Biomedical subjects

T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 127 records · Page 7Linked to original sources

PubMed1997

Changes in extracellular nitrite and nitrate levels after inhibition of glial metabolism with fluorocitrate.

The role of glial cells in nitric oxide production in the cerebellum of conscious rats was investigated with a glial selective metabolic inhibitor, fluorocitrate. The levels of nitric oxide metabolites (nitrite plus nitrate) in the dialysate following in vivo microdialysis progressively increased to more than 2-fold the basal levels during a 2-h infusion of fluorocitrate (1 mM), and the increase persisted for more than 2 h after the treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester attenuated the fluorocitrate-induced increase in nitric oxide metabolite levels. None of the glutamate receptor antagonists, including D(-)-2-amino-5-phosphonopentanoic acid, 6,7-dinitroquinoxaline-2,3-dione, and (+/-)-alpha-methyl-4-carboxyphenylglycine, inhibited the fluorocitrate-induced increase. The L-arginine-induced increase was significantly reduced by fluorocitrate treatment, while N-methyl-D-aspartate, (+)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and trans-(+/-)-1-amino-(1S,3R)-cyclopentane-dicarboxylic acid increased nitric oxide metabolites levels in the fluorocitrate-treated rats, as much as in control animals. These results suggest that glial cells play an important role in modulating nitric oxide production in the cerebellum by regulating L-arginine availability.

Aconitate Hydratase↗

PubMed1997

Effects of antidepressants on phencyclidine-induced enhancement of immobility in a forced swimming test in mice.

We have previously found that repeated phencyclidine (PCP) treatment enhances the immobility induced by forced swimming and suggested that this behavioral change could be used as a model of the negative symptoms, particularly depression, of schizophrenia. The present study attempted to examine the effects of antidepressants on the depressive states (immobility) induced by forced swimming in mice repeatedly treated with PCP, compared with those in mice repeatedly treated with saline. In mice repeatedly treated with saline, desipramine (5 and 10 mg/kg) and imipramine (5 and 10 mg/kg) significantly attenuated immobility, whereas mianserin (5-20 mg/kg) and clomipramine (10 and 50 mg/kg) had no affect. In mice repeatedly treated with PCP, the enhancing effect of PCP on immobility was attenuated by mianserin (5-20 mg/kg) at doses which did not have any effect in saline-treated mice, and by desipramine at higher doses (20 and 50 mg/kg). However, imipramine (5-20 mg/kg) and clomipramine (10-50 mg/kg) did not affect PCP-induced enhancement of immobility. In the biochemical study, the content of 5-hydroxyindoleacetic acid (5-HIAA) and the 5-HIAA/5-hydroxytryptamine (5-HT) ratio in the prefrontal cortex in mice repeatedly treated with PCP, but not with saline, following the forced swimming test were significantly increased, compared with those in the corresponding control mice (which did not perform the test). The present findings suggest that the depressive states induced by the forced swimming in mice repeatedly treated with PCP are less sensitive to acute treatment with tricyclic antidepressants, and this may be due to increase in 5-HT turnover. Antidepressants such as mianserin, which have the 5-HT2 receptor antagonist properties, may be useful for the treatment of negative symptoms of schizophrenia.

Animals↗

PubMed1997

Unrestrained nociceptive response and disregulation of hearing ability in mice lacking the nociceptin/orphaninFQ receptor.

In the G-protein-coupled receptor superfamily, the opioid receptor subfamily is constituted of the three distinct opioid receptors (namely delta-, mu- and kappa-subtypes) and the receptor for nociceptin (also designated orphaninFQ). The members of the opioid receptor subfamily were known to mediate a variety of cellular inhibitory effects. The three opioid receptors are known to play central roles in mediating analgesia and many other physiological activities; however, the nociceptin receptor was identified recently and less is known about its physiological roles. Here we report the generation and characterization of mice lacking the nociceptin receptor. The knockout mice showed no significant differences in nociceptive threshold and locomotor activity compared with control mice, but they lost nociceptin-induced behavioral responses. These results indicate that the nociceptin system is not essential for regulation of nociception or locomotor activity. On the other hand, we found insufficient recovery of hearing ability from the adaptation to sound exposure in the mutant mice. Thus, the nociceptin system appears to participate in the regulation of the auditory system.

Animals↗

PubMed1997

Effects of metrifonate on memory impairment and cholinergic dysfunction in rats.

Metrifonate is an organophosphorous compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of metrifonate on the impairment of learning and on central cholinergic dysfunction in scopolamine-treated and basal forebrain-lesioned rats. Oral administration of metrifonate (5.0-15.0 mg/kg) ameliorated the scopolamine- and basal forebrain. lesion-induced learning impairment in the water maze and passive avoidance tasks. Metrifonate (50 and 100 mg/kg) also significantly increased extracellular acetylcholine levels but decreased choline levels in the cerebral cortex of the basal forebrain-lesioned rats. The basal forebrain lesion decreased the cholinesterase activity in the cerebral cortex, and metrifonate (100 mg/kg) further reduced the cholinesterase activity. However, cholinesterase inhibition was not observed at the dose that ameliorated learning impairments. These results indicated that metrifonate ameliorated the impairment of learning in both scopolamine-treated and basal forebrain-lesioned rats by not only increasing extracellular acetylcholine levels by inhibiting cholinesterase, but also by undefined other mechanism(s). This finding suggests the usefulness of metrifonate for the therapy of Alzheimer's disease.

Acetylcholine↗

PubMed1997

Role of (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors in amelioration of conditioned fear stress in rats: association with mesolimbic dopaminergic systems.

Rats exhibited a marked suppression of motility when they were re-placed in the same environment as that in which they had previously received an electric footshock. We examined the behavioral and neurochemical effects of (+)-N-allylnormetazocine hydrochloride ((+)-SKF-10,047) and (+)-pentazocine, putative sigma 1 receptor ligands, on this psychological-stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently attenuated the conditioned fear stress, whereas (+)-pentazocine failed to do so even at a higher dose (32 mg/kg). In rats showing the conditioned fear stress, dopamine turnover (i.e., the ratio of dopamine metabolites/dopamine contents) was decreased in the nucleus accumbens and was increased in the medial prefrontal cortex, but remained unchanged in the striatum. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently reversed the decreased dopamine turnover in the nucleus accumbens without changing the increased dopamine turnover in the medial prefrontal cortex. (+)-Pentazocine (32 mg/kg) did not affect the stress-induced changes in dopamine turnover in these brain regions. Thus, the decreased dopamine turnover in the nucleus accumbens appears to be involved in the conditioned fear stress. These results suggest that (+)-SKF-10,047 ameliorates the conditioned fear stress by reversing the psychological stress-induced dysfunction in the mesolimbic dopaminergic systems, and that the (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors may play in important role in this stress response.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

No changes in cerebrospinal fluid levels of nitrite, nitrate and cyclic GMP with aging. Short communication.

Nitric oxide (NO) is a free radical gas that plays a role in various signal transduction processes. NO has been proposed to have a function in the mechanism of synaptic plasticity, including long-term potentiation and memory formation in vivo. Because a failure in synaptic plasticity is considered to be involved in aging-associated brain dysfunction, NO production in the brain may be altered by aging. In the present study, we measured the levels of NO metabolites, nitrite and nitrate, and cyclic GMP in the cerebrospinal fluid (CSF) of human subjects without neurological or psychiatric disorders. There were no age-related changes in the CSF levels of either nitrite, nitrate or cyclic GMP. These results suggest that NO production in the brain may be maintained during the aging process.

Adult↗

PubMed1997

Effects of dynorphin A (1-13) on carbon monoxide-induced delayed amnesia in mice.

The effects of dynorphin A (1-13) on carbon monoxide (CO)-induced amnesia in mice were investigated. Memory deficiency was apparent during Y-maze testing 5 days after CO exposure (delayed amnesia). Percent alternation in the CO-exposed group was significantly lower than that in the control group. Administration of dynorphin A (1-13) (1.5 nmol, i.c.v.) 15 min before the Y-maze test session reversed the impairment of spontaneous alternation performance in the CO-exposed group. To determine whether this effect was mediated via kappa opioid receptors, we attempted to block the effect of dynorphin A using the kappa opioid receptor antagonist nor-binaltorphimine. Nor-binaltorphimine (5.44 nmol, i.c.v.) blocked the effect of dynorphin A (1-13) on delayed amnesia. Dynorphin A (1-13) did not affect the impairment of alternation induced by the blockade of NMDA-receptors by dizocilpine (MK-801), but significantly prevented the impairment induced by mecamylamine. These results suggest that dynorphin A (1-13) modulates the kappa receptor-mediated opioid neuronal system, and reverses the impairment of spontaneous alternation performance induced by CO exposure.

Amnesia↗

PubMed1997

Effects of nefiracetam on amnesia animal models with neuronal dysfunctions.

The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (nefiracetam; DM-9384), on learning and memory in several amnesia animal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiazepoxide- and cycloheximide-induced amnesia. Anti-amnesic action of nefiracetam on scopolamine model was antagonized by nifedipine and flunarizine, but not by diltiazem. Repeated administration of nefiracetam to AF64A-treated animals improved impairment of learning and memory as well as the alterations in cholinergic and monoaminergic neurotransmitters in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning accompanied by a marked reduction in choline acetyltransferase (ChAT) and acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxide-induced delayed and acute amnesia. Nefiracetam stimulated acetylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, gamma-aminobutyric acid (GABA) turnover and glutamic acid decarboxylase activity, and facilitated the Na(+)-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca2+ channel. The dose-response curves of nefiracetam were bell-shaped in both behavioral and biochemical studies. Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca2+ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia.

Amnesia↗

PubMed1997

Orally active NGF synthesis stimulators: potential therapeutic agents in Alzheimer's disease.

The degeneration of cholinergic neurons may be responsible for cognitive impairment in patients with Alzheimer's disease (AD). Since nerve growth factor (NGF) plays an important role in the survival and maintenance of cholinergic neurons in the central nervous system, this factor may have some beneficial effects on the cognitive impairment observed in patients with AD. However, since NGF does not cross the blood-brain barrier and is easily metabolized when administered peripherally, it can only be used when directly injected into the brain. In this review, we show that repeated oral administration of the NGF synthesis stimulators, idebenone and propentofylline, partially restored the age-associated decrease of NGF in the frontal and parietal cortices. Furthermore, this treatment attenuated the impairment of performance in the water maze, passive avoidance, and habituation tasks in rats with bilateral forebrain lesions, and in rats which had received continuous infusion of anti-NGF antibody into the septum. The behavioral improvement induced by idebenone and propentofylline was accompanied by recovery of both the reduced activity of choline acetyltransferase and the changes in [3H]QNB binding. These results suggest that the use of NGF synthesis stimulators may provide a novel therapeutic approach to cholinergic dysfunction.

Alzheimer Disease↗

PubMed1997

Role of nitric oxide in the effect of aging on spatial memory in rats.

Since there is evidence that nitric oxide (NO) plays an important role as a diffusible messenger in learning and memory, we examined the role played by NO in the effect of aging on spatial memory in rats. The performance of aged rats (30 months old) in a radial-arm maze task was significantly impaired compared to that of adult rats (3 months old). The number of neurons containing NADPH-diaphorase (NADPH-d) reactivity in the cerebral cortex and striatum of aged rats was significantly less than that in the adult rats. The daily administration of NG-nitro-L-arginine methyl ester (L-NAME; 10-60 mg/kg, i.p.) resulted in a dose-dependent impairment of acquisition in the radial-arm maze task, while it failed to affect previously acquired performance, i.e., retention, in the adult rats. The content of 5-hydroxyindoleacetic acid in the hippocampus and of 3,4-dihydroxyphenylacetic acid in the striatum was significantly decreased and increased, respectively, in the L-NAME (60 mg/kg/day)-treated adult rats compared with that in controls. These findings demonstrate that NO production in the brain may be decreased in aged rats, suggesting that this alteration may be involved in memory processes, especially in the acquisition, but not in the retention, of spatial learning in rats, and further, that endogenous NO may be involved in the regulation of dopamine and 5-hydroxytryptamine metabolism.

Aging↗

PubMed1997

Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats.

Several studies have indicated the possibility of using cholinesterase (ChE) inhibitors as therapeutic drugs for Alzheimer's disease. Metrifonate (MTF) is an organophosphorus compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of MTF on the impairment of learning and memory, decreased ChE activity and extracellular acetylcholine (ACh) levels in basal forebrain (BF)-lesioned rats. The oral administration of MTF improved the BF-lesion-induced impairment of performance on passive avoidance task. Further, MTF reduced ChE activity in the cerebral cortex. In vivo brain microdialysis studies showed that MTF significantly increased the release of ACh, but decreased that of choline (Ch) in the cerebral cortex of BF-lesioned rats. These results indicated that MTF ameliorates the impairment of performance on passive avoidance task in BF-lesioned rats by increasing the extracellular ACh levels by inhibiting ChE. This suggested that MTF may be useful as a therapeutic drug for Alzheimer's disease.

Acetylcholine↗

PubMed1997

A synergistic interaction between dopamine D1 and D2 receptor subtypes in the memory impairments induced by concussive brain injury (CBI) in mice.

Profound latent learning and memory deficits with increased monoamine levels in the brain following concussive brain injury (CBI) have been documented in our previous work. The purpose of the present study was to determine the role of dopamine (DA) receptor subtypes in the memory deficits associated with CBI. Profound latent learning and memory impairments were observed in the vehicle-treated CBI mice. SCH-23390 administered 15 min post-injury had no significant effects on the impairments of latent learning and memory in the CBI mice. Sulpiride significantly improved the impairments of latent learning and memory in a dose-dependent manner, indicating that activation of dopaminergic neuronal function is involved in the CBI-induced amnesia. Interestingly, co-administration of sulpiride and SCH-23390, at doses which alone has no significant effect, significantly ameliorated the impairments of latent learning and memory. These results strongly suggested that D1 and D2 receptor subtypes are synergistically involved in the dysfunction of learning and memory associated with CBI.

Animals↗

PubMed1997

(+)-Eburnamenine-14-carboxylic acid (2-nitroxyethyl) ester (VA-045), a putative cognitive enhancer, facilitates recovery from concussive brain injury-induced learning and memory impairments in mice.

We characterized alterations in the ability of concussive brain injury (CBI) models to perform a water-finding task and examined effects of (+)-eburnamenine-14-carboxylic acid (2-nitroxyethyl) ester (VA-045), a novel apovincaminic acid derivative, on post-traumatic impairments in latent learning and memory processes. Two types of CBI-induced amnesia (retrograde and anterograde) were produced by means of post- or preacquisition head impact using a simple weight-drop device. Profound impairments of latent learning and memory processes related to retention and retrieval were observed in the CBI mice. In the CBI-induced retrograde amnesia model, VA-045 (0.5-4.0 mg/kg) significantly ameliorated impairments of latent learning and retention in both the retention test and the retest. In the CBI-induced anterograde amnesia model, the protective effects of the compound on impairments in latent learning and retention or retrieval were significant in both the retention test and the retest. These results suggested that VA-045 may be a novel cognitive enhancer for attenuating or protecting against the learning and memory dysfunction associated with CBI.

Amnesia, Retrograde↗

PubMed1997

Oral administration of propentofylline, a stimulator of nerve growth factor (NGF) synthesis, recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum.

We have reported that the continuous infusion of anti-nerve growth factor (NGF) monoclonal antibody into the septum of rats produces an impairment of memory and a decrease in choline acetyltransferase (ChAT) and cholinesterase (ChE) activities in the hippocampus. Propentofylline, a xanthine derivative, has potent stimulatory effects on NGF synthesis/secretion in mouse astrocytes in vitro. To investigate the pharmacological effects of propentofylline in vivo, we induced amnesia in rats by infusing anti-NGF antibody into the septum for 16 days. One group of rats was given no further treatment, while the other group was treated with propentofylline orally once a day for 19 days, commencing 3 days before the implantation of the mini-osmotic pump, and continuing throughout the period during which the animals performed the behavioral tasks. In the treated amnesic rats, learning and memory in the 3 tasks and ChAT and ChE activity were reduced compared to values in control rats. The administration of propentofylline recovered the decreased learning capacity and the deficit in cholinergic marker enzyme activity. These results suggest that the use of NGF stimulators may provide a new approach to the treatment of dementia.

Amnesia↗

PubMed1997

The effect of the loss of molar teeth on spatial memory and acetylcholine release from the parietal cortex in aged rats.

It has been demonstrated that a loss of teeth is a troublesome problem among age-related pathological phenomena of the oral cavity, which influences the entire body, due to the impairment of mastication. The present studies investigated the abilities of learning and memory and acetylcholine (ACh) release in the parietal cortex in aged rats without molar teeth (hereafter referred to as 'teethless'). After the molar teeth of rats were extracted, the rats were fed with powdered food for 135 weeks. Although the performance in the radial arm maze was progressively acquired by daily training, an increase in the number of errors and a decrease in the initial correct responses were observed in the teethless aged rats compared to the control aged rats, indicating impaired acquisition of spatial memory in the teethless aged rats. The basal level of extracellular ACh in the parietal cortex was not different between the teethless aged rats and the control aged rats. However, the extracellular ACh level of the teethless aged rats under high-concentration of K+ and atropine sulfate stimulation was significantly low compared to that of the control aged rats. These results suggest that the impairment of spatial memory in the teethless aged rats may be due to the functional deterioration of the cholinergic neuronal system induced by tooth loss and that there is a possibility that the loss of teeth may be one of the risk factors for senile dementia.

Acetylcholine↗

PubMed1997

Two pathways of nitric oxide production through glutamate receptors in the rat cerebellum in vivo.

The effects of N-methyl-D-aspartate (NMDA), (+)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (ACPD) on nitric oxide (NO) production in the cerebellum of conscious rats were investigated by measuring the levels of total NO metabolites (nitrite plus nitrate, NOx-) in dialysates obtained by in vivo microdialysis. All glutamate receptor agonists dose-dependently increased NOx- levels. Pharmacological characterization with various glutamate receptor antagonists indicated that the effects of NMDA, AMPA and ACPD are mediated by NMDA, non-NMDA, and L(+)-2-amino-3-phosphonopropionic acid (L(+)-AP-3)-sensitive metabotropic glutamate receptors, respectively. The NO synthase (NOS) inhibitors, including NG-nitro-L-arginine methyl ester (L-NAME), NG-nitro-L-arginine (L-NA), 7-nitroindazole (7-NI), and NG-monomethyl-L-arginine, inhibited NMDA-induced, but not AMPA- or ACPD-induced, increase in NOx- levels. L-Arginine enhanced NMDA-induced, but not AMPA- or ACPD-induced, increase in NOx- levels. Cytochrome P-450 inhibitors, SKF525A and erythromycin, inhibited the effect of NMDA, but not AMPA or ACPD. These results suggest that AMPA and ACPD may induce NO production through a NOS-independent pathway although NMDA receptor-mediated NO production is dependent on NOS activity in the rat cerebellum in vivo.

Animals↗

PubMed1997

In vivo hypoxia-induced neuronal damage in dentate gyrus of rat hippocampus: changes in NMDA receptors and the effect of MK-801.

Hypoxia is a major cause of ischaemia-induced neuronal damage. In the present study, we examined the effects of in vivo hypoxia on N-methyl-D-aspartate receptors (NMDAR) in the rat hippocampus. This model of in vivo hypoxia involved placing rats in a hypoxic chamber containing 5% O2 and 95% N2 for 30 min. In the hippocampus, neuronal cells in the CA3, the hilus of the dentate gyrus and the dentate gyrus (DG) were damaged. In the CA1, which is known to be vulnerable to ischaemic damage, neuronal cells did not show hypoxia-induced damage. In vivo hypoxia-induced damage caused morphological changes in neuronal cells, such as shrunken, spindle or triangular shapes accompanied by pyknotic nuclei, but did not induce the loss of neuronal cells. On the other hand, the number of binding sites for [3H]-1-[1-(2-thienyl)cyclohexyl]-3,4-piperidine hydrochloride (TCP) gradually decreased on and after 7 days, and then maximally decreased by 25% at 21 days after hypoxia. The number of NMDAR1-immunopositive cells was decreased by 22% in the DG, but was unchanged in the CA3. Furthermore, we examined the effect of a non-competitive NMDA antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,b] cyclohepten-5,10-imine hydrogen maleate (MK-801), on against in vivo hypoxia. The administration of MK-801 (3 mg/kg, i.p.), 30 min before hypoxia treatment, partly protected against neuronal damage in the DG, but not in the CA3. These results suggest that hypoxia-induced neuronal damage in the DG involves, in part, the activation of NMDAR.

Animals↗

PubMed1997

Possible involvement of catalase in the protective effect of interleukin-6 against 6-hydroxydopamine toxicity in PC12 cells.

We examined the effects of various neurotrophic factors and cytokines on 6-hydroxydopamine (6-OHDA)-induced toxicity in PC12 cells. Exposure of PC12 cells to 6-OHDA resulted in a concentration- and time-dependent cell death, as evidenced by the release of lactate dehydrogenase into the culture medium. Addition of catalase, but not superoxide dismutase, to the culture medium protected PC12 cells from the 6-OHDA-induced toxicity. Interleukin (IL)-6 provided a dose-dependent protection against the 6-OHDA toxicity, as did nerve growth factor (NGF). In addition, basic fibroblast growth factor and dibutyryl cyclic AMP partially protected PC12 cells from 6-OHDA toxicity. Neither IL-1alpha, IL-2, IL-4, transforming growth factor-beta, nor leukemia inhibitory factor had any effect. The protective effect of IL-6 was attenuated by 3-amino-1,2,4-triazole, an inhibitor of catalase. These results suggest that IL-6 may protect PC12 cells against the 6-OHDA toxicity by activating free radical detoxifying mechanisms, such as catalase activity.

Animals↗