Biomedical subjects

Hiroyuki Ohba

Publications and source records attributed to Hiroyuki Ohba.

9 recordsLinked to original sources

PubMed2006

Neuroprotection by a central nervous system-type prostacyclin receptor ligand demonstrated in monkeys subjected to middle cerebral artery occlusion and reperfusion: a positron emission tomography study.

BACKGROUND AND PURPOSE: Recently, we found that a novel subtype of prostacyclin (PGI(2)) receptor clearly distinct from the peripheral subtype in terms of ligand specificity is expressed in the central nervous system (CNS). (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) was synthesized and demonstrated to be a specific ligand for this CNS-type PGI(2) receptor. Previously, we demonstrated 15R-TIC to be neuroprotective in vivo during transient forebrain ischemia in gerbils and permanent middle cerebral artery occlusion (MCAO) in rats. Furthermore, this compound was shown to exert an anti-apoptotic effect on primary cultured hippocampal neurons, indicating its neuroprotective effect against ischemic insults occurs via direct action on CNS-type PGI(2) receptor. METHODS: Local cerebral hemodynamics and oxygen metabolism were measured simultaneously by using positron emission tomography with the (15)O steady-state method, before and up to 18 hours after 3-hour transient MCAO reperfusion in cynomolgus monkeys. Methyl ester of 15R-TIC (50 microg/kg, n=4) or its vehicle (10% Intralipos, n=4) was injected intravenously within 5 minutes after onset of MCAO and continuously infused for 5 hours (50 microg/kg per hour). RESULTS: Neuropathology showed that 15R-TIC significantly reduced cortical damage after 3-hour MCAO. Positron emission tomography results showed 15R-TIC significantly reduced the volume of "infarct" region of interest and attenuated the decrease in cerebral metabolic rate of oxygen and oxygen extraction fraction, and these protective effects were not attributable to improvement of cerebral circulation. CONCLUSIONS: These results suggest that 15R-TIC has a potent neuroprotective effect against focal cerebral ischemia in a monkey MCAO via its direct action on CNS-type PGI(2) receptors.

Animals↗

PubMed2005

Regulation of homologous integration in yeast by the DNA repair proteins Ku70 and RecQ.

The product of the BLM gene, which is mutated in Bloom syndrome in humans, and the Saccharomyces cerevisiae protein Sgs1 are both homologous to the Escherichia coli DNA helicase RecQ, and have been shown to be involved in the regulation of homologous recombination. Mutations in these genes result in genome instability because they increase the incidence of deletions and translocations. We present evidence for a genetic interaction between SGS1 and YKU70, which encodes the S. cerevisiae homologue of the human DNA helicase Ku70. In a yku70 mutant background, sgs1 mutations increased sensitivity to DNA breakage induced either by treatment with camptothecin or by the expression of the restriction enzyme EcoRI. The yku70 mutation caused a fourfold increase in the rate of double-strand break (DSB)-induced target integration as that seen in the sgs1 mutant. The combination of yku70 and sgs1 mutations additively increased the rate of the targeted integration, and this effect was completely suppressed by deletion of RAD51. Interestingly, an extra copy of YKU70 partially suppressed the increase in targeted integration seen in the sgs1 single mutant. These results suggest that Yku70 modulates the repair of DSBs associated with homologous recombination in a different way from Sgs1, and that the inactivation of RecQ and Ku70 homologues may enhance the frequency of gene targeting in higher eukaryotes.

Camptothecin↗

PubMed2004

Sox21 is a repressor of neuronal differentiation and is antagonized by YB-1.

Sox21, a high-mobility group box transcription factor, is expressed throughout the immature neural stem/progenitor population in ventricular zone but not in the cortical plate in embryonic mouse brain and its expression is restricted to the subventricular zone in the adult brain. In undifferentiated PC12 cells, endogenous Sox21 expression is detected but its expression ceases during the nerve growth factor (NGF)-induced neuronal differentiation. Overexpression of Sox21 results in a substantial repression of NGF-induced neurite outgrowth in PC12 cells. Further, we biochemically identified a Sox21-associating protein, Y-box binding protein 1 which not only binds to Sox21 but also partially restores NGF-induced neurite outgrowth of PC12 cells inhibited by Sox21. These results suggest that Sox21 is a repressor of neuronal differentiation in the developing nervous system.

Animals↗

PubMed2004

Non-stationary convolution subtraction scatter correction with a dual-exponential scatter kernel for the Hamamatsu SHR-7700 animal PET scanner.

A spatially variant convolution subtraction scatter correction was developed for a Hamamatsu SHR-7700 animal PET scanner. This scanner, with retractable septa and a gantry that can be tilted 90 degrees, was designed for studies of conscious monkeys. The implemented dual-exponential scatter kernel takes into account both radiation scattered inside the object and radiation scattered in gantry and detectors. This is necessary because of the relatively large contribution of gantry and detector scatter in this scanner. The correction is used for scatter correction of emission as well as transmission data. Transmission scatter correction using the dual-exponential kernel leads to a measured attenuation coefficient of 0.096 cm(-1) in water, compared to 0.089 cm(-1) without scatter correction. Scatter correction on both emission and transmission data resulted in a residual correction error of 2.1% in water, as well as improved image contrast and hot spot quantification.

Animals↗

PubMed2004

Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: Functional imaging of the conscious monkey brain using animal PET in combination with microdialysis.

This study demonstrated the effects of acute acetylcholinesterase (AChE) inhibition by donepezil (Aricept) on the cerebral cholinergic neuronal system in the brains of young (5.2 +/- 1.1 years old) and aged (20.3 +/- 2.6 years old) monkeys (Macaca mulatta) in the conscious state. Donepezil at doses of 50 and 250 microg/kg suppressed AChE activity, analyzed by metabolic rate (k(3)) of N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), in all cortical regions in a dose-dependent manner in both age groups. However, the suppression degree was more marked in young than in aged monkeys. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex of young animals as measured by microdialysis. Binding of (+)N-[(11)C]propyl-3-piperidyl benzilate ([(11)C](+)3-PPB) to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition. These results demonstrate that the PET imaging technique with specific labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful method to clarify the mechanism of drugs in the living brains of experimental animals.

Aging↗

PubMed2004

Potential of [(18)F]beta-CFT-FE (2beta-carbomethoxy-3beta-(4-fluorophenyl)-8-(2-[(18)F]fluoroethyl)nortropane) as a dopamine transporter ligand: A PET study in the conscious monkey brain.

A dopamine transporter (DAT) ligand 2beta-carbomethoxy-3beta-(4-fluoro-phenyl)-8-(2-[(18)F]fluoroethyl)nortropane ([(18)F]beta-CFT-FE) was synthesized and evaluated in comparison with [(11)C]beta-CFT in monkey brain using animal positron emission tomography (PET). [(18)F]beta-CFT-FE and [(11)C]beta-CFT were injected intravenously to conscious monkeys for a 91-min PET scan with arterial blood sampling for metabolite analysis. In the conscious state, [(18)F]beta-CFT-FE provided a peak about 20 min after the injection and declined thereafter in the striatum of monkey brain, while [(11)C]beta-CFT continuously increased with time up to 91 min after injection. Metabolite analysis revealed that [(18)F]beta-CFT-FE was more rapidly metabolized in plasma than [(11)C]beta-CFT. The striatal binding of both ligands was dose-dependently displaced by preadministration of a specific DAT inhibitor, GBR12909, at doses of 0.5 and 5 mg/kg; however, the displacement degree of [(11)C]beta-CFT-FE was higher than that of [(18)F]beta-CFT. The effects of the anesthetics, ketamine and isoflurane, on binding were more prominent in [(11)C]beta-CFT than [(18)F]beta-CFT-FE. Specificity and affinity of beta-CFT-FE to DAT were evaluated in an in vitro assay using cloned human DAT, serotonin transporter, and norepinephrine transporter in comparison with other conventional DAT ligands, showing that beta-CFT-FE had lower affinity and higher specificity to DAT than beta-CFT and beta-CIT. These results suggested that [(18)F]beta-CFT-FE could be a potential imaging agent for DAT, providing excellent selectivity and tracer kinetics for quantitative PET imaging.

Anesthetics↗

PubMed2003

An increase of sigma receptors in the aged monkey brain.

We evaluated in vivo the effect of aging on the sigma(1) receptors in the monkey brain by the quantitative analysis of the binding of [11C]SA4503 to sigma(1) receptors with positron emission tomography. Based on a three-compartment model, the influx rate constant K(1) of [11C]SA4503 from plasma to brain across the blood-brain barrier in all 10 regions investigated became smaller in the aged monkeys (20-28 years old, n=5) than in the young adult monkeys (4-8 years old, n=5), but the reduction was not significant due to the individual differences. On the other hand, the binding potential, which was calculated as the ratio of the association rate constant k(3) to the dissociation rate constant k(4) for the binding of [11C]SA4503 to sigma(1) receptors in the brain, significantly increased in nine of the brain regions of the aged monkeys to the 160-210% levels of the young monkeys. We concluded that the sigma(1) receptor binding sites increased in the aging process of the monkey brain.

Aging↗

PubMed2002

Age differences in phosphodiesterase type-IV and its functional response to dopamine D1 receptor modulation in the living brain: a PET study in conscious monkeys.

The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2002

Age-related changes in cerebral blood flow and glucose metabolism in conscious rhesus monkeys.

Regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc) were measured in aged and young monkeys by positron emission tomography (PET). Our purpose was to examine whether the age-related changes observed in the human brain also occur in the monkey brain. Studies were performed on six aged and six young-adult male rhesus monkeys (Macaca mulatta). rCBF and the rCMRglc were serially measured using PET with [(15)O]H(2)O and 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG), respectively. In order to minimize the bias induced by anesthesia, the PET emission scans were performed in the conscious state. ROIs were taken for the cerebellum, hippocampus with adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex and cingulate. Group differences and correlations between rCBF and rCMRglc in each group were determined. Aged monkeys had significantly lower rCBF in the cerebellum, hippocampus with the adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex, and significantly lower rCMRglc in the cerebellum, hippocampus with the adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex and cingulate, compared to young monkeys. There were significant correlations between rCBF and rCMRglc in both the aged and young groups, but no significant difference was found in relationship between the two groups. Age-related changes were observed not only in rCMRglc, but also in rCBF in aged monkeys, while the coupling between rCBF and rCMRglc was maintained even in aged monkeys. These results demonstrated the potential of aged monkeys to serve as an aged human model using PET.

Aging↗