The role of the brain histaminergic neuron system in methamphetamine-induced behavioral sensitization in rats.
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Animals↗
Biomedical subjects
C Ito
Publications and source records attributed to C Ito.
The effect of methamphetamine on histamine level and histidine decarboxylase activity in the rat brain.
To examine biochemical changes in the brain histamine (HA) neuron system after acute and chronic administrations of methamphetamine (MAP), HA levels and histidine decarboxylase (HDC) activities in the rat cortex, striatum, diencephalon, midbrain, pons-medulla and cerebellum were measured. In the cortex and striatum, acute administration of MAP (1 and 3 mg/kg) increased HA levels 1 h later. Acute administration of MAP (10 mg/kg) and chronic administration of MAP (3 mg/kg) for 21 days also increased HA levels and HDC activities in the cortex and striatum I h after the last injection. In the diencephalon, acute administration of MAP (3 and 10 mg/kg) and chronic administration of MAP (3 mg/kg) decreased HA level 1 h after the last injection, but chronic administration of MAP (3 mg/kg) increased HDC activity 1 h after the last injection. There were no significant changes in HA levels and HDC activities in other regions after acute and chronic administrations of MAP. These findings suggest that MAP may activate the brain HA neuron system, although MAP acts more strongly on the cortex and striatum than on the diencephalon.
Animals↗
CD38-mediated growth suppression of B-cell progenitors requires activation of phosphatidylinositol 3-kinase and involves its association with the protein product of the c-cbl proto-oncogene.
The signalling pathways that arrest the cell cycle and trigger cell death are only partially known. Dimerization of CD38, a 45-kD transmembrane type II glycoprotein highly expressed in immature B cells, inhibits cell growth and causes apoptosis in normal and leukemic B-cell progenitors, but the molecular mechanisms underlying these cellular responses are unknown. In the present study, we found that CD38 ligation in the immature B-cell lines 380, REH, and RS4;11 caused rapid tyrosine phosphorylation of the protein product of the proto-oncogene c-cbl. Dimerization of CD38 was accompanied by the association of cbl with the p85 subunit of phosphatidylinositol 3-kinase (Pl 3-K), resulting in markedly increased Pl 3-K activity in antiphosphotyrosine and anti-cbl immunoprecipitates. Wortmannin and LY294002, two potent inhibitors of Pl 3-K, rescued immature B cells from CD38-mediated growth suppression. This effect was observed not only in model B-cell lines, but also in cultures of leukemic lymphoblasts from patients, and in normal bone marrow B-cell progenitors as well. Concentrations of inhibitors that reversed cellular responses to CD38 significantly decreased Pl 3-K activity. By contrast, rapamycin, a p70 S6-kinase inhibitor, did not rescue immature B cells from CD38-mediated suppression. These results suggest that Pl 3-K activity is essential for CD38-mediated inhibition of lymphopoiesis and that cbl and Pl 3-K are regulatory molecules whose activation can result in suppression of cell proliferation and apoptosis in immature lymphoid cells.
ADP-ribosyl Cyclase↗
CD38 signal transduction in human B cell precursors. Rapid induction of tyrosine phosphorylation, activation of syk tyrosine kinase, and phosphorylation of phospholipase C-gamma and phosphatidylinositol 3-kinase.
Ligation of CD38 inhibits proliferation and induces apoptosis of human immature B cells, but the molecular mechanisms underlying this function are unknown. We found that CD38 dimerization with the specific mAbs T16 and IB4 induces rapid and transient tyrosine phosphorylation of several intracellular proteins in the immature B cell lines RS4;11, REH, 380, Nalm6, and OP-1. This effect could be markedly reduced by incubating cells with the tyrosine kinase inhibitors genistein, staurosporine, and herbimycin A. CD38 dimerization induced tyrosine phosphorylation of the protein kinase syk and increased syk kinase activity. CD38 dimerization also induced tyrosine phosphorylation of phospholipase C-gamma and of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). The latter was accompanied by a distinct increase in PI 3-kinase activity in the immunoprecipitates obtained with an anti-phosphotyrosine Ab. In contrast to the signaling triggered by surface Ig engagement in B lymphocytes, CD38 ligation did not appear to induce tyrosine phosphorylation of the src-like protein tyrosine kinases lyn, fyn, and btk, or of vav- and ras-GTPase-activating protein, nor did it induce detectable changes in cytosolic CA2+ concentrations. CD38 signaling also differed from cytokine-induced signaling in that it did not cause tyrosine phosphorylation of Jak1 and Jak2. Finally, CD38 ligation did not inhibit IL-3-induced tyrosine phosphorylation of Jak2. These results identify CD38 as a cell surface receptor with signal transduction properties activated by dimerization. Induction of signal transduction by CD38 ligation implies the existence of a yet unidentified natural ligand of CD38.
ADP-ribosyl Cyclase↗
Gastric bypass in obesity. 1967.
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Animals↗
T2 shortening in childhood moyamoya disease.
We examined T2 shortening in six children with infarcts due to moyamoya disease to clarify whether there are characteristic patterns of T2 shortening in the deep grey and white matter. Profound T2 shortening in the deep grey and white matter was observed in the acute stage of infarct in two cases, which changed to high intensity in the chronic stage; in this stage no T2 shortening was demonstrated in any case. Neither haemorrhagic infarction nor calcification was seen on CT or MRI. There could be longitudinally different T2 shortening patterns between infarcts due to moyamoya disease and other disorders.
Cerebral Cortex↗
Estimation of radiation doses for atomic-bomb survivors in the Hiroshima University Registry.
The present study presents the Hiroshima University Registry of atomic bomb survivors, of which the total number is about 270,000, and application of absorbed doses. From this registry, we picked up 49,102 survivors and applied organ doses based on the dosimetry system 1986 (DS86), which is named the Atomic Bomb Survivor 1993 Dose (ABS93D). The applied dose data are based on the tables listed in the DS86 final report such as the free-in-air kermas, the house shielding factors, and organ dose factors for the active bone marrow and the breast. Calculations for the 13 other organs provided in DS86 are possible. To obtain the organ doses for each survivor, it is necessary to obtain information concerning (1) place exposed, (2) whether they were shielded or not, and (3) age. ABS93D body transmission factors for active bone marrow for neutrons and gamma rays agreed with DS86 to within a few percent. Of the survivors studied, 35,123 of them were used for the relative risk estimation of leukemia mortality, adopting the same method as the Radiation Effects Research Foundation (RERF) for comparison. For the observation period from 1968 to 1989, the analyzed relative risks for leukemia mortality at 1 Gy by shielded kerma and by active bone marrow dose are 2.01 and 2.37, respectively, which are consistent with the RERF results.
Dose-Response Relationship, Radiation↗
Detection of human herpesvirus 6 and human herpesvirus 7 in the submandibular gland, parotid gland, and lip salivary gland by PCR.
In order to define the major sites of persistence of human herpesvirus 6 (HHV-6) and HHV-7, PCR with DNAs from more than 100 specimens of 3 different salivary glands was performed. HHV-6 DNA was detected in 52 (88.1%) of 59 submandibular gland, 17 (63.0%) of 27 parotid gland, and 9 (52.9%) of 17 lip salivary gland specimens. On the other hand, HHV-7 DNA was detected in 59 (100%) of 59 submandibular gland, 23 (85.2%) of 27 parotid gland, and 10 (58.8%) of 17 lip salivary gland specimens. These findings demonstrate that salivary glands are a site of persistent infection of both HHV-6 and HHV-7 and that among the three types of salivary gland examined, the submandibular gland is the primary one in which these herpesviruses, especially HHV-7, persist.
Herpesvirus 6, Human↗
Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia.
PURPOSE: The relative cytotoxicity of prednisolone and dexamethasone in acute lymphoblastic leukemia (ALL) is controversial. We therefore compared the direct antileukemic activities of these compounds in stroma-supported cultures of leukemic lymphoblasts. MATERIALS AND METHODS: Bone marrow samples from children with B-lineage ALL were cultured on allogeneic bone marrow-derived stromal layers and exposed to various concentrations of glucocorticoids. After 4 days of culture, the number of viable leukemic cells was counted by flow cytometry and compared with that in parallel cultures without drugs. RESULTS: In 28 B-lineage ALL samples tested, the concentration producing 50% cytotoxicity (LC50) of prednisolone ranged from 2.0 to 7,978 nmol/L (median, 43.5 nmol/L), and that of dexamethasone from 0.6 to 327 nmol/L (median, 7.5 nmol/L). Despite the wide variability of responses among samples, there was an excellent correlation between LC50 values obtained with the two drugs (linear r = .99, P < .0001; Spearman rank-order r = .77, P < .0001). The median ratio of dexamethasone to prednisolone LC50 and LC90 values was 1:5.5 (range, 1:1.0 to 1:24.4 for LC50; 1:1.1 to 1:25.5 for LC90). Studies with ALL cell lines demonstrated that both drugs were cytotoxic through induction of apoptosis. Stromal layers did not absorb or inactivate measurable amounts of corticosteroids, which indicates that the assay system did not bias results toward increased drug resistance. CONCLUSION: In a bone marrow-derived microenvironment, dexamethasone is five to six times more cytotoxic (on a molar basis) than prednisolone, in agreement with the antiinflammatory activities of these drugs. This finding may serve to guide the selection of dexamethasone dosage in the treatment of ALL.
Adolescent↗
Effects of dopamine antagonists on neuronal histamine release in the striatum of rats subjected to acute and chronic treatments with methamphetamine.
In this study, we examined the changes in neuronal histamine (HA) release in the rat striatum after acute and repeated administration of methamphetamine (METH). We studied the regulation of METH-induced HA release by dopamine receptors and the relationship between METH-induced HA release and stereotyped behavior. Acute administration of METH (1 mg/kg) significantly increased HA release 60 min later. Pretreatments with the dopamine D2 antagonists sulpiride and haloperidol blocked the METH-induced increase of HA release, whereas pretreatment with a dopamine D1 antagonist, SCH23390, did not. Moreover, repeated administration of METH (3 mg/kg) greatly enhanced the METH-induced increase of HA release 60, 80, 100, 120 and 180 min after rechallenge of METH (1 mg/kg). Repeated treatment with haloperidol and METH blocked the increase of HA release induced by the rechallenge of METH. The METH-induced increase of HA release was still found after the METH-induced stereotyped behavior decreased in both acute and repeated administrations of METH. These findings suggest that the METH-induced HA release in the striatum is controlled by dopamine D2 receptors and may play an important inhibitory role in the METH-induced stereotyped behavior. Furthermore, a persistent change in the HA neuron system through DA neurotransmission may be partially responsible for the METH-induced behavioral sensitization.
Animals↗
[Hereditary background and natural history in glucose-intolerance group].
For non-obese IGT, frequency of 1st degree DM relatives was 29.9%, a rate higher than normal. NIDDM development rate was higher in IGT with family history of DM (86.9/1000 PY) than in IGT without family history (75.4/1000PY). For IGT-2 (2hr. PG > or = 170 mg/dl), the rate was higher in the group with family history (140.1/1000 PY) than that without family history (113.6/1000 PY). The odds ratio for NIDDM was 1.76 with obesity and 1.55 with family history. With regard to the natural course, plasma glucose (PG) increased slowly with rising of IRI over a long period, then PG increased suddenly without rising IRI and reached NIDDM onset. From these results, intervention trials for prevention of NIDDM are possible during long glucose-intolerance period.
Blood Glucose↗
Prediction of diabetes mellitus (NIDDM).
This study was made to analyze predictive NIDDM markers using a long-term GTT follow-up observation period of 1-30 years. Subjects of this study were 5446 cases (3994 males, 1452 females). Results are as follows: (1) NIDDM development rate increased gradually with increasing 2 h-PG levels at GTT, but for groups with 2 h-PG > or = 170 mg/dl, the rate rose rapidly. (2) PG at GTT was higher in the NIDDM development group than in the control group. Mean 1 h-PG reached > or = 200 mg/dl for 4 years before onset in the NIDDM group. Frequency of 1 h-PG > or = 200 mg/dl was 54% 4 years before and 67% 1 year before onset. (3) The highest NIDDM prediction accuracy was in 1 h-PG levels of 200 mg/dl or more and/or 2 h-PG levels of 170 mg/dl or more. Sensitivity was 75.2%, and specificity, 63.4% within 3 years before onset. (4) With addition of delta IRI/delta PG, sensitivity increased, but specificity decreased. (5) The highest relationship with NIDDM development was for high PG levels (1 h-PG > or = 200 mg/dl and/or 2 h-PG > or = 170 mg/dl), the odds ratio being 5.65. The odds ratio of delta IRI/delta PG was lower than ratio of high PG levels. (6) NIDDM development rate increased about 50% in the under-60-years age group and in the group of BMI > or = 25.
Adolescent↗
Human B-cell progenitors and bone marrow microenvironment.
Apoptosis of normal and leukemic immature B-cells in vitro is suppressed by contact with bone marrow-derived stromal layers. In stroma-supported cultures of immature B-cells, we found that ligation of CD38, a type II transmembrane protein, inhibited the cell growth and induced apoptosis. CD38 ligation also induced tyrosine phosphorylation and activation of intracellular substrates, including syk, phospholipase C-gamma, c-cbl, and phosphatidylinositol 3-kinase (PI 3-K). Wortmannin and LY294002, two potent inhibitors of PI 3K, rescued immature B cells from CD38-mediated growth suppression. In vitro culture of leukemic lymphoblasts may have potentially important clinical application. First, stroma-supported cultures of acute lymphoblastic leukemia (ALL) cells can determine the growth potential of leukemic cells. In a series of 70 children enrolled in a single program of chemotherapy, cell growth on stroma was a powerful and independent prognostic indicator. Second, a culture system capable of maintaining the majority of ALL blast cells at high levels of viability is also ideally suited for testing antileukemic drugs. Promising results were obtained with 2-chloro-deoxyadenosine and interleukin-4, leading to clinical trials of these two compounds in children with refractory ALL. In addition, we compared the direct antileukemic activities of dexamethasone and prednisolone and found that dexamethasone is five to six times more cytotoxic (on a molar basis) than prednisolone, in agreement with the anti-inflammatory activities of these drugs. This finding may serve to guide the selection of dexamethasone dosage in the treatment of ALL.
ADP-ribosyl Cyclase↗
The anti-emetic activity of GK-128 in Suncus murinus.
In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.
Animals↗
Studies on the inhibitory effects of some acridone alkaloids on Epstein-Barr virus activation.
Twenty-five acridone alkaloids from Citrus plants were examined for their inhibitory effects on Epstein-Barr virus activation by a short-term in vitro assay. 5-Hydroxynoracronycine (20) and acrimarine-F (25) showed remarkable inhibitory effects.
Acridines↗
Difference of myosin heavy chain expression between mesangial cells and vascular smooth muscles.
Contraction of the pre- and postglomerular arteries play an important role in the regulation of glomerular blood flow. Mesangial cells may also be involved in the mechanism of this regulation, but it has not been clarified yet whether or not mesangial cells and vascular smooth muscles show an identical phenotype, especially in terms of their contractile proteins. In this study, in order to elucidate any difference in the cellular phenotypes between mesangial cells and renal vascular smooth muscles, we investigated the localization of myosin heavy chain isoforms using a monoclonal antibody against SM1 and SM2. Both SM1 and SM2 are specific to smooth muscles. SM1 is specifically expressed in smooth muscles from early development and SM2 appears after birth. In normal renal tissues, SM1 and SM2 were expressed only in the smooth muscle cells of the arterioles and small arteries. However, glomerular cells, including mesangial cells, were not stained with either anti-SM1 antibody or anti-SM2 antibody. Localization of SM1 and SM-2 was similar to that of alpha-smooth muscle actin (SM alpha-actin). Staining for SM-1 was not observed in the mesangial areas of renal tissues with glomerular disease. These results clearly indicate that mesangial cells have a different phenotype from that of vascular smooth muscle cells in terms of their contractile proteins.
Fluorescent Antibody Technique↗
U-92032, a T-type Ca2+ channel blocker and antioxidant, reduces neuronal ischemic injuries.
Several diphenylmethylpiperazine derivatives are potential therapeutic agents for prevention of ischemic injuries in the heart and brain, because of their ability to block Ca2+ currents and their antioxidant activity. In this study, the current lead compound, U-92032 ((7-((bis-4-fluorophenyl)methyl)-1-piperazinyl)-2-(2-hydroxyethylamin o)- 4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunarizine and nifedipine (well-known T- and L-type Ca2+ channel antagonists, respectively) for their effects on Ca2+ channels in a mouse neuronal cell line, N1E-115 cells, and their ability to preserve the phenomenon of long-term potentiation and to improve neurological symptoms in gerbil ischemic models. U-92032, like flunarizine, blocked transient Ba2+ currents (IBa) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient IBa was reduced by U-92032 at a constant rate, the magnitude of which depended on the drug concentration, probably because of a time-dependent accumulation of the lipophilic drug in the membrane phase. For instance, the drug at 6 microM reduced IBa by 21% per min and abolished it in less than 5 min, about 3 times faster than flunarizine at the same concentration. Otherwise, U-92032 behaved like flunarizine, showing a use-dependent block without noticeable effects on the current-voltage relationship for transient IBa. Oral administration of U-92032 (1 and 25 mg/kg) or flunarizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h prior to bilateral carotid artery occlusion, preserved long-term potentiation in hippocampal CA1 neurons, which were largely abolished by ischemia without the drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Inhibition of neural and neuroendocrine activity by alpha-interferon: neuroendocrine, electrophysiological, and biochemical studies in the rat.
In our earlier studies we have demonstrated that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-alpha A/D, and a leucocyte-derived rat IFN-alpha preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha 2A (10(3) U), rHu-IFN-alpha A/D (10(4) U), and of Rat-IFN-alpha (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-alpha preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-alpha A/D up to 10(6) U (i.p.) or 7 x 10(5) U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5 x 10(3) U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5 x 10(3) U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A (10(4) U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-alpha to mu-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly mu-receptors, are sensitive to rHu-IFN-alpha 2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.70-11.04) nM for this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma x rat glioma hybrid cells (expressing delta-receptors) were affected by rHu-IFN-alpha 2A.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗