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T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 109 records · Page 6Linked to original sources
PubMed1998

Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats.

We investigated the role of nitric oxide (NO) in learning and memory formation in a radial maze test, by using the NO synthase (NOS) inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), and an NO precursor, L-arginine. Rats were trained on a working and reference memory task in an eight arm radial maze for 30 days, wherein the same four arms were baited for each daily training trial. Daily administration of the specific neuronal NOS inhibitor 7-NI, as well as the non-selective NOS inhibitor L-NAME, impaired the acquisition of the task. Analysis of memory categories affected by NOS inhibitors revealed that reference memory formation was impaired by the treatment with L-NAME and 7-NI. L-NAME also impaired working memory although 7-NI had no effect. L-Arginine significantly increased the choice accuracy, by reducing the reference memory errors, of the radial arm maze task during the last ten days although it had no effect during the first 20 trials. These results suggest that NO plays an important role in spatial reference memory formation.

Animals↗
PubMed1998

Dissociation of impairment between spatial memory, and motor function and emotional behavior in aged rats.

We investigated changes in learning and memory in aged rats, in relation to motor function and emotional behavior. Male Kbl Wistar aged rats (108-weeks-old) were divided into two groups, memory impaired and non-impaired, based on performance during six training trials in the Morris water maze task. Aged rats with a goal latency longer than the mean plus the 99% confidence limit of young rats, were regarded as memory impaired, whereas those with a goal latency within the range of the 99% confidence limit of the mean of young rats, were considered as memory non-impaired. Although the performance of the memory impaired aged rats in the standard test of the Morris water maze improved after six re-training trials to the level of the non-impaired aged rats and young rats, working memory impairment was evident. There were no differences in motor function and emotional behavior between the impaired and non-impaired aged rats. These results suggest that deficits of learning and memory in memory impaired aged rats can be dissociated from changes in motor function and emotional behavior.

Aging↗
PubMed1998

Synthesis and preliminary evaluation of [11C]NE-100 labeled in two different positions as a PET sigma receptor ligand.

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with 11C in two different positions by the alkylation of an N-despropyl precursor with [11C]propyl iodide and of an O-desmethyl precursor with [11C]methyl iodide and was evaluated for the potential as a tracer for mapping sigma 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl-11C]NE-100 or [O-methyl-11C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl-11C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl-11C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl-11C]NE-100, but not that of [O-methyl-11C]NE-100. The regional brain distribution assessed with [O-methyl-3H]NE-100 was consistent with the distribution pattern of the sigma receptors. Four sigma drugs reduced the regional brain uptake of [O-methyl-3H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl-11C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl-11C]NE-100 has limited potential as a PET ligand for mapping sigma 1 receptors in the peripheral organs and the CNS because of high nonspecific binding.

Animals↗
PubMed1998

Disruption of the midkine gene (Mdk) resulted in altered expression of a calcium binding protein in the hippocampus of infant mice and their abnormal behaviour.

BACKGROUND: Midkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. However, its in vivo function has not been clarified. RESULTS: Knockout mice lacking the MK gene (Mdk) showed no gross abnormalities. We closely analysed postnatal brain development in Mdk(-/-) mice using calcium binding proteins as markers to distinguish neuronal subpopulations. Intense and prolonged calretinin expression was found in the dentate gyrus granule cell layer of the hippocampus of infant Mdk(-/-) mice. In infant Mdk(+/+) mice, calretinin expression in the granule cell layer was weaker, and had disappeared by 4 weeks after birth, when calretinin expression still persisted in Mdk(-/-) mice. Furthermore, 4 weeks after birth, Mdk(-/-) mice showed a deficit in their working memory, as revealed by a Y-maze test, and had an increased anxiety, as demonstrated by the elevated plus-maze test. CONCLUSION: Midkine plays an important role in the regulation of postnatal development of the hippocampus.

Animals↗
PubMed1998

Effect of transmucosal fluid movement on zinc and copper absorption from the rat small intestine.

1. The effects of transmucosal fluid movement on zinc and copper absorption from rat small intestine were investigated using an in situ recirculating perfusion method. 2. Transmucosal fluid movement was obtained by using hypo-, iso- or hyperosmotic perfusate containing various concentrations of sodium chloride. Linear correlations were obtained between net fluid movement and absorption rate constants, which were calculated from the perfusion decline of zinc (n = 15; r = 0.77) and copper (n = 15; r = 0.75). 3. The changes in serum levels of these metals did not correlate with the increase in the absorption rate. 4. The present study indicates that zinc and copper absorption is dependent on transmucosal fluid movement.

Animals↗
PubMed1998

Time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic drug-metabolizing enzyme activity in rats.

The time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic cytochrome P450-dependent drug-metabolizing capacity (cytochrome P450 and b5 content, activity of aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase and benzphetamine N-demethylase) and on the pharmacokinetics of antipyrine have been determined in rats. Measurement of enzyme activity and antipyrine (after intravenous injection of 20 mg kg(-1)) were performed 2, 24 and 96 h after a single intraperitoneal injection of endotoxin (1 mg kg(-1)) and after repeated doses (once daily for 4 days). The contribution of tumour necrosis factor alpha (TNFalpha) to the endotoxin-induced changes was also examined in rats pretreated with granulocyte colony-stimulating factor (G-CSF). The systemic clearance of antipyrine and the activity of hepatic cytochrome P450-dependent drug-metabolizing enzymes were dramatically reduced 24 h after a single injection of endotoxin, but had returned to control levels by 96h. The magnitudes of these decreases in these measurements after repeated doses of endotoxin were similar to those seen 24h after the single dose. The systemic clearance of antipyrine correlated significantly with cytochrome P450 content and aminopyrine N-demethylase activity. In histopathological experiments, moderate hypertrophy of Kupffer cells was observed, with no evidence of severe liver-tissue damage. G-CSF pretreatment suppressed the increased plasma concentrations of TNFalpha produced 2 h after single endotoxin injection, but did not eliminate the endotoxin-induced decrease in the systemic clearance of antipyrine, suggesting that TNFalpha is not the sole component responsible for the reduction of cytochrome P450-mediated drug-metabolizing enzyme activity. These results provide evidence that a single intraperitoneal injection of 1.0 mgkg(-1)K. pneumoniae endotoxin in rats reduces hepatic P450 and b5 levels, and reduces the activity of various cytochrome P450-mediated drug-metabolizing enzymes without causing severe liver-tissue damage. This suggests that the effect of endotoxin on hepatic cytochrome P450-mediated drug-metabolizing isozymes is non-selective.

Animals↗
PubMed1998

Possible mechanism by which the carbapenem antibiotic panipenem decreases the concentration of valproic acid in plasma in rats.

There is evidence indicating that the carbapenem antibiotic panipenem decreases plasma concentrations of valproic acid (VPA) in epileptic patients during VPA therapy. The mechanism for panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of panipenem on the pharmacokinetics of diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was administered intravenously under the steady-state plasma panipenem concentration of 4 microgram/ml, which had been achieved by a constant infusion rate. Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However, panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma diclofenac concentration observed in the absence of panipenem was diminished in the presence of panipenem. These findings suggest that panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a panipenem-induced decrease in the numbers of enteric bacteria.

Animals↗
PubMed1998

Granulocyte colony-stimulating factor enhances endotoxin-induced decrease in biliary excretion of the antibiotic cefoperazone in rats.

We have recently reported that endotoxin (lipopolysaccharide [LPS]) derived from Klebsiella pneumoniae dramatically decreased the biliary excretion of the beta-lactam antibiotic cefoperazone (CPZ), which is primarily excreted into the bile via the anion transport system, in rats. The present study was designed to investigate the effect of human recombinant granulocyte colony-stimulating factor (G-CSF), which is reported to be beneficial in experimental models of inflammation, on the pharmacokinetics and biliary excretion of CPZ in rats. CPZ (20 mg/kg of body weight) was administered intravenously 2 h after the intravenous injection of LPS (250 microgram/kg). G-CSF was injected subcutaneously at 12 microgram/kg for 3 days and was administered intravenously at a final dose of 50 microgram/kg 1 h before LPS injection. Peripheral blood cell numbers were also measured. LPS dramatically decreased the systemic and biliary clearances of CPZ and the bile flow rate. Pretreatment with G-CSF enhanced these decreases induced by LPS. The total leukocyte numbers were increased in rats pretreated with G-CSF compared to the numbers in the controls, while the total leukocyte numbers were decreased (about 3,000 cells/microliter) by treatment with LPS. Pretreatment with G-CSF produces a deleterious effect against the LPS-induced decrease in biliary secretion of CPZ, and leukocytes play an important role in that mechanism.

Animals↗
PubMed1998

Modulation of nitric oxide production in vivo in the brain.

Nitric oxide (NO) is a free radical gas that is synthesized from L-arginine (L-Arg) by NO synthase (NOS). Activation of N-methyl-D-aspartate (NMDA), non-NMDA or metabotropic glutamate receptor (mGluR) causes NO formation through NOS activation. We propose that there may be two pathways for NO production; NOS-dependent and independent pathways. Activation of NMDA receptors results in an increase in NO production via the NOS-dependent pathways whereas activation of non-NMDA receptors or mGluR may produce NO through not only the NOS-dependent pathway but also an NOS-independent pathway. Furthermore, it is suggested that glial cells may play a role in modulating NO production by regulating L-Arg availability.

Animals↗
PubMed1998

Neuronal mechanisms of phencyclidine-induced place aversion and preference in the conditioned place preference task.

Place conditioning paradigms are widely used for determining the motivational properties of drugs. Phencyclidine (PCP) has been a common drug of abuse during the past two decades and has a rewarding effect in animals. However, PCP produces place aversion in the conditioned place preference (CPP) task in animals. Here, we report the possible neuronal mechanisms of PCP-induced place aversion and preference in the CPP task in rodents. In naive rats and mice, PCP dose-dependently produced place aversion and PCP had a significant effect at the doses of 4 and 8 mg/kg in rats and mice, respectively. The aversive effect of PCP (4 mg/kg) in rats was significantly attenuated by ritanserin (3 and 10 mg/kg), a serotonin 15-HT2) receptor antagonist whereas the lesion of serotonergic (5-HTergic) neurons by 5,7-dihydroxytryptamine (100 micrograms i.c.v.) and alpha-methyl-rho-tyrosine (AMPT; 100 mg/kg), a tyrosine hydroxylase inhibitor, did not affect the aversive effect of PCP. In rats pretreated with PCP (10 mg/kg/day) for 14 days, tolerance was developed to PCP (4 mg/kg)-induced place aversion. In rats and mice pretreated with PCP (10 mg/kg/day) for 28 days, however, PCP dose-dependently produced place preference but not aversion. The preferred effect of PCP (8 mg/kg) in mice preteated with PCP (10 mg/kg/day for 28 days) was significantly attenuated by AMPT (100 mg/kg) and 6-hydroxydopamine (100 micrograms i.c.v.) a dopaminergic (DAergic) neurotoxin, but not by DSP-4 (30 mg/kg), a noradrenergic neurotoxin and ritanserin. In mice pretreated with methamphetamine (1 mg/kg/day) for 14 days, PCP (8 mg/kg) produced place preference. These findings suggest that 5-HTergic and DAergic systems are involved in the PCP-induced place aversion and preference, respectively, and some changes in the neuronal systems including DAergic systems, induced by repeated PCP treatment play a critical role in the addiction of PCP.

Animals↗
PubMed1998

Effects of sigma receptor ligands on conditioned fear stress.

Mice or rats exhibit a marked suppression of motility when they are replaced in the same environment in which they previously received an electric footshock. To clarify the functional role of sigma receptors in a stressful situation, we investigated the behavioral and neurochemical effects of various sigma receptor ligands on this psychological stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 and dextromethorphan, putative sigma receptor agonists, reversed the conditioned fear stress. However, other sigma receptor ligands, (+)-pentazocine and 1,3-di(2-tolyl)guanidine had no effect. Further, (+)-SKF-10,047, but not (+)-pentazocine, restored the decreased dopamine turnover in the nucleus accumbens in the stressed group to the control level, the effect being consistent with its behavioral effect. We indicated that these controversial results may be due to the presence of multiple types of sigma receptors, and that the activation of phenytoin-sensitive sigma 1 receptors may be involved in the ameliorating effects of sigma receptor agonists on this stress. Our findings suggest that the dysfunction in the mesolimbic dopaminergic neurons is responsible for the development of conditioned fear stress, and that this stress response is restored through phenytoin-sensitive sigma 1 receptors, which are closely connected to the dopaminergic neuronal systems.

Animals↗
PubMed1998

A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine.

Morphine is the most potent opioid analgesic currently available and its use is increasing for treatment of severe pain, however, long-term morphine exposure induces physical dependence/tolerance. Although the mechanisms underlying this phenomenon have not been established, several biochemical changes including intracellular cAMP systems and Ca2+ mobilization have been suggested. To evaluate the contribution of cAMP, we investigated the effects of nefiracetam [N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl)acetamide] and phosphodiesterase inhibitors (theophylline, enprofylline and rolipram) on the development of morphine dependence/tolerance. Mice administered morphine (6 or 10 mg/kg, s.c.) twice daily for 5 days, showed withdrawal signs (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg/kg, i.p.), indicating the physical dependence to morphine. Further, the tolerance to antinociceptive effect of morphine was observed in these mice on the tail-flick test. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated. Acute administration of nefiracetam failed to reduce the withdrawal signs and did not affect the antinociceptive effect of morphine in morphine-naive mice. Theophylline (3 or 10 mg/kg, p.o.) tended to attenuate the development of morphine dependence/tolerance. The present findings suggest that coadministration of compounds which increase cAMP level with morphine may be a useful strategy to attenuate the development of morphine dependence/tolerance in the clinic.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1998

Effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairment in rats.

The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 mumol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 mumol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 mumol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 mumol/kg) and mecamylamine (12 mumol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Involvement of dopaminergic system in phencyclidine-induced place preference in mice pretreated with phencyclidine repeatedly.

In the conditioned place preference test, phencyclidine (PCP) produces place aversion in naive rats, whereas PCP produces place preference in rats treated with PCP repeatedly. Although the PCP-induced place aversion is thought to involve the serotonergic system, the mechanisms of the PCP-induced place preference are unclear. We investigated whether the dopaminergic system is involved in place preference induced by PCP in mice repeatedly treated with PCP, because it is well known that the dopaminergic system plays an important role in the rewarding effect of drugs. PCP (2-8 mg/kg s.c.) induced a dose-dependent place aversion in naive mice, whereas PCP (2-8 mg/kg s.c.) induced a dose-dependent place preference in mice pretreated with PCP (10 mg/kg/day s.c.) for 28 days. The place preference induced by PCP (8 mg/kg s.c.) was attenuated significantly by alpha-methyl-rho-tyrosine (100 mg/kg i.p.), a tyrosine hydroxylase inhibitor, 6-hydroxydopamine (100 micrograms/mouse i.c.v.), a dopaminergic neurotoxin, and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine (0.5 mg/kg s.c.), a dopamine D1 receptor antagonist. These agents themselves produced neither the place preference nor aversion. In contrast to the attenuating effects of these agents, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (30 mg/kg i.p.), a noradrenergic neurotoxin, ritanserin (1 mg/kg i.p.), a serotonin2 receptor antagonist, and (-) sulpiride (50 and 100 mg/kg i.p.), a dopamine D2 receptor antagonist, failed to affect the PCP-induced place preference. In mice pretreated with methamphetamine (1 mg/kg/day s.c.) for 14 days, PCP (8 mg/kg s.c.) induced the place preference, but not aversion. These results demonstrate that the PCP-induced place preference depends on dopaminergic, but not on serotonergic and noradrenergic, neuronal systems and suggest a role for D1 receptors in the mediation of the PCP-induced place preference.

Animals↗
PubMed1998

[Mitochondrial benzodiazepine receptors (MBR) in association with neurological disorders].

Ro 5-4864, a specific agonist of the peripheral-type benzodiazepine receptor (PBR), elicited convulsions 2.6 times more potently in EL mice (an animal model of epilepsy) than in DDY mice (control animal). A binding assay revealed a 50% higher density of [3H] Ro 5-4864 binding sites in the mitochondrial fraction (i.e., mitochondrial benzodiazepine receptors; MBR) of the brain tissues in EL mice as compared with DDY mice. On an elevated plus-maze, EL mice showed fear responses similar to those increased in DDY mice after PBR stimulation, suggesting a hyperfunction of MBR underlying the abnormal behaviors of EL mice. In fluorometric studies using NG108-15 cells, Ro 5-4864 depolarized mitochondrial membranes and, possibly as a consequence of this, raised intracellular Ca2+. Finally, we propose that MBR could be a major target of therapy for various neurological disorders, so drugs such as "mitochondrial membrane stabilizers" should be developed.

Animals↗
PubMed1997

Subcutaneous tissue distribution of vancomycin from a fibrin glue/Dacron graft carrier.

We investigated the tissue distribution of vancomycin (VCM) incorporated in fibrin glue (FG) in a rat model. One VCM-loaded FG Dacron graft (VCM-FG, VCM 0.6 mg/ graft) was implanted in the subcutaneous tissue of the anterior abdominal wall of each rat. VCM was injected intravenously at an equal dose (0.6 mg/rat) after implantation of one control graft (without VCM-FG). After the implantation and the iv injection of an equal dose of VCM (0.6 mg/rat), the tissue distribution of VCM for up to 24 h was determined through analysis of the implanted VCM-FG grafts, which released VCM over a 24 h period. The area under the VCM concentration-time curve (AUC) of the tissue was 89.58 micrograms.h/g after the implantation of the VCM-FG graft, and 7.40 micrograms.h/g after the iv injection of VCM, respectively. The targeting index of the tissue, defined as the ratio of AUC after the implantation of the VCM-FG graft to that after VCM iv injection, was 12.11. None of the six VCM-FG Dacron grafts after implantation became infected following inoculation with S. aureus ATCC 25923 (0.1 mL 10(8) CFU/mL). These results suggest that this VCM-FG Dacron graft delivery may be useful in preventing local infection by enhancing the delivery of VCM to the local areas of the implanted site in rats.

Animals↗
PubMed1997

Abnormalities of sensory and memory functions in mice lacking Bsg gene.

Basigin is a highly glycosylated transmembrane protein belonging to the immunoglobulin superfamily. We used mutant mice lacking the basigin gene (Bsg) to investigate its involvement in learning and memory. Mutations were generated by the gene targeting method. Various kinds of learning and memory tasks were performed in mutant, hetero and wild type mice. The mutant mice showed worse performance than the wild and hetero mice in the Y-maze task, which assesses short-term memory, and in the water finding task, which examines latent learning, without any motor dysfunction. Moreover, the mutant mice showed less acclimation in the habituation task compared with the wild-type mice. The mutant mice were also more sensitive to electric foot-shock. These findings are consistent with the expression profile of basigin in the central nervous system. Thus, basigin may play an important role in learning and memory as well as in the sensory functions.

Animals↗