Biomedical subjects

T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 235 records · Page 13Linked to original sources

PubMed1994

Antitumor effects and distribution of adriamycin incorporated into hydroxyapatite implants in a cancer rat model bearing swarm rat chondrosarcoma.

We investigated the antitumor effects and tissue distribution of adriamycin (ADR) incorporated into a hydroxyapatite (HAP) bead in a cancer rat model bearing Swarm rat chondrosarcoma. The Porous HAP bead (8.48 mm in diameter, 531 +/- 0.7 mg in weight) was used as a model bone graft. One ADR-HAP bead (ADR 0.4 mg-6.0 mg/bead) was implanted s.c. into a Sprague-Dawley rat at 6 days postinoculation of Swarm rat chondrosarcoma. ADR-HAP beads showed strong antitumor activities in a dose dependent manner. The dose of 6.0 mg/bead showed the highest efficacy with no toxic death: It caused a 98% growth inhibition on Day 31 postinoculation and a survival advantage of a 339% increase in life span. After the implantation of the ADR-HAP bead (0.4 mg/bead/body) and the i.v. administration of an equal dose of free adriamycin, we determined the tissue distribution of ADR for up to 90 days. ADR-HAP bead implanted in the tumors released ADR over a 12-week period in the target area. The diffusion of the drug to other organs such as the heart and liver was very low compared with the tumors. The area under the ADR concentration-time curve (AUC) of the tumors was 181.6 micrograms.day/g and 5.22 micrograms.day/g after the implantation of the ADR-HAP bead and the i.v. administration of free ADR, respectively. The targeting index of the tumors, defined as the ratio of the AUC after the implantation of the ADR-HAP bead to that after administration of free ADR, was 34.8.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effects of Kamikihito, a traditional Chinese medicine, on neurotransmitter receptor binding in the aged rat brain determined by in vitro autoradiography (2): changes in GABAA and benzodiazepine receptor binding.

We investigated the effects of the long-term administration of Kamikihito (KKT) on the specific binding of [3H]muscimol and [3H]flunitrazepam in the brains of young and aged rats using in vitro quantitative autoradiography. Specific [3H]muscimol binding in aged rats was decreased in all brain regions examined compared with that in young rats, whereas [3H]flunitrazepam binding did not change in any of the brain regions. Scatchard analysis revealed that the maximal number of [3H]muscimol binding sites in the cortex and thalamus was significantly decreased in aged rats compared with young rats, while its affinity remained unchanged. Long-term administration of KKT in young rats had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast, the same treatment in aged rats produced a significant increase in [3H]flunitrazepam binding to the cortex, caudate/putamen and accumbens, and it tended to decrease the [3H]muscimol binding. These results suggest that the selective reduction of specific [3H]muscimol binding in the brain may be responsible, at least in part, for anxiety-related behavior in aged rats. Furthermore, it appears that the significant increase in specific [3H]flunitrazepam binding produced in the brains of aged rats by the long-term administration of KKT may be responsible for the anxiolytic effects of this agent.

Aging↗

PubMed1994

Memory impairment and neuronal dysfunction induced by beta-amyloid protein in rats.

Alzheimer's disease (AD) is characterized by the presence of senile plaques. The core of the plaque consists of beta-amyloid protein. In AD patients, learning and memory are impaired with a concomitant loss of the cholinergic marker enzyme, choline acetyltransferase (ChAT). However, direct evidence that beta-amyloid protein is related to the impairment of learning and memory has not been demonstrated. In this study, we investigated whether memory impairment and neuronal dysfunction were produced after 2 weeks continuous infusion of beta-amyloid protein (3, 30 and 300 pmol/day) into the cerebral ventricles in adult rats. To investigate the ability of learning and memory in beta-amyloid protein-treated rats, water maze and passive avoidance tasks were carried out. The performance of both tasks in beta-amyloid protein-treated rats was impaired. ChAT activity in the frontal cortex (3 and 30 pmol/day) and hippocampus (300 pmol/day) significantly decreased. These results suggest that beta-amyloid protein is related to the impairment of learning and memory, and neurodegeneration, and that beta-amyloid protein-treated rats could be used as an animal model for AD.

Acetylcholinesterase↗

PubMed1994

[Experimental techniques for developing new drugs acting on dementia (6)--Carbon monoxide-induced amnesia model in experimental animals].

Cell death, neuronal dysfunction and deterioration of memory function can be produced after carbon monoxide exposure in mice as in human. These deficiencies are developed in a delayed manner (delayed amnesia). The neurotoxicity of excitatory amino acids may be involved in this model, since dizocilpine (MK-801) fully protects against carbon monoxide-induced cell death, learning impairment and delayed amnesia. In the present paper, we described the method of carbon monoxide exposure and the characteristic of behavioral and biochemical changes after carbon monoxide exposure. These data indicate that carbon monoxide can provide an amnesic model for the investigation of memory deterioration and the development of new anti-amnesic drugs.

Amnesia↗

PubMed1994

Possible involvement of the activation of voltage-sensitive calcium channels in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance task.

We investigated the effects of various types of calcium channel antagonists on the amelioration by nefiracetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] of scopolamine-induced impairment of performance in a passive avoidance task in mice. The reversal of the scopolamine-induced impairment of performance by nefiracetam showed a bell-shaped plot. Both i.p. and i.c.v. injection of L-type calcium channel antagonists such as nifedipine and flunarizine attenuated the ameliorating effects of nefiracetam, although diltiazem had no effect. Neomycin, an N-type calcium channel antagonist, also attenuated these effects of nefiracetam in a dose-dependent manner. Further, LaCl3 but not NiCl2 showed inhibitory effects on the amelioration by nefiracetam. These results suggest that the activation of high-voltage-activated, but not low-voltage-activated, calcium channels is involved in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance task.

Animals↗

PubMed1994

Lack of effect of Chinese medicines on bioavailability of ofloxacin in healthy volunteers.

Recently, Chinese medicines have become available as OTC drugs and are frequently prescribed with Western medicine for the treatment of various chronic diseases. In this study, the effect of the Chinese medicines Sho-saiko-to (TJ-9), Rikkunshi-to (TJ-43) and Sairei-to (TJ-114) on the bioavailability of ofloxacin (OFLX) was investigated in seven volunteers in an open, random crossover fashion. Subjects received a single oral dose of OFLX (200 mg) alone and with coadministrations of each Chinese medicine, at one-week intervals. Plasma and urine samples were analyzed by high-performance liquid chromatography. No significant differences in any estimated bioavailability parameters of OFLX were observed between the two phases. The urinary recovery of OFLX excreted within 24 h after the administration of OFLX alone, 80.6 +/- 3.9% (mean +/- SEM), was not significantly different from those after the coadministrations of the Chinese medicines (79.7 +/- 5.1% for TJ-9, 76.8 +/- 2.3% for TJ-43 and 80.3 +/- 5.3% for TJ-114), suggesting that there was no difference in the systemic availability of the four doses. These findings indicate that the Chinese medicines studied have no significant effect on the rate and extent of bioavailability of OFLX.

Administration, Oral↗

PubMed1994

[Physiological function of sigma receptors: central pharmacological effects of sigma ligands].

N-allylnormetazocine (SKF-10047) and related benzomorphans induce psychotomimetic effects in animals and humans, and bind a unique, non-opioid receptor, denoted the sigma site. Sigma receptors have been found in the cortical and limbic structures in human postmortem brain: their anatomical distribution is different from phencyclidine (PCP) sites. Sigma receptors regulate not only dopamine, excitatory amino acid and PCP receptors, but also interact neuropeptides. Endogenous sigma ligands are not yet determined. Isolation and cloning of the receptor genes have not yet been successful. Selective loss of cerebral cortical sigma, but not PCP binding sites, has been observed in schizophrenia. A more compelling role for sigma sites in schizophrenia is indicated by the high affinity of some neuroleptic drugs, including haloperidol, for sigma sites. Rimcazole, a weak but selective sigma ligand, has very good clinical efficacy as a neuroleptic agent and has few side effects. Thus, sigma ligands may be useful in the treatment of schizophrenia. The present review describes properties of sigma receptors and its roles in relation to sigma ligands in the regulation of the central nervous system on the basis of the results of more recent studies.

Acetylcholine↗

PubMed1994

Effects of vinconate on maze performance deficit induced by monoaminergic dysfunction in rats.

We investigated the effects of vinconate, a novel indolonaphthylidine derivative, on maze performance deficits induced by an electrolytic lesion of the basal forebrain (BF) in rats. Bilateral BF lesions were produced by passing an anodal DC current (2 mA, 20 s). In the BF-lesioned groups, the latency and distance that the rat swam to escape onto the platform during training in Morris's water maze task significantly increased. Vinconate (5 and 10 mg/kg) treatment shortened the increase of escape latency to the platform in the BF-lesioned rats. The electrolytic BF lesion caused marked reductions of the contents of monoamines and their metabolites in the fronto-parietal cortex, hippocampus and striatum, while it slightly decreased choline acetyltransferase activity in the fronto-parietal cortex, but not significantly. Vinconate treatment showed a tendency to reverse the decreases of serotonin in the fronto-parietal cortex and hippocampus and dopamine in the striatum. Moreover, the reductions of their metabolites were also slightly attenuated by vinconate. These data suggest that vinconate has an anti-amnesic effect on the electrolytic BF lesion-induced amnesia by partly ameliorating the dysfunction in monoaminergic neurons.

Animals↗

PubMed1994

Relationship between anti-aversive effects of salmon calcitonin and plasma levels of ACTH, beta-endorphin and prostaglandin E2 in mice.

We investigated whether the anti-aversive effects of salmon calcitonin (SCT) was induced by increasing ACTH and beta-endorphin and/or by decreasing of prostaglandin E2 (PGE2) levels in plasma of mice to elucidate the mechanisms responsible for the analgesic effects of SCT. Intracerebroventricular (i.c.v.) injections of SCT inhibited acetic acid-induced aversive behavior (writhing) in a U-shaped dose response curve, the most effective dose being 0.1 IU/mouse. Intraperitoneal (i.p.) injections of acetic acid increased, but not significantly, the levels of plasma ACTH and PGE2, but not beta-endorphin, which are considered to be psychoneuroendocrines correlated with pain. SCT (0.1 IU/mouse, i.c.v.) significantly increased plasma ACTH levels (p < 0.05) and tended to increase beta-endorphin levels (p = 0.052) in acetic acid-treated mice, whereas no change in PGE2 level was observed (p > 0.1). These results suggest that the anti-aversive effects of SCT may be mediated, at least in part, by the activation of ACTH.

Acetates↗

PubMed1994

Cholecystokinin-related peptides, after systemic or central administration, prevent carbon monoxide-induced amnesia in mice.

The neuroprotective actions of cholecystokinin (CCK) peptides were investigated in a mouse hypoxia model, in which the animals were successively exposed to CO gas. Working memory impairment 5 days after CO exposure was examined by using a Y-maze test; delayed amnesia was examined 7 days after CO exposure, by using a step-down type passive avoidance test. Ceruletide (1-100 micrograms/kg, given s.c. 30 min before CO exposure) significantly prevented the CO-induced impairment of performance in both tests, the improvement being correlated with the severity of hypoxia. This severity was increased by maintaining the body temperature at 38 degrees C. Ceruletide was less effective when injected immediately after a single CO exposure. The order of potency of the CCK-peptides administered systemically was: ceruletide > CCK-8S > CCK-8NS >> CCK-4. Ceruletide (0.03-0.3 micrograms/mouse) and CCK-8S (0.03-1 microgram/mouse) prevented CO-induced amnesia after i.c.v. administration. Under all experimental conditions, dizocilpine [MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate, 500 micrograms/kg s.c. or 10 micrograms/mouse i.c.v.] prevented completely the CO-induced amnesia. The protective effects of systemic ceruletide were blocked, partially but significantly, by the preadministration of L-364,718 (3S-(-)-N-[2,3-dihydro-1-methyl-2-oxo-S-phenyl-1H-1,4- benzodiazepine-3-yl]-1H-indole-2-carboxamide, 1-10 mg/kg i.p.), a selective CCK-A receptor antagonist. L-365,260 ([3R-(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] -N' - [3-methyl-phenyl]urea), a CCK-B antagonist, also decreased ceruletide-induced protection.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗

PubMed1993

Oral administration of idebenone, a stimulator of NGF synthesis, recovers reduced NGF content in aged rat brain.

The relationship between nerve growth factor (NGF) and senile dementia of the Alzheimer type is of interest. We demonstrate here that the oral administration of idebenone, a stimulator of NGF synthesis in vitro, produced recovery of reduced NGF content in aged rat brain. Twenty-one-day successive administration of idebenone produced significant recovery of reduced NGF content in the frontal cortex and parietal cortex of aged rats. These results suggest that NGF content in the brain is low in aged rats and that oral administration of idebenone leads to a recovery of this reduction.

Administration, Oral↗

PubMed1993

Effects of oral administration of a stimulator for nerve growth factor synthesis in basal forebrain-lesioned rats.

Nerve growth factor plays an important role in the survival and maintenance of cholinergic neurons in the central neuronal system. In senile dementia of the Alzheimer type, learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is, therefore, of interest to investigate the role of nerve growth factor in senile dementia of the Alzheimer type. We now found that 6-(4-hydroxybutyl)-2,3,5-trimethyl-1,4- benzoquinone (TMQ) stimulates nerve growth factor synthesis in mouse astroglial cells and that the compound has improving effects on memory and choline acetyltransferase activity in basal forebrain-lesioned rats, an amnesia animal model. TMQ ameliorated amnesia in the water maze and passive avoidance tasks. The compound not only restored the reduced choline acetyltransferase activity in the parietal cerebral cortex, but also increased nerve growth factor content and choline acetyltransferase activity in the hippocampus, although it did not change either of these parameters in any brain region in intact rats. These results suggest that the compound activates cholinergic neurons only in the damaged brain and, further, indicate that nerve growth factor stimulators could be used in clinical trials for the treatment of senile dementia of the Alzheimer type.

Administration, Oral↗

PubMed1993

Effects of repeated administration of propentofylline on memory impairment produced by basal forebrain lesion in rats.

The effects of repeated propentofylline administration on impairments of learning and memory in rats with basal forebrain lesions were investigated in several behavioral tasks (water maze, habituation and passive avoidance tasks). Rats were subjected to all the tasks in sequence. Basal forebrain lesions produced by bilateral injections of ibotenic acid (approximately 6 micrograms on each side) severely impaired performance in water maze, habituation and passive avoidance tasks. Repeated administration of propentofylline (10 and 25 mg/kg per day for 14 days, p.o.) improved the deficits of performance in a water maze task, even when administration began one week after the basal forebrain lesions were produced. The impaired performance in habituation and passive avoidance tasks was also markedly ameliorated after repeated administration (24 and 26 days) of propentofylline. The rats with basal forebrain lesions exhibited a significant decrease in choline acetyltransferase activity in the cortex. Propentofylline significantly increased hippocampal choline acetyltransferase activity in basal forebrain-lesioned rats compared with that in vehicle-treated basal forebrain-lesioned rats. However, cortical choline acetyltransferase activity in basal forebrain-lesioned animals was not affected by repeated propentofylline administration. These results indicate that repeated administration of this agent ameliorated the impaired performance of basal forebrain-lesioned rats in part by increasing hippocampal choline acetyltransferase activity. Propentofylline might be useful for the treatment of amnesia and dementia.

Amnesia↗

PubMed1993

NGF level of is not decreased in the serum, brain-spinal fluid, hippocampus, or parietal cortex of individuals with Alzheimer's disease.

Although the cause of Alzheimer's disease (AD) is unknown, nerve growth factor (NGF) has gained attention as a therapeutic agent for the disease. Because NGF maintains the magnocellular cholinergic neurons that are damaged in AD, research interests have been focused on the change in NGF level in patients with AD. This is the first reported study in which human NGF levels were accurately measured and compared between normal and AD samples. We measured NGF levels using enzyme immunoassay (EIA) system for human NGF and found no difference in NGF level in serum, brain-spinal fluid, or brain (hippocampus and parietal cortex) obtained from normal people and patients with AD. These results suggest that a decrease in the NGF level is not a causative factor of AD.

Alzheimer Disease↗

PubMed1993

Mediation of dopamine D1 and D2 receptors in the effects of GBR 12909 on latent learning and locomotor activity in mice.

We investigated the involvement of dopamine D1 and D2 receptor subtypes in the effects of GBR 12909, a selective dopamine uptake inhibitor, on latent learning in the performance of a water-finding task and on locomotor activity in mice. GBR 12909 (10 and 20 mg/kg) impaired latent learning, and this effect was counteracted by the dopamine D2 receptor antagonist, (-)-sulpiride (20 and 40 mg/kg), but not by the dopamine D1 receptor antagonist, SCH 23390 (0.025 and 0.05 mg/kg). The dopamine D2 receptor agonist, quinpirole (0.5 and 1 mg/kg) and the dopamine D1 receptor agonist, SKF 38393 (20 mg/kg) impaired latent learning, but both effects were less than that of GBR-12909. The effect of quinpirole, but not of GBR 12909, on latent learning was potentiated by combination with SKF 38393. In contrast to its effect on learning, SCH 23390 (0.025 and 0.05 mg/kg) was more effective to suppress the stimulant effect of GBR 12909 on locomotor activity than was (-)-sulpiride (40 and 80 mg/kg). These findings suggest that both dopamine D1 and D2 receptors play an important role in the action of endogenously released dopamine in latent learning and locomotor activity, and that while the dopamine D2 receptor is involved predominantly in latent learning, both dopamine D1 and D2 receptors play a critical role in locomotor activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

MK-801 increases endogenous acetylcholine release in the rat parietal cortex: a study using brain microdialysis.

Glutaminergic and cholinergic neuronal interactions were investigated by using the brain microdialysis method in freely-moving rats. Acute administration of (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801) increased dose-dependently the extracellular acetylcholine (ACh) level in the rat parietal cortex. Significant increases in the extracellular ACh level were observed at doses of 0.4 and 0.5 mg/kg of MK-801, compared with the saline-treated group. The increase of extracellular ACh level was eliminated by infusion of 10(-2) M N-methyl-D-aspartate (NMDA). These results suggest that the glutaminergic neuronal system regulates functions of the cholinergic neuronal system.

Acetylcholine↗

PubMed1993

Effects of propentofylline, a NGF synthesis stimulator, on alterations in muscarinic cholinergic receptors induced by basal forebrain lesion in rats.

Basal forebrain (BF) lesions induced by ibotenic acid produced increases in the Bmax and Kd values of [3H]QNB binding sites in the frontal cortex, parietal cortex, and hippocampus. Twenty-eight-day successive administration of propentofylline (10 and 25 mg/kg, p.o.) significantly reduced the Kd values of [3H]QNB binding sites, to the levels of those in a sham group, in a dose-dependent manner. Moreover, propentofylline (25 mg/kg, p.o.) significantly reduced the Bmax value of [3H]QNB binding sites compared with that in a vehicle-treated BF-lesioned group. These results suggest that successive administration of propentofylline ameliorates changes in muscarinic cholinergic receptors through improving presynaptic cholinergic dysfunction.

Animals↗

PubMed1993

Development of tolerance to amnesic effects of chlordiazepoxide in relation to GABAergic and cholinergic neuronal systems.

Chronic administration of benzodiazepines has been reported to produce tolerance in animals and humans. We investigated whether benzodiazepines produce tolerance to the amnesic effects and effects on benzodiazepine receptors, GABAergic and/or cholinergic neuronal systems of repeated administration of chlordiazepoxide, using a passive avoidance task and autoradiographic techniques. Tolerance developed to the amnesic effect of chlordiazepoxide when the drug was administered at a dose of 30 mg/kg (i.p.) once a day for 14 days. Bicuculline (1.0 and 1.5 mg/kg), a GABAA receptor antagonist, did not induce amnesia in normal mice, but did so in chlordiazepoxide-tolerant mice. Muscimol (0.25 mg/kg), a GABAA receptor agonist, in combination with a low dose of chlordiazepoxide, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. Scopolamine, an acetylcholine receptor antagonist, induced amnesia in normal mice, but not in chlordiazepoxide-tolerant mice. In the autoradiographical study, although repeated treatment with chlordiazepoxide had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, it decreased [3H]muscimol binding to GABAA receptors, with a decrease in affinity in the cortex and hippocampus. Furthermore, repeated administration of chlordiazepoxide increased [3H]quinuclidinyl benzilate binding to muscarinic acetylcholine receptors in the hippocampus. These results suggest that tolerance develops to the amnesic effects of chlordiazepoxide, and that tolerance may be due to down-regulation of GABAA receptors and/or up-regulation of acetylcholine receptors.

Amnesia↗