Biomedical subjects

T Nabeshima

Publications and source records attributed to T Nabeshima.

At least 91 records · Page 5Linked to original sources

PubMed1999

Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells.

In the present study, we found that S-nitroso-N-acetyl-DL-penicillamine, a spontaneous nitric oxide (NO) generator, dose-dependently inhibited basal nerve growth factor (NGF) release from mixed glial cells. To elucidate the function of endogenous NO in the regulation of NGF release, the mixed glial cells were stimulated with lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFNgamma). The results showed that LPS alone induced NGF release and moderate NO production. However, costimulation with LPS plus IFNgamma greatly enhanced NO production but significantly suppressed LPS-induced NGF release. When N(G)-monomethyl-L-arginine, an NOS inhibitor, was added to the culture, the suppression of NGF release by IFNgamma was significantly reduced. Quantitative reverse transcription-polymerase chain reaction demonstrated S-nitroso-N-acetyl-DL-penicillamine was also able to inhibit the LPS-induced NGF mRNA expression. To understand the different contributions of astroglia and microglia to this phenomenon, both cell types were purified. We found purified astroglia produced high amounts of NGF but low amounts of NO. However, purified microglia produced a large amount of NO but very low amounts of NGF after stimulation with LPS or LPS plus IFNgamma. Our data also indicated the second messenger cyclic GMP, but not cyclic AMP, was able to inhibit basal NGF release. In vivo experiments confirmed that NGF protein level was significantly enhanced in rats treated with L-N(omega)-nitro-arginine methyl ester and in endothelial NO synthase mutant mice. Taken together, we conclude NO derived mainly from microglia down-regulates NGF release from astroglia at the transcriptional level by stimulating cyclic GMP pathway.

Animals↗

PubMed1999

[The psychological stress model using motor suppression].

Psychological stress is believed to be implicated in the etiology of affective disorders such as anxiety and depression. To date, a wide range of behavioral responses including analgesia and motor suppression induced by various physiological stressors such as footshock, forced swimming and immobilization have been investigated in animals. However, there is little information concerning behavioral changes in psychological stress. This article describes the experimental procedures and the characteristics of motor suppression in psychological stress, defined as conditioned fear stress (CFS). Mice exhibit a marked suppression of motility when they are re-placed in the same environment in which they had previously received an electric footshock. This motor suppression is regarded as a conditioned emotional response to the environment associated with previous footshock. The motor suppression in CFS is attenuated by sigma receptor agonists such as (+)-N-allylnormetazocine and dextromethorphan, whereas typical anxiolytics (diazepam and chlordiazepoxide) and antidepressants (imipramine and fluoxetine) have no effect. These findings suggest that the CFS model may be useful for investigating the pathogenesis of affective disorders, particularly those considered to be treatment resistant, and for developing their novel therapeutic drugs.

Animals↗

PubMed1999

[Development of sigma-receptor ligands and clinical trials].

There are at least two classes of sigma-receptors, termed sigma 1 and sigma 2. Recently, the sigma 1-receptor has been completely sequenced in different species. The amino acid sequences of the different purified proteins are highly homologous, but it shares no homology to know mammalian proteins. These results suggest that the sigma 1 receptor is a distinct entity from any often known receptors. sigma-Receptors are involved in many physiological functions. Therefore, sigma-ligands show many different pharmacological effects such as glucose utilization, neuroprotective, antipsychotic, antidepressive, anxiolytic, nootropic, antiepileptic, antiabuse, antitussive, antidiarrhea, anti-inflammatory, tear protein releasing stimulant and central anti-micturition reflex actions. These results suggest that sigma-receptors are very promising targets for the development of new drugs that have new mechanisms of action.

Animals↗

PubMed1999

[The 1998 domestic state of development of cognitive enhancers].

Recently, there is a great social problem that geriatric disorders, especially senile dementia, are growing rapidly with the increasing percentage of aged individuals in the total population. However, there is yet no drug that has reliable effects on senile dementia on the market. Therefore, society requires the development of new drugs that can support patients so that they can smoothly live their daily lives by themselves. In this study, we attempted to investigate the 1998 domestic state of development of cognitive enhancers by summarizing many publications and by gathering questionnaires from pharmaceutical, food, synthetic fiber and chemical manufacturing companies. There were 40 currently investigated cognitive enhancers in Japan as of the end of March, 1999 including 37 newly synthesized compounds and 3 new dosage forms or applications of additional effects. On the classification according to the mechanism of drug action, 12 of the investigated drugs are cholinomimetic agents, 12 are ameliorators of neuronal transmission, 1 is an intracellular mediative substance, 3 are neuropeptides, 2 are cerebral metabolic activators, 2 are cerebral circulation enhancers and 7 are neuronal cell protectors, and 1 is another type. For dementia of the Alzheimer's type, there are 1, 3, 10 and 2 drugs in prerecognition, phase late II, early II and I of clinical trials, respectively. For cerebrovascular dementia and cerebrovascular disease, there are 19 drugs being investigated. Seven of these compounds such as E2020 (donepedil HCl), DM-9384 (nefiracetam), TA-0910 (taltirelin), NS-3 (montirelin), TTC-909 (clinprost), DR-3305 (ebselen) and AVS (nicaraven) are at the prerecognition stage for marketing. It is important that effective cognitive enhancers will be supplied for clinical stage use as soon as possible.

Alzheimer Disease↗

PubMed1999

[Sigma-receptor ligands and anti-stress actions].

The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoin-sensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma1 receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.

Animals↗

PubMed1999

Perspectives of pharmacotherapy in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of progressive decline of cognitive function in aged humans, and it is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The senile plaques are composed of amyloid beta-peptides (A beta), 40-42 amino acid peptide fragments of the beta-amyloid precursor protein. Genetic, molecular biological and neuropharmacological evidence support the 'amyloid cascade hypothesis' for the pathogenesis of the disease. We review the in vivo effects of various compounds on behavioral and neuropathological changes in the non-transgenic animal models of AD produced by continuous i.c.v. infusion of A beta. These results support therapeutic strategies such as cholinergic therapy, anti-inflammatory agents, antioxidants and estrogen replacement therapy, as well as other cognition enhancers for the treatment of AD. In addition, the amyloid cascade hypothesis offers a number of potential targets for novel therapeutic strategies in AD. We believe that our non-transgenic animal model, as well as transgenic animal models, are useful for developing novel pharmacotherapeutics in AD.

Alzheimer Disease↗

PubMed1999

Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities.

Neuroactive neurosteroids, including progesterone, allopregnanolone, pregnenolone and dehydroepiandrosterone, represent steroid hormones synthesized de novo in the brain and acting locally on nervous cells. Neurosteroids modulate several neurotransmitter systems such as gamma-aminobutyric acid type A (GABA(A)), N-methyl-D-aspartate (NMDA) and acetylcholine receptors. As physiologic consequences, they are involved in neuronal plasticity, learning and memory processes, aggression and epilepsy, and they modulate the responses to stress, anxiety and depression. The sigma1-receptor protein was recently purified and its cDNA was cloned in several species. The amino-acid sequences are structurally unrelated to known mammalian proteins, but shared homology with a fungal sterol C8-C7 isomerase. The sigma1-receptor ligands exert a potent neuromodulation on excitatory neurotransmitter systems, including the glutamate and cholinergic systems. Consequently, selective sigma1 agonists show neuroprotective properties and beneficial effects in memory processes, stress and depression. The evidence of a direct interaction between neurosteroids and sigma1 receptors was first suggested by the ability of several steroids to inhibit the binding of sigma1-receptor radioligands in vitro and in vivo. A crossed pharmacology between neurosteroids and sigma1-receptor ligands was described in several physiological tests and behavioral responses. This review will detail the recent evidence for a common mechanism of action between neurosteroids and sigma1-receptor ligands and focus on the potential therapeutic interests of such interaction in the physiopathology of learning and memory impairments, stress, depression and neuroprotection.

Animals↗

PubMed1999

[Behavioral pharmacological characterization of mice lacking the nociceptin receptor].

Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the central nervous system, however, the physiological role of modulation via the nociceptin receptor is still unclear. Here, we report the behavioral pharmacological characterization of mice lacking the nociceptin receptor. Nociceptin produced hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice showed no significant abnormalities in nociceptive thresholds (tail-flick, hot-plate, electric, and acetic acid-induced writhing tests) and locomotion. In the learning and memory tests, nociceptin induced impairment of learning and memory in wild-type mice. Nociceptin receptor-knockout mice possessed greater learning ability and had better memory than wild-type mice. These results suggest that the nociceptin system plays a role in regulation of nociception or locomotion and seems to play negative roles in learning and memory. Next, we compared nociceptive responses induced by various opioids between the nociceptin receptor-knockout and wild-type mice. As previously reported, morphine (mu-opioid receptor agonist), U-50,488 H (kappa 1-opioid receptor agonist), and naloxone benzoylhydrazone (NalBzoH; kappa 3-opioid receptor agonist) induced antinociceptive effects in wild-type mice. Surprisingly, knockout mice lacked the antinociceptive effect induced by NalBzoH, but not by morphine and U-50,488H. Further, NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion in wild-type mice. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed in [3H]-nociceptin binding and attenuated the nociceptin-induced inhibition of cyclic AMP accumulation induced by forskolin. These results clearly suggest that NalBzoH acts as a potent antagonist for the nociceptin receptor. Our studies suggest that the nociceptive system and/or learning and memory processes could be modulated by ligands to the nociceptin receptor, and further that the antagonists are worth testing for the alleviation of pain and memory disorders.

Animals↗

PubMed1998

Motor and learning dysfunction during postnatal development in mice defective in dopamine neuronal transmission.

Mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of the catecholamine biosynthetic pathway, in dopaminergic neuronal cell types were generated by a transgenic rescue approach to clarify the role of dopamine signaling during postnatal development. Introduction of the TH transgene directed by the dopamine beta-hydroxylase gene promoter into TH knockout mice restored noradrenaline and adrenaline synthesis, preventing perinatal lethality and cardiac dysfunction in the knockout mice. Lack of TH expression in the cells that normally express the dopaminergic phenotype resulted in a marked reduction of dopamine accumulation in the tissues, which led to multiple behavioral abnormalities at the juvenile stage. These abnormalities were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defects in active avoidance learning. In contrast, development of the pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained, despite defective dopamine synthesis. These results demonstrate that dopamine neurotransmission is essential for controlling spontaneous and voluntary movement and associative learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways.

Animals↗

PubMed1998

Changes in NMDA receptor/nitric oxide signaling pathway in the brain with aging.

The N-methyl-D-aspartate (NMDA) receptor/nitric oxide (NO) signaling pathway plays an important role in neuronal plasticity. Previous studies with in vitro autoradiography showed that the number of NMDA receptor/ion channel complexes in the cerebral cortex and hippocampus is decreased by aging. Confocal laser scanning microscopy reveals circuit-specific alterations of NMDA receptor subunit 1 in the dentate gyrus of aged monkeys. Histochemistry for NADPH diaphorase (NADPH-d), a marker for neurons containing NO synthase (NOS), reveals that the number of NADPH-d-positive neurons in the cerebral cortex and striatum is significantly reduced from that in young rats. In the hippocampus, no age-related changes in NADPH-d staining are reported, while in situ hybridization histochemistry indicates an increase in the level of mRNA for neuronal NOS. NOS activity in the brain also appears to decrease with aging. These results suggest that the function of the NMDA receptor/NO signaling pathway in the brain is impaired by aging, and that dysfunction of this signaling pathway may underlie aging-associated memory impairment in rats.

Aging↗

PubMed1998

Sigma receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats.

This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.

Animals↗

PubMed1998

Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors.

The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

Animals↗

PubMed1998

Loss of antinociception induced by naloxone benzoylhydrazone in nociceptin receptor-knockout mice.

Animals↗

PubMed1998

NC-1900, an active fragment analog of arginine vasopressin, improves learning and memory deficits induced by beta-amyloid protein in rats.

We have reported that the continuous infusion of beta-amyloid protein-(1-40) into the rat cerebral ventricle produces learning and memory deficits accompanied by dysfunction in the cholinergic and dopaminergic systems. L-Pyroglutamyl-L-asparaginyl-L-seryl-L-prolyl-L-arginylglycinamide (NC-1900), an active fragment analog of arginine vasopressin in the rat brain, is a stable peptide with a five-fold longer half-life than that of arginine vasopressin-(4-9). In the present study, we examined the effects of NC-1900 on learning and memory deficits in beta-amyloid protein-(1-40)-infused rats. The rats were injected subcutaneously with NC-1900 (0.1 and 1 ng kg(-1)) once a day throughout the period of behavioral examination. In the beta-amyloid protein-infused rats, learning and memory in water maze and passive avoidance tasks were impaired compared with these in the control rats. NC-1900 prevented the learning and memory deficits in beta-amyloid protein-infused rats. Moreover, NC-1900 tended to increase the choline acetyltransferase activity in the frontal cortex of the beta-amyloid protein-infused rats. These results suggested that NC-1900 could be useful for the treatment of patients with Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed1998

Propentofylline improves learning and memory deficits in rats induced by beta-amyloid protein-(1-40).

We have reported that continuous infusion of beta-amyloid protein-(1-40) into the cerebral ventricle produces learning and memory deficits in rats. Propentofylline has potent stimulatory effects on nerve growth factor (NGF) synthesis/secretion in mouse astrocytes in vitro and increases cerebral NGF content in aged rats. In the present study, we examined the effects of propentofylline on learning and memory deficits in beta-amyloid protein-infused rats. The rats were given propentofylline orally once a day throughout the period of behavioral examination. In the beta-amyloid protein-infused rats, spontaneous alternation behavior in a Y-maze, and performance in water maze and passive avoidance tasks were significantly impaired compared to sham-operated rats. Propentofylline prevented these behavioral deficits, but did not change the reduction of the activity of choline acetyltransferase in the hippocampus in the beta-amyloid protein-infused rats. These results suggest that propentofylline is useful for the treatment of patients with Alzheimer's disease.

Administration, Oral↗

PubMed1998

Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study.

We determined the effect of nefiracetam, a novel cognitive enhancer, on the extracellular acetylcholine (ACh) level in the frontal cortex of freely moving rats, using a microdialysis technique without an acetylcholinesterase inhibitor in the perfusate. Treatment with nefiracetam (10 mg/kg, p.o.) produced a significant increase in the level of ACh in the brain dialysate, compared with the vehicle-treated group. This enhancing effect was also observed when the ACh level was elevated by administration of scopolamine (1 mg/kg, i.p.) at 45 min after the treatment with nefiracetam. In addition, perfusion of nefiracetam at the concentration of 10 microM significantly increased the extracellular ACh level in the frontal cortex of basal forebrain (BF)-lesioned rats, in which a marked decrease of the basal ACh level was observed in this region. These results suggest that enhancement of cortical ACh release by nefiracetam may contribute to an anti-amnesic effect on the learning deficits induced by treatment of scopolamine or BF-lesion in rats.

Acetylcholine↗

PubMed1998

Enhancement of spatial attention in nociceptin/orphanin FQ receptor-knockout mice.

We isolated genes for the opioid receptor homologue MOR-C, namely nociceptin receptor (designated alternatively as orphanin FQ receptor) and generated nociceptin receptor-knockout mice. Previously, we have reported that the nociceptin system appears to participate in the regulation of the auditory system. However, the behavior of the nociceptin receptor-knockout mice has yet to be fully characterized. In the present study, we investigated changes in several behavioral performances in mice which lack nociceptin receptor. Nociceptive thresholds of nociceptin receptor-knockout mice were unchanged in the hot-plate and electric foot-shock tests as well as tail-flick and acetic-acid-induced writhing tests compared to those of wild-type mice. The nociceptin receptor-knockout mice did not show any behavioral changes in the elevated plus-maze task. Surprisingly, in the water-finding test, the nociceptin receptor-knockout mice showed an enhanced retention of spatial attention (latent learning) compared to wild-type mice. In a biochemical study, dopamine content in the frontal cortex was lower in nociceptin receptor-knockout mice than wild-type mice. These results suggest that nociceptin receptor plays an important role in spatial attention by regulating the dopaminergic system in the brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Oral mucosal adhesive film containing local anesthetics: in vitro and clinical evaluation.

In vitro and in vivo studies were conducted to gauge the effectiveness of a novel oral mucosa adhesive, moderately water-soluble, pliant polymer artificial dentifrice (AD) film containing dibucaine (DC) for relief of pain due to oral erosion. The film was prepared from a hydroxypropyl cellulose-M (HPC-M) ethanol solution containing varying amounts of DC, as well as polyethylene glycol. In the in vitro experiments, the disintegration of HPC-M showed a lag time of about 50 min, a much lower rate than that of drug release, which more or less leveled off after 50 min. Twenty-five percent of the DC was released from the film (0.113 and 0.225 mg/cm2) after the initial 5 min, which then reached about 80% after 50 min, the time at which the polymer began to break up. In the in vivo study, the local anesthetic effect of the film was evaluated in 23 patients (10 males, 13 females) suffering from the adverse effects of chemotherapy. When applied to the wet surface of the mucosa, the AD film absorbed moisture and showed excellent adhesion. Pain relief in patients lasted 2.2 +/- 0.21 and 4.3 +/- 0.25 h at DC doses of 0.113 and 0.225 mg/cm2, respectively. These results suggest that the AD film may cover mucositis sites of oral mucosa long enough to allow DC release and bring relief from pain arising from chemotherapy and/or radiotherapy.

Adhesives↗