Hiroshi Ohtsu - Academia.edu (original) (raw)

Papers by Hiroshi Ohtsu

Brain Res, 2003

The role of brain histamine on seizure development of pentylenetetrazol (PTZ)-induced kindling wa... more The role of brain histamine on seizure development of pentylenetetrazol (PTZ)-induced kindling was examined in H1-receptor gene knockout (H1KO), histidine decarboxylase-deficient (HDC−/−) and mast cell-deficient (W/Wv) mice. All H1KO, HDC−/− and W/Wv mice had accelerated seizure development of PTZ-induced kindling when compared to their respective wild-type mice. The daily PTZ-kindling increased histamine content in the cortex and diencephalon of H1KO mice, whereas the histamine content in the diencephalon of W/Wv mice was decreased. The present study indicates that histamine plays a suppressive role in seizure development through H1-receptors.

Cell Tissue Res, 1994

The first component of complement C1s has been shown to degrade type I and type II collagens (Yam... more The first component of complement C1s has been shown to degrade type I and type II collagens (Yamaguchi et al. 1990), the latter of which is a major constituent of the cartilage matrix. In order to understand the physiological roles of C1s in cartilage resorption, the expression of C1s was examined by immunohistochemistry in the primary ossification center where the matrix is removed and replaced by bone marrow. Hypertrophic chondrocytes, endothelium and hematogenous elements in the capillary buds were intensely stained by a monoclonal antibody against C1s. Matrix metalloproteinase 9 (MMP-9, 92kDa gelatinase/type IV collagenase) was also immunolocalized in hypertrophic chondrocytes, mesenchymal cells in the primitive bone marrow and the cartilage matrix adjacent to the marrow. In addition, C1s was found to activate the zymogen of MMP-9. These observations suggest that C1s and MMP-9 coordinately participate in matrix degradation in cartilage.

PloS one, 2015

Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, ... more Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakef...

The hypothesis that histaminergic neurons are involved in brain arousal is supported by many stud... more The hypothesis that histaminergic neurons are involved in brain arousal is supported by many studies. However, the effects of the selective long-term abolition of histaminergic neurons on the sleep-wake cycle, indispensable in determining their func- tions, remain unknown. We have compared brain histamine (HA)-immunoreactivity and the cortical-EEG and sleep-wake cycle under baseline conditions or after behavioral or pharma- cological stimuli

Neuroscience letters, 2015

Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, bu... more Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifest by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation they showed increased grooming. Heterozygotes exhibited normal freezing and intermediate g...

Experimental dermatology, 2015

Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH)... more Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-β1 in this model. Recombinant TGF-β1 or anti-TGF-β1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to de...

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2014

Tic disorders produce substantial morbidity, but their pathophysiology remains poorly understood.... more Tic disorders produce substantial morbidity, but their pathophysiology remains poorly understood. Convergent evidence suggests that dysregulation of the cortico-basal ganglia circuitry is central to the pathogenesis of tics. Tourette syndrome (TS), the most severe end of the continuum of tic disorders, is substantially genetic, but causative mutations have been elusive. We recently described a mouse model, the histidine decarboxylase (Hdc) knockout mouse, that recapitulates a rare, highly penetrant mutation found in a single family; these mice exhibit TS-like phenomenology. These animals have a global deficit in brain histamine and a consequent dysregulation of DA in the basal ganglia. Histamine modulation of DA effects is increasingly appreciated, but the mechanisms underlying this modulation remain unclear; the consequences of modest DA elevation in the context of profound HA deficiency are difficult to predict, but understanding them in the Hdc knockout mouse may provide generali...

Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia, Jan 20, 2015

Preoperative radiological predictions of pathological invasiveness must be objective and reproduc... more Preoperative radiological predictions of pathological invasiveness must be objective and reproducible in addition to being accurate when considering limited surgery for early lung cancer. Two cohorts were used for the analysis. Two independent observers traced lesion edges and measured areas and proportions of solid component on tumor images with the largest diameter by high resolution computed tomography images and "Image J" software. The value of the intraclass correlation was 0.997 (95% confidence interval [CI], 0.996-0.998) for the area of solid component and 0.979 (95%CI, 0.958-0.986) for the proportion of solid component, suggesting such parameters were reliable in terms of reproducibility. Az value was 0.898 (95%CI, 0.842-0.953) for the area of solid component and 0.882 (95%CI, 0.816-0.949) for the proportion of solid component, demonstrating 2 parameters were both highly predictive of non-invasive adenocarcinoma. The optimal prediction of non-invasive adenocarcinom...

Japanese Journal of Radiology, 2011

To retrospectively evaluate criteria for differentiating biliary tract changes in autoimmune panc... more To retrospectively evaluate criteria for differentiating biliary tract changes in autoimmune pancreatitis (AIP-BTC) from extrahepatic cholangiocarcinoma (ECCA) based on CT findings and to determine predictors for differentiation between the two disorders. CT findings of 22 patients with AIP-BTC and 45 patients with ECCA, both with positive CT findings in the biliary system, were retrospectively assessed. The images were assessed for presence of biliary obstruction, diameter of the maximally dilated biliary duct, maximum thickness of the involved duct, presence of masses inside or around the involved ducts, lengths of the biliary lesions, concentricity of wall thickening, multifocality of the lesion, and degree of lesion enhancement. Compared with AIP-BTC, ECCA was significantly more frequently associated with biliary obstruction (p = 0.0037), shorter lengths of the biliary lesions (p = 0.0036), and masses (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). No significant differences were found for other items. Presence of obstructive dilatation of the bile ducts and intraluminal or peri-ductal masses and length of the thickened wall may help differentiate between AIP-BTC and ECCA.

Radiological physics and technology, 2015

Our aim was to show whether sensitivity for detecting volume changes in regional gray matter in d... more Our aim was to show whether sensitivity for detecting volume changes in regional gray matter in default mode network (DMN) at converted [from mild cognitive impairment to Alzheimer's disease (from MCI to AD)] phase was improved by use of a standardized volume with global gray-matter volume. T1-weighted MR images (T1WI) of seven normal subjects and seven converted (from MCI to AD) patients were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Gray-matter images segmented with Statistical Parametric Mapping 5 were measured by the atlas-based method. We focused on five nodes of the DMN. For each phase, region of interest (ROI) volumes in the five nodes were standardized by two methods: (1) the ratio to the screening phase (S_volume) and (2) the ratio to the screening phase after both volumes were standardized by the global gray-matter volume (S_N_volume). Significant group differences between longitudinal gray-matter volume change of the converted ...

Neuron, Jan 8, 2014

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalit... more Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of path...

Psychopharmacology, 2006

Rationale and objectives Lesion studies have shown that the tuberomammillary nucleus (TM) exerts ... more Rationale and objectives Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in that reward inhibitory function, we assessed the stimulant and rewarding effects of cocaine in knockout mice lacking histidine decarboxylase (HDC KO mice), the histamine-synthesizing enzyme. If histamine actually plays an inhibitory role in reward, then it would be expected that mice lacking histamine would be more sensitive to the behavioral effects of cocaine. Materials and methods The first experiment characterized spontaneous locomotion and cocaine-induced hyperactivity (0, 8, and 16 mg/kg, i.p.) in wild-type and HDC KO mice. The rewarding effects of cocaine were investigated in a second experiment with the place-conditioning technique. Results The first experiment demonstrated that histidine decarboxylase mice showed reduced exploratory behaviors but normal habituation to the test chambers. After habituation to the test chambers, HDC KO mice were slightly, but significantly, less stimulated by cocaine than control mice. This finding was replicated in the second experiment, when cocaine-induced activity was monitored with the placeconditioning apparatus. Furthermore, a significant place preference was present in both genotypes for 8 and 16 mg/kg cocaine, but not for 2 and 4 mg/kg. Conclusions Our data confirm previous results demonstrating that HDC KO mice show reduced exploratory behaviors. However, contrary to the hypothesis that histamine plays an inhibitory role in reward, histamine-deficient mice were not more responsive to the psychostimulant effects of cocaine.

PLoS ONE, 2012

Background: Meandering main pancreatic duct (MMPD), which comprises loop type and reverse-Z type ... more Background: Meandering main pancreatic duct (MMPD), which comprises loop type and reverse-Z type main pancreatic duct (MPD), has long been discussed its relation to pancreatitis. However, no previous study has investigated its clinical significance. We aimed to determine the non-biased prevalence and the effect of MMPD on idiopathic pancreatitis using non-invasive magnetic resonance (MR) technique.

Pharmacology Biochemistry and Behavior, 2006

Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding... more Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H(3) receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20 mg/kg thioperamide and saline or 8 mg/kg cocaine, 10 min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8 mg/kg, i.p.) given 2 and 14 days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20 mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32 mg/kg, s.c.), the drugs being given 10 min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14 days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H(3) receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies.

Nucleic Acids Research, 2000

To investigate the regulation of mouse L-histidine decarboxylase (HDC) gene expression, we isolat... more To investigate the regulation of mouse L-histidine decarboxylase (HDC) gene expression, we isolated genomic DNA clones encoding HDC. Structural analysis revealed that the mouse HDC gene was composed of 12 exons, spanning ∼24 kb. Northern blotting analysis indicated that, among the cell lines examined, a high level of HDC gene expression was restricted to mature mast cell lines and an erythroblastic cell line. The gene was induced strongly in the mouse immature mast cell line P815 after incubation in the peritoneal cavity of BDF1 mice. We observed that the promoter region was demethylated in the HDC-expressing cell lines and in induced P815 cells. Interestingly, forced demethylation by 5-azacytidine (5-azaC) treatment induced high expression of HDC mRNA in P815 cells. The activity of a mouse HDC promoter-reporter construct stably transfected in P815 cells was repressed by in vitro patch-methylation. This low promoter activity of the patch-methylated reporter construct was restored after 5-azaC treatment, which demethylated the patch-methylated promoter. These results indicate that DNA methylation state of the promoter region controls HDC gene expression.

Neuroscience Letters, 2011

The neurotransmitter histamine is produced in the tuberomamillary nucleus of the posterior hypoth... more The neurotransmitter histamine is produced in the tuberomamillary nucleus of the posterior hypothalamus; these neurons project broadly throughout central nervous system. Histidine decarboxylase (HDC) synthesizes histamine from histidine; in the brain, its mRNA is expressed exclusively in the posterior hypothalamus. Histamine receptors are expressed throughout the forebrain, including in cortex, hippocampus, and basal ganglia, suggesting functional innervation of these structures. We investigated the distribution of HDC protein in dissected tissue from mouse and rat, anticipating that it would reflect the density of hypothalamic histaminergic axonal projections and thus qualitatively parallel the known distribution of histamine receptors. HDC protein was found at high levels in hypothalamus, as anticipated. Surprisingly, it was found at comparably high levels in mouse striatum. HDC protein was 10-fold lower in cortex, hippocampus, and cerebellum. Specificity of HDC detection by Western blot was confirmed using HDC knockout mice. Similar high levels of HDC protein were found in dissected striatum from rat. Striatum does not, however, contain comparably elevated of histamine, relative to other forebrain structures; we confirmed this fact using HPLC. This discrepancy between HDC protein and histamine levels in the striatum suggests that histamine metabolism and neurotransmission in basal ganglia may have unique characteristics, the details of which remain to be elucidated.

Neuroscience Letters, 2007

In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type ... more In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that alpha-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine-histidine-histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.

Nature Communications, 2014

The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remain... more The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinforces autophagy. The neuroprotection by H3R antagonism is reversed by 3-methyladenine and siRNA for Atg7, and is diminished in Atg5 À / À mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3R CT414-436 , which blocks CLIC4 binding with H3Rs, or siRNA for CLIC4, further increases I/R-induced autophagy and protects against I/R injury. Therefore, H3R promotes I/R injury while its antagonism protects against ischaemic injury via histamine-independent mechanisms that involve suppressing H3R/CLIC4 binding-activated autophagy, suggesting that H3R inhibition is a therapeutic target for cerebral ischaemia.

Muscle & Nerve, 2013

We investigated the long-term effects of leuprorelin on leg-muscle strength in spinal and bulbar ... more We investigated the long-term effects of leuprorelin on leg-muscle strength in spinal and bulbar muscular atrophy (SBMA). We hypothesized that testosterone suppression by leuprorelin would prevent the progression of muscle weakness. In a prospective, long duration, open trial, 16 SBMA patients underwent medical castration with leuprorelin for 3.5 years. Chlormadinone was coadministered initially to prevent a testosterone surge. The strength of knee extension and flexion were quantitated using a torque machine. Our hypothesis was rejected. The leg strength measures decreased significantly with the mean reduction of 22.3-27.8%. In a post hoc analysis, the leg strength of 4 patients with higher pretreatment baseline total testosterone levels and short disease duration of 1-6 years were stronger at baseline and decreased by only 12.3-15.7% after treatment. Leuprorelin was not effective in this small long-term treatment trial in SBMA. The possibility that earlier treatment might be beneficial may deserve further study.