Biomedical subjects

F Shintani

Publications and source records attributed to F Shintani.

At least 19 recordsLinked to original sources

PubMed2001

Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.

6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Combination of inflammatory cytokines increases nitrite and nitrate levels in the paraventricular nucleus of conscious rats.

Inflammatory cytokines stimulate glial cells in vitro to produce nitric oxide (NO) from inducible NO synthase (iNOS). Whether the stimulation with cytokines produces NO derived from iNOS has not hitherto been demonstrated in the vivo brain. Nitrite and nitrate (NOx(-)) levels in the rat paraventricular nucleus (PVN) were measured before and after intraparenchymal microinjection of cytokines with a microdialysis technique. The cytokines, tumor necrosis factor (TNF)-alpha (10 ng), interleukin (IL)-1 beta (2 ng), and interferon (IFN)-gamma (2 ng) were microinjected. None of the cytokines alone had any effect on the NOx(-) levels for 8 h. But a combination of TNF-alpha and IFN-gamma gradually increased NOx(-) levels beginning at 140 min after the microinjection, and NOx(-) levels reached 1.8 times the basal level at 380 min. A combination of TNF-alpha and IL-1 beta increased NOx(-) beginning at 340 min, reaching 1.7 times the basal level at 440 min, whereas a combination of IL-1 beta and IFN-gamma had no effect. Microinjection of a mixture of all three cytokines increased NOx(-) levels beginning at 120 min, reaching 3.3 times the basal level at 400 min. Aminoguanidine, which is a selective inhibitor of iNOS, reduced NOx(-) levels induced by the mixed cytokine treatment. Semi-quantitative RT-PCR for iNOS mRNA was done. The intensity of the iNOS mRNA band for the cytokine-treated PVN was stronger than that for the vehicle-treated PVN. These results suggest that the increased NOx(-) after the treatment with mixed cytokines were dependent on iNOS activity. This is the first report to indicate that only cytokines induce NOS in vivo in the brain.

Animals↗

PubMed2000

Serum interleukin-18 levels are elevated in schizophrenia.

Interleukin-18 (IL-18) is a recently discovered proinflammatory cytokine which plays a pivotal role in T helper 1 (Th1) responses. IL-18 is produced by macrophage-like cells, and inappropriate IL-18 production has been known to be involved in immunological disturbances. Schizophrenia is a common disease whose pathogenesis is still unclear; however, an activation of the inflammatory response system, including the Th1 cytokine response, may be related to the pathophysiology of schizophrenia. We measured the serum IL-18 levels of 66 schizophrenics and age- and sex-matched control subjects by using an ELISA assay. We found significantly increased serum IL-18 levels in the schizophrenic patients (P=0.0002). This finding supports the hypothesis that immune activation is involved in the pathophysiology of schizophrenia.

Adult↗

PubMed2000

Glufosinate ammonium stimulates nitric oxide production through N-methyl D-aspartate receptors in rat cerebellum.

Glufosinate ammonium, a structural analogue of glutamate, is an active herbicidal ingredient. The neuronal activities of this compound were investigated by use of a microdialysis system that allowed us to measure nitric oxide production in the rat cerebellum in vivo. Kainate (0.3-30 nmol/10 microliter), N-methyl-D-aspartate (NMDA) (3-300 nmol/10 microliter) and glufosinate ammonium (30-3000 nmol/10 microliter), which were administered through the microdialysis probe at a rate of 1 microliter/min for 10 min, stimulated nitric oxide production. The glufosinate ammonium-elicited increase in nitric oxide production was suppressed by an inhibitor of nitric oxide synthase and was antagonized by NMDA receptor antagonists, but not by a kainate/(+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. These results suggest that glufosinate ammonium stimulates nitric oxide production through NMDA receptors.

Aminobutyrates↗

PubMed1998

Endothelium-independent and -dependent vasoactivity of 6-nitronorepinephrine.

Vasoactivities of 6-nitronorepinephrine were investigated using rat aorta. 6-Nitronorepinephrine (> 100 microM) caused dose-dependent contraction in both endothelium-intact and -denuded aorta, although the latter showed greater contraction than the former. Prazosin (> 3 nM), an alpha1-adrenoceptor antagonist, attenuated significantly the 6-nitronorepinephrine-induced contractions, thereby suggesting the alpha1-adrenoceptor involvement. Aortic rings prepared from reserpine-pretreated rats showed the 6-nitronorepinephrine-induced a contraction to the extent similar to those from untreated rats, suggesting that endogenous norepinephrine does not play a role in the 6-nitronorepinephrine-induced contraction. 6-Nitronorepinephrine (> 10 microM) potentiated norepinephrine-induced contraction only in the presence of endothelium. The augmentation was attenuated by catalase (1200 U/ml). H2O2 (10-300 microM) augmented the norepinephrine-induced contraction only in the endothelium-intact rat aortic rings. 6-Nitronorepinephrine attenuated significantly acetylcholine-induced relaxation. Catalase prevented the 6-nitronorepinephrine-induced inhibition of the acetylcholine-induced relaxation. These results suggest that 6-nitronorepinephrine has a weak alpha1-adrenoceptor agonistic property and that the endothelium-dependent potentiation by 6-nitronorepinephrine of the norepinephrine-induced contraction is mediated through production of H2O2.

Acetylcholine↗

PubMed1998

Aberrant interleukin-2 receptor-mediated blastoformation of peripheral blood lymphocytes in a severe major depressive episode.

BACKGROUND: We examined interleukin-2 (IL-2) related immune pathways in depression to elucidate mechanisms underlying various immunological disturbances associated with depression. METHODS: Subjects comprised 35 unmedicated patients with a major depressive episode without psychotic features and 36 age- and sex-matched healthy volunteers. The immune parameters examined included the numbers of B and T cells, IL-2 receptor-mediated blastoformation (IL-2R-mediated blastoformation), IL-2 production and expression of the IL-2 receptor alpha-subunit. RESULTS: The patients with a severe episode showed significantly lower IL-2R-mediated blastoformation than the controls. There was a statistically significant negative correlation between IL-2R-mediated blastoformation and the severity of depression at the time of entry. CONCLUSION: The reduced IL-2R-mediated blastoformation may partly explain several previously reported abnormal immune functions associated with depression.

Acute Disease↗

PubMed1997

Endothelium-dependent and -independent vasoactive actions of a Japanese kampo medicine, Saiko-ka-ryukotsu-borei-to.

Saiko-ka-ryukotsu-borei-to (TJ-12) is a Japanese kampo medicine used clinically for the treatment of hypertension and atherosclerosis. We investigated the effects of TJ-12 on the contraction of rat thoracic aorta induced by norepinephrine, 5-hydroxytryptamine and high potassium. TJ-12 relaxed endothelium-denuded rings, which had been precontracted with 1 microM norepinephrine, in a dose-dependent manner with an IC50 of 50 micrograms/mL. However, in the presence of TJ-12, endothelium-intact rings initially showed enhanced norepinephrine-induced contraction, followed by relaxation. Interestingly, TJ-12 dose-dependently reversed nitric oxide (2 microM)-induced relaxation of norepinephrine-induced precontraction ofendothelium-denuded rings, with an IC50 of 20 micrograms/mL. In serotonin-contracted rings, TJ-12 caused slight, though statistically significant, relaxation only at high doses (> 200 micrograms/mL). In constrat to these receptor-mediated contractions, TJ-12 failed to affect the tension produced by high potassium 40 mM). These results suggest that the antihypertensive effects of TJ-12 could be related to inhibition of norepinephrine-induced vasoconstriction. In addition, our in vitro experiments revealed an inhibitory effect on nitric oxide-induced relaxation.

Analysis of Variance↗

PubMed1997

Immobilization stress increases mRNA levels of interleukin-1 receptor antagonist in various rat brain regions.

1. Interleukin-1 receptor antagonist (IL-1Ra), as well as the interleukin-1 beta (IL-1 beta) gene response to immobilization stress (IMS), was examined in the rat brain. The reverse transcription-polymerase chain reaction was employed to determine mRNA levels. 3. IL-1 beta and IL-1Ra mRNA levels peaked at approximately 0.5 and 2-4 hr, respectively. The maximum mRNA levels of IL-1 beta were 15-fold higher than pre-IMS levels, whereas those of IL-1Ra were 250-fold higher in the hypothalamus. 3. After the biosynthesis of IL-1 beta has peaked, IL-1Ra may contribute to attenuation of the IL-1 activity which has been enhanced by IMS.

Animals↗

PubMed1997

Dexamethasone and nitric oxide synthase gene expression in brain.

Systemic administration of lipopolysaccharide (LPS), which causes endotoxemia and systemic inflammation, has been reported to induce expression of the gene for type II inducible nitric oxide synthase (iNOS) in peripheral organs. This study was carried out to examine whether intraperitoneally injected LPS elicits the expression of iNOS messenger ribonucleic acid (mRNA) in the rat brain. We also investigated whether intraperitoneal treatment with dexamethasone (DEX) prevents this induction. To determine levels of iNOS mRNA, a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method was employed. Treatment with LPS induced the expression of iNOS mRNA in various brain regions, accounting for approximately 1 x 10(5) to 4 x 10(5) molecules per micrograms of poly A+ RNA, and these inductions were markedly suppressed by DEX. The results suggest that, during systemic inflammation, iNOS mRNA induction occurs in brain through a DEX-sensitive mechanism.

Animals↗

PubMed1996

Induction of interleukin-1 beta and interleukin-1 receptor antagonist mRNA by chronic treatment with various psychotropics in widespread area of rat brain.

We investigated whether psychotropics orally administered to rats affect levels of interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1Ra) mRNA in the hypothalamus, hippocampus, frontal cortex, and brain stem, using a reverse transcription-polymerase chain reaction method. The psychotropics tested were chlorpromazine, haloperidol, imipramine, maprotiline, fluvoxamine, and diazepam. Treatment for 28 days raised the levels of both mRNAs. The increase in IL-1Ra mRNA was 6-112 times larger than that of IL-1 beta mRNA in most brain regions examined. These results suggest that chronic treatment with psychotropics causes greater amplifying effects on IL-1Ra mRNA than IL-1 beta mRNA in the brain.

Animals↗

PubMed1996

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders.

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.

Adult↗

PubMed1996

Bioactive 6-nitronorepinephrine identified in mammalian brain.

Norepinephrine (NE) (von Euler, U. S. (1972) in Catecholamines (Blaschko, H., and Muscholl, E., eds.) pp. 186-230, Springer-Verlag, Berlin) and nitric oxide (NO.) function as neurotransmitters in the nervous system. We have shown that NE levels in the rat hypothalamic paraventricular nucleus (Shintani, F., Kato, R., Kinoshita, N., Kanba, S., Asai, M., and Nakaki, T.(1995) Proceedings of the Satellite Symposium, 4th IBRO World Congress on Neuroscience, Otsu, 1995) diminish in the presence of NO.. This observation prompted us to explore the possibility of an in vivo interaction between NE and NO. or NO.-related molecules. In fact, nitration of NE has been shown to occur in vitro (d'Ischia, M., and Costantini, C. (1995) Bioorg. Med. Chem. 3, 923-927). We now report the identification of 6-nitronorepinephrine in the mammalian brain. Amounts of 6-nitronorepinephrine in the rat brain were attenuated by intraperitoneal administration of an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (L-NAME). This was reversed by coadministration of L-arginine, suggesting that nitric oxide synthase participated in the formation of 6-nitronorepinephrine. Moreover, we found that 6-nitronorepinephrine inhibits the activity of catechol O-methyltransferase, as well as NE transport into rat synaptosomes. A rat brain microdialysis experiment showed that perfusion of 6-nitronorepinephrine into the rat paraventricular nucleus significantly elevated NE while decreasing 3-methoxy-4-hydroxyphenylglycol and that L-NAME administered intraperitoneally decreased NE and increased 3-methoxy-4-hydroxyphenylglycol. These observations suggest that 6-nitronorepinephrine generated in nuclei containing both adrenergic and nitrergic neurons inhibits NE inactivation. We propose that 6-nitronorepinephrine is a potential signal molecule linking the actions of NE and NO..

Animals↗

PubMed1995

Schizophrenic patients with deficit syndrome have higher plasma homovanillic acid concentrations and ventricular enlargement.

In order to investigate the biological characteristics of deficit syndrome in schizophrenia (Carpenter et al 1988), we examined cerebroventricular ratios (CVRs) and plasma concentrations of homovanillic acid (HVA) in a group of schizophrenic inpatients with deficit syndrome (n = 20) and in a control group of age- and sex-matched schizophrenic inpatients without deficit syndrome (n = 20). Symptoms and intelligence levels were measured using the Brief Psychiatric Rating Scale (BPRS) and the Wechsler Adult Intelligence Scale (WAIS), respectively. Patients in the deficit group had significantly higher CVRs as well as significantly elevated plasma HVA concentrations when compared with patients in the nondeficit group. We also found that the mean total WAIS score in the deficit group was significantly lower than that in the nondeficit group. These findings suggest the biological heterogeneity of schizophrenia. Increased central dopaminergic turnover, as indicated by higher plasma HVA concentrations, may partially account for the pathogenesis of deficit syndrome.

Adult↗

PubMed1995

Role of interleukin-1 in stress responses. A putative neurotransmitter.

Recently, the central roles of interleukin-1 (IL-1) in physical stress responses have been attracting attention. Stress responses have been characterized as central neurohormonal changes, as well as behavioral and physiological changes. Administration of IL-1 has been shown to induce effects comparable to stress-induced changes. IL-1 acts on the brain, especially the hypothalamus, to enhance release of monoamines, such as norepinephrine, dopamine, and serotonin, as well as secretion of corticotropin-releasing hormone (CRH). IL-1-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in vivo depends on secretion of CRH, an intact pituitary, and the ventral noradrenergic bundle that innervates the CRH-containing neurons in the paraventricular nucleus of the hypothalamus. Recent studies have shown that IL-1 is present within neurons in the brain, suggesting that IL-1 functions in neuronal transmission. We showed that IL-1 in the brain is involved in the stress response, and that stress-induced activation of monoamine release and the HPA axis were inhibited by IL-1 receptor antagonist (IL-1Ra) administration directly into the rat hypothalamus. IL-1Ra has been known to exert a blocking effect on IL-1 by competitively inhibiting the binding of IL-1 to IL-1 receptors. In the latter part of this review, we will attempt to describe the relationship between central nervous system diseases, including psychological disorders, and the functions of IL-1 as a putative neurotransmitter.

Animals↗

PubMed1995

Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat.

We investigated whether interleukin-1 (IL-1) activity in the rat hypothalamus was increased by immobilization stress (IS), and whether pretreatment with an interleukin-1 receptor antagonist (IL-1Ra) is capable of inhibiting IS-induced elevations of hypothalamic norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and the levels of their metabolites as well as of plasma adrenocorticotropic hormone (ACTH). IL-1 activity was estimated with a bioassay using mouse thymocyte proliferation in the presence of concanavalin A. IL-1Ra was administered directly into the anterior hypothalamus, and monoamines were determined using a microdialysis technique and an HPLC system. First, we found that levels of IL-1 activity in the rat hypothalamus reached a maximum at 60 min after starting IS. Second, IL-1Ra (2 micrograms) significantly inhibited IS-induced increases in hypothalamic NE, DA, and 5-HT levels as well as the levels of their metabolites. In addition, IL-1Ra (2 micrograms) also inhibited the IS-induced elevation of plasma ACTH levels. Third, timing effects of IL-1Ra administration on the IS-induced monoamines or ACTH responses were examined. IL-1Ra (2 micrograms) administered at 5 or 60 min before the start of IS, but not at 5 or 60 min after IS had been started, exerted inhibitory effects on these responses, indicating that the effects of IL-1 occurred within 5 min after the initiation of IS. In summary, these results suggest that IS enhances biologically active IL-1 in the hypothalamus, and that hypothalamic IL-1 plays a role in the regulation of IS-induced responses including elevated monoamine release in the hypothalamus and activation of the hypothalamo-pituitary-adrenal axis. Moreover, since 5 min is too short a time for IS to induce production of IL-1, IS may augment the effects of preexisting IL-1 in the hypothalamus.

Adrenocorticotropic Hormone↗

PubMed1994

Longitudinal changes in symptoms and plasma homovanillic acid levels in chronically medicated schizophrenic patients.

A correlation has been noted between the changes in plasma homovanillic acid concentrations and changes in psychiatric symptoms induced by neuroleptic treatment. Our objective was to determine whether plasma homovanillic acid concentration changed in accordance with the changes in symptoms over time. Twenty-eight chronically medicated schizophrenic inpatients received the same treatment regimen for 1 year. Symptoms and plasma homovanillic acid concentrations were examined every month and whenever conditions deteriorated. Plasma homovanillic acid concentrations were significantly higher in the patients in the worst condition than in the patients in the best condition. Further, when comparing the best and worst conditions of both the positive and negative symptoms, the change in psychiatric rating of positive and negative symptoms was correlated significantly with the change in plasma homovanillic acid level. These results suggest that a change in plasma homovanillic acid concentration can be produced not only by neuroleptic-induced dopaminergic blocking but also by a change in positive and negative symptoms of schizophrenia.

Adult↗

PubMed1994

Inhibition by lithium of cyclic GMP formation without inhibition of nitric oxide generation in the mouse neuroblastoma cell (N1E-115).

We investigated the effects of lithium ion (Li+) on muscarinic receptor-mediated nitric oxide (NO) generation, and guanylate cyclase (GCase) activation using the mouse neuroblastoma clone, N1E-115. The levels of released NO were determined by measuring the levels of nitrite/nitrate in the incubation medium, and the activity of GCase was measured with an assay for cellular cyclic [3H] GMP levels. We determined that Li+ had no effects on muscarinic receptor-activated elevation of nitrite/nitrate levels, which were significantly inhibited by 100 microM L-NG-monomethylarginine, although it has been reported that Li+ inhibits muscarinic receptor-activated cyclic GMP formation in the cells. In addition, Li+ inhibited the cyclic GMP formation induced by an NO donor, sodium nitroprusside (SNP), in both intact cells and a crude cellular homogenate; thus, the inhibition by Li+ of muscarinic receptor-mediated cyclic GMP synthesis appeared to be at the level of GCase, but not NO synthase.

Animals↗

PubMed1994

[Two applications of in vivo brain microdialysis: administration of high-molecular-weight drugs through a microinjection tube and measurement of nitric oxide production].

A brain microdialysis technique has made it possible to determine neurotransmitter levels in the targeted region of the brain of a freely moving rat. In this article, two kinds of application of the brain microdialysis are demonstrated. First, to study central nervous effects of large molecular weight substances that cannot cross the blood-brain barrier, we used a microdialysis probe equipped with a microinjection tube for administering the substance in the same region into which the probe had been inserted. We proved that interleukin-1 beta (1 ng) injected directly into the anterior hypothalamus elicited releases of NE, DA and 5-HT, as well as increases in their metabolites. Second, using a new method combining a brain microdialysis technique with measurement of nitrite/nitrate by the Griess reaction, we demonstrated that activation of N-methyl-D-aspartate (NMDA) receptors in the cerebella of rats induces the release of nitric oxide (NO). Since L-NG-monomethyl-arginine (L-NMMA), which competitively blocks NO synthesis from L-arginine, significantly inhibited the release of nitrite/nitrate from the rat cerebellum, these results indicate that this new method is capable of measuring NO formation from L-arginine following the stimulation of NMDA receptors.

Animals↗