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Biomedical subjects

T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 253 records · Page 14Linked to original sources
PubMed1993

Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA receptors.

Repeated administration of benzodiazepines has been reported to produce tolerance in animals and humans. Using an elevated plus-maze test and an autoradiographic technique, we investigated whether repeated administration of chlordiazepoxide produced tolerance to its anxiolytic effects, and whether such repeated administration altered benzodiazepine and GABAA receptors. Tolerance to the anxiolytic effect of chlordiazepoxide was produced when it was administered at a dose of 30 mg/kg (i.p.) once a day for 10 and 14 days. In the quantitative autoradiographical study, although repeated chlordiazepoxide treatment had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, such treatment reduced [3H]muscimol binding to GABAA receptors in the cortex, caudate putamen, and hippocampus. These results suggest firstly, the production of tolerance to the anxiolytic effects of chlordiazepoxide, and, secondly, that this tolerance may be due to the down-regulation of GABAA receptors, but not of benzodiazepine receptors.

Animals↗
PubMed1993

Development of plasticity of brain function with repeated trainings and passage of time after basal forebrain lesions in rats.

Basal forebrain (BF) lesion-induced amnesia in rats is widely used as an animal model of Alzheimer's disease (AD). To study the plasticity of brain function in BF-lesioned rats, we examined the effects of repeated trainings and the passage of time after the lesion on learning ability 3 weeks and 3 months after BF-lesions with ibotenic acid, using an eight-arm radial maze and passive avoidance tasks, and measured choline acetyltransferase (ChAT) activity. Both time and re-training played important roles in the recovery of the ability to learn, as measured with the eight-arm radial maze task, but not the passive avoidance task. In contrast, ChAT activity in the frontal cortex, which was low 3 weeks after the lesion, still low 3 months after lesion, even though the ability to learn had recovered. Recovery of the ability to learn can be attributed to undamaged cholinergic neurons, or to other neuronal systems, or to both. This animal model can be used to demonstrate the plasticity of brain function.

Animals↗
PubMed1993

Memory impairment and neural dysfunction after continuous infusion of anti-nerve growth factor antibody into the septum in adult rats.

Nerve growth factor is required for the survival and maintenance of cholinergic neurons in the central nervous system. The direct infusion into the rat's septum of an anti-nerve growth factor monoclonal antibody, which inhibits nerve growth factor bioactivity seven times more strongly than a polyclonal antibody, caused very severe damage to the hippocampal cholinergic system. Anti-nerve growth factor polyclonal antibody also neutralized endogenously occurring nerve growth factor. The infusion of anti-nerve growth factor polyclonal antibody produced a dysfunction of memory and decreased choline acetyltransferase activity and acetylcholinesterase staining in the hippocampus. The cholinergic dysfunction and impairment of memory recovered to the normal level two weeks after cessation of the infusion of the anti-nerve growth factor polyclonal antibody. These results suggest that a deficit of nerve growth factor in the adult brain causes neuronal dysfunction.

Acetylcholinesterase↗
PubMed1993

The effect of lipopolysaccharide on the disposition of xanthines in rats.

The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0.25 mg kg-1 over a period of 20-30 min, 2 h before the administration of theophylline (10 mg kg-1) or MPX (2.5 mg kg-1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.

Animals↗
PubMed1993

Influence of a bacterial lipopolysaccharide on the pharmacokinetics of tobramycin in rats.

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg-1) and inulin (100 mg kg-1) were administered intravenously 2 h after administration of 50, 250 or 500 micrograms kg-1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 micrograms kg-1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.

Animals↗
PubMed1993

The effects of N-benzoyl-beta-alanine, a new nephroprotective drug, on the distribution and renal excretion of enprofylline in rats.

The effects of the new nephroprotective drug N-benzoyl-beta-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2.5 mg kg-1 under three different steady-state plasma BA concentrations (100, 200 and 400 micrograms mL-1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 micrograms mL-1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 micrograms mL-1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.

Alanine↗
PubMed1993

Alterations in pharmacokinetics and protein binding behavior of cefazolin in endotoxemic rats.

The possible alterations in the pharmacokinetics and protein binding behavior of the beta-lactam antibiotic cefazolin (CEZ) were investigated in endotoxemic rats induced by Klebsiella pneumoniae O3 lipopolysaccharide (LPS). LPS (250 micrograms/kg of body weight) was infused for 20 to 30 min 2 h before an intravenous administration of CEZ (20 mg/kg). Significant decreases in systemic clearance and renal clearance of CEZ were observed in LPS-treated rats without any changes in fraction of urinary excretion in unchanged CEZ (> 0.8). The volume of distribution at steady state showed a tendency to increase. The protein binding parameters of CEZ, the binding capacity, and number of binding sites on the albumin molecule were decreased by LPS, whereas the dissociation constant did not change. Significant decreases in systemic and renal clearances for unbound CEZ were observed in LPS-treated rats. The glomerular filtration rate estimated as inulin clearance was also decreased by LPS. The ratio of renal clearance of unbound CEZ to glomerular filtration rate (clearance ratio) dropped to 70% of that in control rats, and the net tubular secretion of CEZ was also dramatically reduced. The present study suggests that LPS has an effect on the pharmacokinetics of CEZ by changes which occur in renal handling and protein binding.

Animals↗
PubMed1993

Effects of nerve growth factor (NGF) in rats with basal forebrain lesions.

Effects of nerve growth factor (NGF) on the basal forebrain (BF) lesion-induced amnesia in rats were investigated. When NGF infusion was begun immediately after the formation of BF lesions, NGF ameliorated amnesia in a water maze task and showed a tendency to increase choline acetyltransferase (CAT) activity in the fronto-parietal cortex. The amnesia and the decrease of CAT activity were not ameliorated when NGF infusion was begun 4 weeks after BF lesion formation. These observations suggest that NGF may act as a trophic and/or a protective factor on partially damaged cholinergic neurons and that the efficacy of NGF was influenced by the phase of neuronal damage.

Amnesia↗
PubMed1993

Effects of BMY-21502 on anoxia in mice.

The protective effects of BMY-21502 (1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone) against cerebral anoxia were investigated using various models in mice, in comparison with those of other cerebroactive drugs. Oral administration of BMY-21502 (10-100 mg/kg) significantly prolonged the survival time in KCN (2.4 mg/kg, i.v.)-induced anoxia. Oxiracetam and idebenone exerted similar but weak protection at doses above 100 mg/kg, p.o. and only at a dose of 100 mg/kg, p.o., respectively. Significant protection by BMY-21502 against moderate hypobaric hypoxia was observed at doses of 30 and 100 mg/kg, p.o. Idebenone (100 and 300 mg/kg, p.o.) significantly prolonged the survival time of mice in this model, but oxiracetam (30-300 mg/kg, p.o.) did not. Oral administration of all of these drugs (BMY-21502, 3-300 mg/kg; Oxiracetam, 100-1000 mg/kg; Idebenone, 100-1000 mg/kg) failed to increase the number of gasps and the duration of gasping in the decapitated head of mice as a complete ischemic model. The anti-anoxic effect of BMY-21502 in the KCN-anoxia model was blocked by pretreatment with scopolamine. These findings suggest that BMY-21502 has an anti-anoxic action superior to those of the other cerebroactive drugs used, and activation of the CNS cholinergic system is involved as one of the causative mechanisms for the anti-anoxic effect of BMY-21502.

Animals↗
PubMed1993

Neuropharmacological characterization of voltage-sensitive calcium channels: possible existence of neomycin-sensitive, omega-conotoxin GVIA- and dihydropyridines-resistant calcium channels in the rat brain.

We attempted to characterize the functional roles of subtypes of voltage-sensitive calcium channels in the brain. The maximal number of [125I]omega-conotoxin GVIA (omega-CTX) binding sites in rat brain associated with N-type calcium channels (N-channels) was approximately 10 times more than that of [3H]-PN200-110 associated with L-type calcium channels (L-channels). [125I]omega-CTX binding was inhibited by aminoglycoside antibiotics, neomycin and dynorphin A(1-13), but not by various classes of L-channel antagonists. A 6-hydroxydopamine-induced lesion of the striatum resulted in a marked reduction of both [125I]-omega-CTX and [3H]PN200-110 binding. Kainic acid-induced lesion of the striatum reduced [3H]PN200-110 binding by 57%, but did not reduce [125I]omega-CTX binding. Omega-CTX produced a small (18%) but significant reduction of potassium-stimulated Ca2+ influx into rat brain synaptosomes, although it produced a concentration-dependent inhibition in chick brain synaptosomes. Neomycin inhibited Ca2+ influx in both preparations in a concentration-dependent manner. Both omega-CTX and neomycin inhibited potassium-stimulated [3H]dopamine (DA) release from rat striatal slices. The L-channel antagonists had no effect on either Ca2+ influx or [3H]DA release. These results suggest that DA release in the striatum is regulated by Ca2+ influx through N-channels located in presynaptic nerve terminals, and that the most of the Ca2+ influx in rat brain appears to be governed by neomycin-sensitive, omega-CTX- and DHP-resistant calcium channels.

Animals↗
PubMed1993

Characteristics of transient cerebral ischemia-induced deficits on various learning and memory tasks in male Mongolian gerbils.

We examined the characteristics of 5-min cerebral ischemia-induced behavioral deficits in spontaneous locomotor activity and their effects on the performance of habituation (HAB), passive avoidance (PA) and 8-arm radial maze (RM) tasks in Mongolian gerbils. Performances in HAB, PA and RM were impaired within 2 days after occlusion, and gerbils showed hyperlocomotion during this period. Ten days after ischemia, the hyperlocomotion disappeared and performance in the HAB and PA was the same as that in the sham-operated group. Retention in the RM was impaired at that period, but this impairment was overcome, and retention recovered easily to the sham-operated level with a few additional trials. When the acquisition trial in the RM began at 11 days after occlusion, severe learning impairment was found. Destruction of hippocampal CA1 neurons appears from 2-3 days after ischemic insult, with most CA1 neurons having disappeared by day 7. These findings suggest that the impairment of performance in the HAB and PA within 2 days after occlusion may be related to an early phase of CA1 neuronal death and to hyperlocomotion, although the impairment of spatial learning and memory was clearly associated with CA1 injury 10 days after ischemia.

Animals↗
PubMed1993

Dopaminergic agonists impair latent learning in mice: possible modulation by noradrenergic function.

The effects of the dopamine agonists apomorphine, GBR-12909, nomifensine and methamphetamine on latent learning were investigated using a one-trial, water-finding task in mice. Mice without water deprivation were given these agonists or their vehicle before a training trial which consisted of exposure to a novel open-field environment containing a water tube. Twenty-four hours later and after 20 hr of water deprivation, animals were placed in the same apparatus and tested for the time required to find the water tube. Vehicle control animals exposed to the training trial demonstrated latent learning as measured by a significantly shorter time taken to find the water tube during the test trial as compared with naive controls that had not been exposed to the training trial. All of the dopamine agonists impaired the development of latent learning. The effects of nomifensine and methamphetamine were relatively weaker than those of apomorphine and GBR-12909. (-)-Sulpiride, a dopamine D2 antagonist, counteracted the disruptive effect of apomorphine on latent learning, whereas SCH 23390, a dopamine D1 antagonist, did not. The noradrenaline uptake inhibitor desipramine had no significant effect on latent learning. The disruptive effect of GBR-12909 on latent learning was significantly reduced when desipramine was given concurrently. Moreover, noradrenaline depletion with the neurotoxin, DSP4, impeded latent learning. These results suggest that activation of dopaminergic systems by dopamine agonists suppresses acquisition of latent learning. The qualitative and quantitative differences in the effects produced by the various agonists may be associated with their effects on noradrenergic transmission.

Animals↗
PubMed1993

Effect of a high linoleate and a high alpha-linolenate diet on general behavior and drug sensitivity in mice.

Semi-purified diets supplemented with either a high linoleate (n-6) (safflower) oil or a high alpha-linolenate (n-3) (perilla) oil were fed to mouse mothers and their offspring through 6 weeks of age. The proportions of n-3 and n-6 highly unsaturated fatty acids in brain phospholipids reflected the n-3/n-6 balance of the diets while no difference was found in phospholipid compositions or cholesterol/phospholipid ratios. In the elevated plus maze task, the total number of entries into the open- and enclosed-arms was smaller and the time spent in the dark enclosed arms tended to be longer in the perilla group than the safflower group. The time required to reach a safe platform in Morris's water maze test was less in the perilla group, but no significant difference was observed in the entries into the arms darkened with a movable cover in Y-maze dark-preference task. The safflower group was more sensitive to pentobarbital; the anesthesia onset time was less and the anesthetic time was longer than in the perilla group. Increased locomotion induced by scopolamine injection was less in the safflower group as compared with the perilla group. These results indicate that in mice the dietary alpha-linolenate/linoleate balance affects the n-3/n-6 ratio of brain phospholipid acyl chains and that this is accompanied by general behavioral changes as well as changes in sensitivities to drugs known to affect behavior.

Analgesia↗
PubMed1993

Impairment of learning and memory and the accessory symptom in aged rat as senile dementia model (3): Oral administration of propentofylline produces recovery of reduced NGF content in the brain of aged rats.

The relationship between nerve growth factor (NGF) and senile dementia of the Alzheimer type is of interest. The administration of NGF in clinical trials has been expected; however, NGF cannot cross the blood brain barrier, since it is a polypeptide. We demonstrate here that oral administration of propentofylline, a stimulator of NGF synthesis in vitro, produced recovery of reduced NGF content. In aged rats (24-months-old), NGF content in the frontal cortex, parietal cortex, and hippocampus was lower than in young rats (8-weeks-old). Twenty-one-day successive administration of propentofylline (10 and 25 mg/kg, p.o.) produced recovery of reduced NGF content in the frontal cortex and parietal cortex of aged rats to a significant extent. There were no differences among aged, young, and propentofylline-treated groups in choline acetyltransferase activity in any brain regions. These results suggest that NGF content in the brain is reduced in aged rats and that oral administration of propentofylline leads to a recovery of this reduction.

Administration, Oral↗
PubMed1993

The inhibitory effects of salmon calcitonin on intrathecally-injected N-methyl-D-aspartate-induced aversive behavior in mice.

The effects of salmon calcitonin (SCT) on intrathecally-injected N-methyl-D-aspartate (NMDA)-induced aversive behavior were investigated to clarify the involvement of the NMDA receptor/ionophore complex on the analgesic effects of SCT. Intracerebroventricular (i.c.v.) injection of SCT significantly inhibited acetic acid-induced writhing. Intrathecal (i.t.) injection of NMDA (0.25-1.0 nmol/mouse) dose-dependently induced aversive behavior such as scratching and tail biting. SCT at the doses of 0.01 and 0.1 IU/mouse (i.c.v.) significantly inhibited the NMDA-induced aversive behavior. This inhibitory effects of SCT on NMDA (i.t.)-induced aversive behavior were neither potentiated nor antagonized by i.c.v. injection of MK-801 and NMDA, respectively. Further, MK-801 (i.c.v.) and NMDA (i.c.v.) themselves did not affect the NMDA (i.t.)-induced aversive behavior. These results suggest that the NMDA receptor/ionophore complex in the brain is not directly involved in the antinociceptive effects of intracerebrally-injected SCT.

Analgesics↗
PubMed1993

[Impairment of learning and memory and the accessory symptom in aged rats as senile dementia model (1)--Emotional behavior].

It is well known that there is an increase of emotional behavior in senile dementia. There are few studies investigating age-related emotional behavior. We attempted to investigate emotional behavior of aged rats using various tests. Locomotor activity for 24 h decreased in aged rats compared with that in young rats. There was no difference in locomotor activity between light and dark periods in aged rats. There was no visual abnormality on light/dark discrimination test in aged rats. It suggests that locomotor activity during dark period may be impaired by aging. Head-dips and social interaction time in hole board and social interaction tests, respectively decreased, while start latency, defecation and urination in open field test increased in aged rats. Furthermore, ambulation and rearing in hole board, social interaction and open field tests decreased, and entries into open or closed arms in elevated plus-maze test reduced in aged rats compared with those in young rats. These findings suggest that anxiety may increase, but spontaneous activity decrease in aged rats. These results indicate that aged rats may be useful as an accessory symptom model of senile dementia.

Aging↗
PubMed1993

[Impairment of learning and memory and the accessory symptom in aged rats as senile dementia model (2)--Learning and memory].

We attempted to investigate the ability of learning and memory of aged rats. Swimming speed of aged rats in Morris's water maze was slower compared with that of young rats. Therefore, we used goal distance to indicate ability of learning and memory. In training session, distance for both groups decreased with training, but in aged rats it was significantly longer than that in young rats. In retention test 24 d after the training, distance in aged rats was longer than that in young rats, although there was no difference in distance for both groups between acquisition and retention tests. The distance in the working memory tended to increase with aging. There was no difference in time spent within platform phase in probe trial, in percent movement of first trial in habituation test, and in step-through latency in passive avoidance, between young and aged rats. Drinking latency for aged rats in water finding task was significantly longer compared with that in young rats. These findings suggest that learning and memory were impaired by aging in spatial and latent learning tasks. Aged rats could acquire and maintain memory of simple tasks, but in spatial tasks they tended to show decreased ability of retention and working memory.

Aging↗