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Biomedical subjects

K Yanai

Publications and source records attributed to K Yanai.

At least 37 records · Page 2Linked to original sources
PubMed2000

L-Histidine decarboxylase protein and activity in rat brain microvascular endothelial cells.

OBJECTIVE AND DESIGN: L-Histidine decarboxylase (HDC) is the primary enzyme regulating histamine biosynthesis. This study was carried out to examine whether the cultured rat brain microvascular endothelial cells (BMEC), which constitute the blood-brain barrier (BBB), have the ability to form histamine, and whether HDC mRNA is expressed in rat BMEC. MATERIAL: Male, 3-week-old Wistar rats were used. For in vitro studies, rat BMEC were isolated from rat brains, and subculture cells were grown on collagen-coated culture flask and slide. METHODS: HDC assay, immunofluorescence analysis and expression of HDC mRNA by RT-PCR were performed in rat BMEC. RESULTS: The HDC activity of the BMEC was estimated to be 0.14 +/- 0.05 p mol/min/mg protein. This activity was completely inhibited by (S)-alpha-fluoromethylhistidine, a specific inhibitor of HDC. Using a polyclonal anti HDC antibody and immunofluorescence microscopy, we confirmed the presence of HDC protein in rat BMEC. RT-PCR also showed the expression of HDC mRNA in rat BMEC. CONCLUSIONS: L-Histidine uptaken by rat BMEC was shown to be converted to histamine, suggesting that HDC plays an important role in BBB.

Animals↗
PubMed2000

Histamine H(1) receptors in patients with Alzheimer's disease assessed by positron emission tomography.

Cerebral histamine H(1) receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients with Alzheimer's disease by positron emission tomography and [11C]doxepin, a radioligand for H(1) receptors. The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis, and were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H(1) receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer's disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer's disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer's disease brain. However, the difference in the binding potential (total concentration of receptor/equilibrium dissociation constant) between the Alzheimer's disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer's disease was greater than the rate of decrease in the cerebral blood flow. This study reveals the predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer's disease. This study suggests that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits of Alzheimer's disease patients.

Adult↗
PubMed2000

A new, convenient method for the preparation of 4-[18F]fluorobenzyl halides.

A convenient method suitable for automated preparation of 4-[18F]fluorobenzyl halides from no-carrier-added [18F]fluoride has been developed. 4-[18F]Fluorobenzaldehyde, synthesized from [18F]fluoride by aromatic nucleophilic substitution on 4-trimethylammoniumbenzaldehyde triflate, was first retained on a C18 cartridge and there efficiently reduced to 4-[18F]fluorobenzyl alcohol simply by flowing an aqueous solution of NaBH4. The conversion of 4-[18F]fluorobenzyl alcohol to 4-[18F]fluorobenzyl halide was investigated using PBr3, PI3, P2I4, Ph3PBr2 and Ph3PI2 in CH2Cl2. 4-[18F]Fluorobenzyl halides were purified by passing through a disposable silica cartridge. The conversion rapidly proceeded in radiochemical yields of nearly 90% at 40 degrees C with P2I4 and almost quantitatively at room temperature with Ph3PBr2. With this last reagent 4-[18F]fluorobenzyl bromide was obtained in overall radiochemical yields of 50-60% within 30 min from EOB.

Journal Article↗
PubMed2000

Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine.

Antihistamine induced cognitive decline was evaluated using positron emission tomography (PET) measurement of histamine H1 receptor (H1R) occupancy and regional cerebral blood flow (rCBF). Cognitive performance in attention-demanding task deteriorated dose-dependently and the effects were statistically significant after the treatment of 2 mg of d-chlorpheniramine. There was no significant change in subjective sleepiness in the same dose. The regional blockade of H1R was observed mainly in the frontal, temporal and anterior cingulate cortices, and the intravenous administration of d-chlorpheniramine as a therapeutic dose (2 mg) blocked over 60% of H1R in the frontal cortices. The results from activation study using visual discrimination tasks demonstrated that enhanced activity in the right prefrontal and anterior cingulate cortices as well as a decreased activity in the left temporal and frontal cortices and midbrain after the treatment of d-chlorpheniramine. There were no changes in global CBF for the subjects treated with 2 mg d-chlorpheniramine (pre; 44.8+/-3.3 ml dl(-1) min(-1) vs post; 44.4+/-4.7 ml dl(-1) min(-1)). The results indicated that the attention system of human brain could be altered by therapeutic doses of H1R antagonists. These findings provide the information as to the potential risk of antihistamines in our daily activities. British Journal of Pharmacology (2000) 129, 115 - 123

Adult↗
PubMed2000

Relationship between effects of alcohol on psychomotor performances and blood alcohol concentrations.

Ethanol is a social drug and has been generally known to be a CNS depressant. A large fluctuation of blood alcohol concentration (BAC) is well-known to occur due to main factors such as the genetic polymorphism of the main alcohol metabolizing enzymes and the effect of blood. Few studies have substantially discussed the relationship between impaired CNS activities and BAC. In this study, focusing on the correlation of BAC, we investigated the acute effects of alcohol intake on cognitive performance in humans by objective evaluation methods consisting of the attention-demanding cognitive tasks. Tasks were administered to ten healthy male volunteers before and after ingesting established amounts of alcohol. With increased BAC, we observed prolongation of reaction time performances and lowering of a coordination performance. From the results, we concluded that cognitive performance deteriorates with an increase of BAC. Additionally, the BAC threshold that causes significant impairment of cognitive performance was estimated to be approximately 50 mg/dl (ca. 10 mM).

Adult↗
PubMed2000

[The role of positron emission tomography in neuropharmacology in the living human brain and drug development].

Neuroimaging is a powerful and innovative tool for studying the pathology of psychiatric and neurological diseases and, more recently, for studying the drugs used in their treatment. Technological advances in imaging have made it possible to noninvasively extract information from the human brain regarding a drug's mechanism and site of action. Until now, our understanding of human brain pharmacology has depended primarily on indirect assessments or models derived from animal studies. However, the advent of multiple techniques for human brain imaging allows researchers to focus directly on human pharmacology and brain function. In this review article, our PET studies on histaminergic neuron system were presented as an example. We have developed and used the PET techniques for 10 years in order to examine the functions of histaminergic neurons in the living human brain. This review outlines available PET techniques and examines how these various methods have already been applied to the drug development process and neuropharmacology in the living human brain.

Brain↗
PubMed1999

Hypernuclear acetylation in atherosclerotic lesions and activated vascular smooth muscle cells.

Recent studies have implicated acetylation of several nuclear proteins such as histones and p53 on their epsilon-portion of lysine residues in eukaryotic transcription. Here we raised a specific polyclonal antibody against epsilon-acetylated lysine. Using the antibody, we detected hypernuclear acetylation (HNA) in atherosclerotic vascular smooth muscle cells (VSMCs). Thrombin, a humoral factor known to cause activation and proliferation of VSMCs, strongly potentiated HNA in cultured VSMCs. MAP kinase pathway and a signal coactivator CREB binding protein (CBP) were involved in thrombin-induced HNA of VSMCs. Our results suggest that coactivators cooperating with signal-dependent transcription activators play an important role in atherosclerogenesis via HNA in VSMCs.

Acetylation↗
PubMed1999

Regulated expression of human angiotensinogen gene by hepatocyte nuclear factor 4 and chicken ovalbumin upstream promoter-transcription factor.

We previously identified various upstream and downstream regulatory elements and factors important for hepatic expression of the human angiotensinogen (ANG) gene, the precursor of vasoactive octapeptide angiotensin II. In the present study, to further investigate the molecular mechanism of human ANG transcriptional regulation, we generated transgenic mice carrying the fusion gene composed of the 1. 3-kilobase promoter of the human ANG gene, its downstream enhancer, and the chloramphenicol acetyltransferase reporter gene. Because expression of the chloramphenicol acetyltransferase gene was observed strongly in the liver and weakly in the kidney, we suspected that hepatocyte nuclear factor (HNF) 4 with a tissue expression pattern similar to that of the reporter gene would regulate ANG transcription. In vitro assays indicated that HNF4 bound to the promoter elements and strongly activated the ANG transcription, but that chicken ovalbumin upstream promoter transcription factor (COUP-TF), a transcriptional repressor, dramatically repressed human ANG transcription through the promoter elements and the downstream enhancer core elements. Furthermore, COUP-TF dramatically decreased the human ANG transcription in the mouse liver by the Helios Gene Gun system in vivo. These results suggest that an interplay between HNF4 and COUP-TF could be important in hepatic human ANG transcription.

Angiotensins↗
PubMed1999

Molecular cloning and expression of human neurochondrin-1 and -2.

Human neurochondrins have been cloned from a brain cDNA library. The human neurochondrin-1 and -2 predict leucine-rich (15.8 and 15.9%) proteins of 729 and 712 amino acid residues, with molecular weights of 78.9 and 77.2 kDa, respectively. The deduced amino acid sequence indicates 98% identity among human, mouse and rat species. Northern analysis indicates that about 4 kb human neurochondrin mRNAs are abundant in the fetal and the adult brain.

Amino Acid Sequence↗
PubMed1999

Induction of hydroxyapatite resorptive activity in bone marrow cell populations resistant to bafilomycin A1 by a factor with restricted expression to bone and brain, neurochondrin.

Bone, one of the favored sites for tumor metastasis, is a dynamic organ undergoing formation and resorption. We found bone metastasis with osteolytic lesion in the bone marrow of the femur by injecting BW5147 T-lymphoma cells into the tail vein of AKR mice. To understand this bone destruction, we constructed a cDNA library from BW5147 with a cloning vector that allowed in vitro synthesis of mRNAs, and then identified a particular cDNA clone by adding the conditioned medium from Xenopus oocytes following injection of the mRNA synthesized in vitro to primary bone marrow heterogeneous cell populations on hydroxyapatite thin films. By means of this method, we isolated a factor with 16% leucine residues, termed neurochondrin, that induces hydroxyapatite resorptive activity in bone marrow cells resistant to bafilomycin A1, an inhibitor of macrophage- and osteoclast-mediated resorption. Expression of the gene was localized to chondrocyte, osteoblast, and osteocyte in the bone and to the hippocampus and Purkinje cell layer of cerebellum in the brain. This may provide insights into the molecular mechanisms underlying bone resorption with potential implications for the activation of cells other than macrophages and osteoclasts in bone marrow cells.

Amino Acid Sequence↗
PubMed1999

Chronological change of distribution in nitric oxide and peptidergic neurons after rat small intestinal transplantation.

BACKGROUND/PURPOSE: Nitric oxide (NO) has been considered one of the putative neurotransmitters of nonadrenergic, noncholinergic inhibitory neurons. To examine the effect of transplantation on NO neurons in the intestine, the distribution of NO neurons was examined and compared with that of peptide-containing neurons. METHODS: A jejunal graft measuring about 20 cm was harvested from a Lewis rat, syngeneically transplanted as a Thiry-Vella loop, and later was replaced to the recipient small bowel 20 days after transplantation. Tissue specimens of the grafts were taken on days 1, 3, 6, 10, and 20, and 1 year after transplantation (n = 5 each). The distribution of the neurons was examined immunohistochemically, using antisera against protein gene product 9.5 (PGP 9.5, general neuronal marker), brain nitric oxide synthase (bNOS), vasoactive intestinal polypeptide (VIP), and substance P. In addition, NADPH diaphorase staining also was performed to visualize NO neurons. RESULTS: In the PGP 9.5 immunoreactivities, no significant difference in the distribution was observed among the controls and on any day after transplantation. However, the NADPHd activities markedly decreased in muscle layers, especially in the deep muscular layer on day 1 and 3, but quickly recovered by day 6. The distribution of bNOS immunoreactivities was almost same as that of NADPHd staining. The VIP and substance P immunoreactivities also decreased on day 1, and thereafter gradually recovered, and then became normal on day 20. CONCLUSIONS: Both the NO and peptidergic neurons markedly decreased just after transplantation, and the NO neurons recovered faster than the peptidergic neurons. These findings suggested that NO neurons might play an important role in the adaptation process of the graft in the early period after transplantation.

Animals↗
PubMed1999

Involvement of the histaminergic system in leptin-induced suppression of food intake.

The ob gene product leptin is secreted from white adipose tissue, and may regulate food intake by acting on the hypothalamus in the central nervous system. But the mechanism of this effect is still unclear. The central histaminergic system has been suggested to participate in the control of various physiological functions, particularly in feeding behavior, as it mediates anorectic signals like leptin. Thus, we hypothesized that the central histaminergic system is a target for leptin in its control of feeding. To prove this, we first examined the effect of i.p. administration of alpha-fluoromethylhistidine (FMH), a specific and irreversible inhibitor of histidine decarboxylase, on leptin-induced suppression of food intake in normal C57BL strain mice. Leptin treatment (1.3 mg/kg, i.p.) significantly reduced food intake by 60% of that of control at 6 h and by 84% at 24 h compared with control. When mice were injected with FMH (100 mg/kg, i.p.) before being given leptin, leptin-induced suppression of food intake was abolished and there was no significant difference compared with that of control. Additionally, we further examined the effects of leptin on food intake in mutant mice lacking histamine H, receptors (H1R-KO mice). Leptin injection significantly reduced food intake by 56% of that of control at 6 h and by 79% at 24 h in wild-type mice (WT mice), but not in H1R-KO mice. This finding suggests that leptin affects the feeding behavior through activation of the central histaminergic system via histamine H1 receptors.

Animals↗
PubMed1999

Histamine H1 receptor binding capacities in the amygdalas of the amygdaloid kindled rat.

The histamine H1 receptor binding capacity of the amygdalas of amygdaloid kindled rats was studied. In the kindled nonstimulated amygdala, significant decreases in K(D) and B(max) values compared with those of control amygdala were found 1 week after the last kindled seizure. One month after the last kindled seizure, the decreased K(D) value was sustained in the kindled nonstimulated amygdala. This decreased Bmax value 1 week after the last kindled seizure in nonstimulated amygdala may partly and transiently contribute to kindled seizure susceptibility. The decreased K(D) value in nonstimulated amygdala observed until 1 month after the last kindled seizure indicates the long-lasting increment of binding affinity of the pyrilamine binding site of the histamine H1 receptor in the steady state of kindled seizure susceptibility.

Amygdala↗
PubMed1999

[The role of positron emission tomography in neuropharmacology in the living human brain and drug development].

Neuroimaging is a powerful and innovative tool for studying the pathology of psychiatric and neurological diseases and, more recently, for studying the drugs used in their treatment. Technological advances in imaging have made it possible to noninvasively extract information from the human brain regarding a drug's mechanism and site of action. Until now, our understanding of human brain pharmacology has depended primarily on indirect assessments or models derived from animal studies. However, the advent of multiple techniques for human brain imaging allows researchers to focus directly on human pharmacology and brain function. In this review article, our PET studies on the histaminergic neuron system were presented as an example. We have developed and used the PET techniques for 10 years in order to examine the H1 receptors in the living human brain. This review outlines available PET techniques and examines how these various methods have already been applied to the drug development process and neuropharmacology in the living human brain.

Brain↗
PubMed1999

New findings in pharmacological effects induced by antihistamines: from PET studies to knock-out mice.

Antihistamines are efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamines is of central importance because of their widespread use in current medical practice. To better understand the pharmacological effects of antihistamines on the central nervous system (CNS), we used two kinds of new methods, positron emission tomography (PET) and gene targeting regarding on histamine H1 receptors. The histamine H1 receptor occupancy was examined in young male volunteers with[11C]-doxepin (a potent H1 antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The mutant mice lacking H1 receptors were used in the behavioural and neurochemical experiments to re-evaluate the role of H1 receptors. The H1-receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. The behavioural studies of the H1-receptor knock-out mice confirmed the role of H1 receptors in arousal, the sleep-wake cycle, locomotion, nociception and aggressive behaviour. The pharmacological effects induced by H1 antagonism were re-evaluated by the PET and gene-targetting. Although any serious effects could not be observed in mice by the destruction of the H1-receptor gene, the cognitive performance was impaired in humans after taking first generation antihistamines in recommended doses.

Animals↗
PubMed1998

Depletion of brain histamine induced by alpha-fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels.

We examined the effects of repeated administration of (S)-alpha-fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase (HDC), on radial maze performance and brain contents of histamine and amino acids in rats. By daily subcutaneous (s.c.) administration of FMH (100 mg/kg), rats showed significant enhancement of a radial maze performance without changes in locomotion. Six days after FMH treatment, the histamine levels both in the cerebral cortex and diencephalon decreased significantly. However, the glutamate and glycine levels significantly increased in the cerebral cortex and hippocampus. These results suggest that FMH enhances the acquisition phase of radial maze study with the increases in glutamate and glycine levels in the cerebral cortex and hippocampus of rats.

Amino Acids↗
PubMed1998

Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization.

With gene targeting, one can practically knock out a gene in vivo and create a mutant organism that completely lacks the gene product. The mutant mice lacking histamine H1 receptors was generated by the method of gene targeting. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen. The mutant mice showed impaired locomotor activity and exploratory behavior in an open field and activity wheel. Behaviors of the mutant mice were examined with several other tasks such as passive avoidance test, resident-intruder aggression test and formalin test to clarify the role for the H1 receptors in behaviors. Behavioral changes observed in the mutant mice are almost compatible with those obtained by the classical pharmacological tools. In correlation to the behavioral changes in the mutant mice, 5-hydroxytryptamine release was significantly increased in the brains of mutant mice.

Animals↗