 60 and over were subjects of an interview survey of when 856 subjects provided necessary data for analysis. Subjects lived in two separate communities, Nerima-Ward (a metropolitan area) and Kashimadai-Cho (a rural area). Social ties were classified into six types: living with a person, contact with child (ren) living separately, contact with friend, contact with neighbor, and participation in a community group. The elderly metropolitan residents were significantly less likely to be aware of a greater number of services. Contacts with neighbor and participation in community group predicted service awareness. There were no regional differences in the effect of those ties on service awareness.

Aged↗

PubMed1995

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Angiotensin II↗

PubMed1995

Effect of NE-100, a novel sigma receptor ligand, on phencyclidine- induced delayed cognitive dysfunction in rats.

Phencyclidine (PCP), in a dose of 15 mg/kg, produced delayed cognitive dysfunction (at 24 h) in rats subjected to water maze tasks. At 24 h after PCP administration, ataxia, hyperlocomotion and stereotyped behavior were not induced. NE-100, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-enthylamine monohydrochloride, a selective and potent sigma receptor ligand, was administered orally 10 min after PCP administration or 15 min before the first trial (24 h after PCP administration). In both cases, NE-100 dose-dependently attenuated the delayed cognitive dysfunction induced by PCP. As these findings show that ingestion of PCP led to delayed cognitive dysfunction similar to the cognitive signs of psychosis seen in humans, NE-100 is being further studied for possible treatment of subjects with schizophrenia.

Animals↗

PubMed1995

Regional expression of murine intestinal immune cells in normal and isografted intestine.

The spatial organization and differentiation of the gut immune system was studied using immunohistochemistry from Embryonic Day 15 until adulthood. Leukocyte common antigen-positive cells were detected first, followed by macrophages, B, and then T lymphocytes increasing in number and intensity of staining until adulthood. The adult mouse displays regional localization of gut immune cells with highest expression in proximal intestine, decreasing distally to ileum with the fewest cells present in colon. The role of intestinal contents, bone marrow, and thymus on maturation of the gut immune system during development was studied using an isograft model: small intestine from neonatal mice were implanted subcutaneously into SCID mice and developed into morphologically normal intestine. Injected syngeneic mononuclear cells recirculated to the isografted intestine and SCID host intestine with the same regional expression as normal adult. This model is useful to define the mechanisms that establish and maintain cellular and regional differentiation of the normal gut immune system.

Animals↗

PubMed1995

Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF-1 and ATF-2 in the complex at the ATF/CRE site.

The human embryonal carcinoma cell line NEC14 can be induced to differentiate by the addition of N,N'-hexamethylene-bis-acetamide (HMBA). After treatment with HMBA, the level of cyclin A transcript decreased steeply, reaching less than one-tenth of the original level by 48 h. The promoter elements concerned with this down-regulation were studied by using reporter genes and by analyzing DNA-protein complexes. The deletion of the sequence between -608 and -259 containing three GC boxes decreased the promoter activity to about a half, and further deletion up to -194, eliminating the ATF/CRE site, resulted in a decrease to about a tenth of the original level in undifferentiated NEC14 cells. These sequences were involved in down-regulation of the promoter activity in differentiation-induced NEC14 cells. DNA-protein complexes formed at the ATF/CRE site with extracts prepared from undifferentiated and differentiation-induced cells gave the same footprint, but showed different electrophoretic mobilities. The supershift assay with specific antibodies against ATF-1 and ATF-2 indicated that both factors were depleted in the complex after induction of NEC14 cell differentiation. Both the ATF/CRE site and GC boxes seemed to be also involved in up-regulation of the cyclin A promoter in growth-stimulated human fibroblasts at the G1/S boundary.

Acetamides↗

PubMed1995

Stable prostacyclin improves postischaemic microcirculatory changes in hypertensive rats.

The prostacyclin analogue TTC-909 is incorporated in lipid microspheres and is chemically very stable. We examined the efficacy of TTC-909 on cerebral microcirculation following focal cerebral ischaemia. Focal cerebral ischaemia was produced by the occlusion of the distal middle cerebral artery in stroke-prone spontaneously hypertensive rats. Intravenous administration of TTC-909 (100 ng/kg/day) or vehicle was started 30 minutes after the occlusion and repeated for 7 days. On day 7, cerebral blood flow and blood-brain barrier permeability were measured autoradiographically. Brain oedema was estimated by the gravimetric method. The size of the infarction was calculated from area measurements on serial histologic sections. Treatment with TTC-909 resulted in significant improvement in regional blood flow in the ischaemic rim (p < 0.01) and the surrounding area (p < 0.05). With TTC-909 treatment, the increased permeability was significantly reduced in the ischaemic centre (p < 0.01) and rim (p < 0.05). A decrease in specific gravity in the ischaemic region and the remote non-ischaemic regions was prevented by the treatment (p < 0.01). We assumed that the efficacy of TTC-909 maintains the blood supply in the ischaemic area, improves disruption of the blood-brain barrier and prevents development of ischaemic oedema.

Animals↗

PubMed1995

NE-100, a novel sigma ligand: effects on [3H]TCP binding to intact primary cultured neuronal cells.

N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a potent and highly selective sigma ligand, haloperidol, (+)pentazocine, 1-(cyclopropyl-methyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine HBr (DuP 734) and 4-(2'-(4"-cyanophenyl)-2'-oxoethyl) 1-(cyclopropylmethyl)piperidine (XJ 448) inhibited carbachol-induced inositol 1,4,5-triphosphate (IP3) formation in a dose-dependent manner. The rank order of potency of the tested drugs for inhibition was: haloperidol > or = (+)pentazocine = NE-100 > DuP 734 = XJ 448. In addition, the effects of NE-100, DuP 734 and XJ 448 upon [3H]TCP binding were examined using primary cultured neuronal cells derived from the fetal rat telencephalon. These drugs inhibited [3H]TCP binding to intact cells. The ability of the test drugs to inhibit [3H]TCP binding to primary cultured neuronal cells was in the order: NE-100 > DuP 734 > XJ 448. These observations suggest that NE-100 indirectly modulates the N-methyl-D-aspartate (NMDA)/phencyclidine (PCP) receptor ion channel complex (NMDA receptor-ion channel), presumably through sigma-1 sites.

Animals↗

PubMed1995

Antagonizing effects of VA-045 on reduced activity of rat locus coeruleus neurons following head injury or intravenous injection of clonidine.

Based on the finding that VA-045, a novel apovincaminic acid derivative, had improved disturbance in consciousness, we examined the effects of the drug on the electrical activity of locus coeruleus (LC) neurons in animal models of consciousness disturbance. The animal models of consciousness disturbance used in this experiment were closed head injury (CHI) and intravenous injection of clonidine. CHI as well as clonidine injection reduced the spontaneous activity of LC neurons. The reduction of the spontaneus activity of LC neurons following CHI or clonidine injection was restored by intravenous injection of VA-045. The change of LC neuronal activity induced VA-045 preceded desynchronization of EEG. These results suggest that VA-045 exerts its ameliorating effect on consciousness disturbances, at least in part, by augmenting the spontaneous activity of noradrenergic LC neurons.

Animals↗

PubMed1995

Autoradiographic characterization of binding sites for [3H]NE-100 in guinea pig brain.

The receptor binding specificity and neuroanatomical distribution of [3H]NE-100 (N, N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy) phenyl] ethylamine monohydrochloride)-labeled sigma receptor in guinea pig brain were examined using quantitative autoradiography. NE-100 potently inhibited [3H]NE-100 binding to slide-mounted sections of guinea pig brain with the IC50 value of 1.09 nM, therefore, NE-100 apparently has high affinity binding sites. Competition studies, under conditions similar to those used to visualize the receptor, yielded the following rank order of potency: NE-100 > haloperidol > DuP734 > (+)pentazocine >> (-)pentazocine. Non-sigma ligands such as phencyclidine (PCP), MK-801 and (-)sulpiride had negligible affinities for [3H]NE-100 binding sites. High densities of [3H]NE-100 binding sites displaceable by haloperidol were present in the granule layer of the cerebellum, the cingulate cortex, the CA3 region of the hippocampus, the hypothalamus and the pons. The distribution of [3H]NE-100 binding sites was consistent with that of [3H](+)pentazocine, a sigma 1 ligand. These sigma sites may possibly be related to various aspects of schizophrenia.

Animals↗

PubMed1995

The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model.

1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior. 2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethyl-amine monohydrochloride), attenuates the effects of PCP in this procedure. 3. The serotonin2 (5-HT2) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine HBr (Dup734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1- (cyclopropylmethyl)piperidine (XJ448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP. 4. The dopamine D2/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4- methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation. 5. The dopamine D2-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive. 6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT2 antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.

Animals↗

PubMed1995

Effects of VA-045 on peripheral and central circulation in anesthetized dogs.

1. The effects of VA-045, a novel apovincaminic acid derivative, vinpocetine, apovincaminic acid, brovincamine and nicergoline on peripheral and cerebral circulation were examined in anesthetized dogs. 2. Peripheral circulation: VA-045 induced a transient decrease in both blood pressure (BP) and heart rate (HR) andd an increase in vertebral arterial blood flow (VBF) without affecting femoral arterial blood flow (FBF) or carotid arterial blood flow (CBF). Vinpocetine had no effect on BP, HR, VBF, FBF or CBF. Apovincaminic acid decreased HR and increased VBF without affecting FBF, CBF or BP. Brovincamine increased VBF and decreased CBF without affecting BP or FBF. Nicergoline decrease BP without affecting VBF, FBA or CBF. 3. Cerebral circulation: VA-045 increased cerebral blood flow (CerBF) without affecting BP. Brovincamine also increased CerBF and decreased BP. The potency of VA-045 in increasing CerBF was stronger than that of brovincamine. Vinpocetine and apovincaminic acid had no effect on BP or CerBF. Nicergoline decreased BP but did not affect CerBF. 4. These findings indicate that VA-045 has a more selective vasodilative effect on the vertebral and cerebral arteries than the other reference drugs.

Anesthesia↗

PubMed1995

Antibiotic pasting for foul putrefactive cancers.

Putrefaction of cancers in infrequent. Nonetheless, it presents a difficult clinical problem of foulness. We prepared 5% antibiotic pastes by adding sodium polyacrylate to aliquots of antibiotic solutions, and applied them to putrefactive lesions in 4 cases of rectal cancer, 2 of breast cancer and 1 of tongue cancer. The putrefaction was promptly brought under control in all of them, permitting an improved QOL. Concomitant application of anticancer pastes was also found remarkably effective. Use of sulperazone may offer a better chance of overcoming the beta lactamase barrier in cases of prolonged use.

Anti-Bacterial Agents↗