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Biomedical subjects

S Nagao

Publications and source records attributed to S Nagao.

At least 19 recordsLinked to original sources
PubMed1998

Suppression of hyperemia after brain ischemia by L-threo-3,4-dihydroxyphenylserine.

Although several studies have shown that L-threo3,4-dihydroxyphenylserine (DOPS) may provide a neuroprotective effect against ischemic brain damage, its protective mechanism is not fully understood. Glutamate release and hippocampal blood flow in ischemia with administration of DOPS were investigated to elucidate the neuroprotective mechanism of DOPS. Pre- (but not post-) ischemic administration of DOPS rescued 73% of hippocampal CA1 neurons (p < 0.001, compared with ischemia only) 1 week after transient global ischemia in gerbils. While glutamate release induced by ischemia was not affected, the increase of hippocampal blood flow during reperfusion was significantly suppressed by DOPS. These results demonstrate that DOPS may prevent reperfusion injury by suppression of hyperemia after ischemia, resulting in neuroprotection.

Animals↗
PubMed1998

Dynamic characteristics and adaptability of mouse vestibulo-ocular and optokinetic response eye movements and the role of the flocculo-olivary system revealed by chemical lesions.

The dynamic characteristics of reflex eye movements were measured in two strains of chronically prepared mice by using an infrared television camera system. The horizontal vestibulo-ocular reflex (HVOR) and horizontal optokinetic response (HOKR) were induced by sinusoidal oscillations of a turntable, in darkness, by 10 degrees (peak to peak) at 0.11-0.50 Hz and of a checked-pattern screen, in light, by 5-20 degreesat 0.11-0.17 Hz, respectively. The gains and phases of the HVOR and HOKR of the C57BL/6 mice were nearly equivalent to those of rabbits and rats, whereas the 129/Sv mice exhibited very low gains in the HVOR and moderate phase lags in the HOKR, suggesting an inherent sensory-motor anomaly. Adaptability of the HOKR was examined in C57BL/6 mice by sustained screen oscillation. When the screen was oscillated by 10 degrees at 0.17 Hz, which induced sufficient retinal slips, the gain of the HOKR increased by 0.08 in 1 h on average, whereas the stimuli that induced relatively small or no retinal slips affected the gain very little. Lesions of the flocculi induced by local applications of 0. 1% ibotenic acid and lesions of the inferior olivary nuclei induced by i.p. injection of 3-acetylpyridine in C57BL/6 mice little affected the dynamic characteristics of the HVOR and HOKR, but abolished the adaptation of the HOKR. These results indicate that the olivo-floccular system plays an essential role in the adaptive control of the ocular reflex in mice, as suggested in other animal species. The data presented provide the basis for analyzing the reflex eye movements of genetically engineered mice.

Animals↗
PubMed1998

Central pressor effect of parathyroid hormone-related protein in conscious rats.

Although the parathyroid hormone-related protein gene is widely expressed in the central nervous system, the role of this protein in blood pressure is unknown. This article examines whether parathyroid hormone-related protein is involved in the central regulation of blood pressure. An intraventricularly injected solution of parathyroid hormone-related protein elicited a dose-dependent increase of mean arterial pressure accompanied by a decrease of heart rate in conscious Sprague-Dawley rats. An anti-parathyroid hormone-related protein monoclonal antibody, given in an intraventricularly injected solution, blocked the pressor effect of parathyroid hormone-related protein. Furthermore, this pressor effect of parathyroid hormone-related protein was also abolished after pretreatment by intravenous administration of either hexamethonium bromide or doxazosin mesylate. These results suggest that central parathyroid hormone-related protein is implicated in the regulation of blood pressure, and that this effect may be mediated through sympathetic activation.

Analysis of Variance↗
PubMed1998

Significance of multimodal cerebral monitoring under moderate therapeutic hypothermia for severe head injury.

The therapeutic significance of moderate hypothermia and cerebral monitorings was assessed in the 10 patients with severe head injury. Cooling was begun as soon as possible after admission, using water blankets under general anesthesia. Jugular venous or tympanic temperature of patients was maintained at 32 degrees C for 3 to 5 days, then rewarming at the rate of 1 degree C a day was started. The intracranial pressure was controllable less than 20 mmHg under hypothermia. Moderate hypothermia reduced the jugular venous lactate (33.5%) as well as the cerebral blood flow velocity at M1 portion of middle cerebral artery (CBFV-M1) measured by transcranial Doppler (7.2%), while increase of the jugular venous oxygen saturation (SjO2) (17.9%) was observed in a majority of the patients. Our results demonstrated that moderate therapeutic hypothermia significantly reduced cerebral circulation and metabolism. Measurement of SjO2 and CBFV-M1 seems to be useful for estimation of cerebral circulation and metabolism in therapeutic hypothermia.

Adolescent↗
PubMed1998

Hyperglycemia induces progressive changes in the cerebral microvasculature and blood-brain barrier transport during focal cerebral ischemia.

Hyperglycemia generally enhances cerebral ischemic injury. Most attention on a mechanism has focused on the adverse effect of increased lactate production (acidosis) leading to neuronal injury. The effects of hyperglycemia on another possible primary target, the cerebral microvasculature, is examined in this study. Focal cerebral ischemia was achieved by thread occlusion of the middle cerebral artery (MCA). Preischemic hyperglycemia was induced by intraperitoneal administration of 50% of D-glucose solution. In contrast to normoglycemic controls, glucose-injected rats showed a well demarcated pale infarct after 2 or 4 hours of ischemia reflecting a reduction in cerebral plasma volume (CPV) to 73 +/- 9 and 55 +/- 6% of contralateral by 2 and 4 hours respectively. Cerebral blood flow (CBF) measured by laser-Doppler flowmetry indicated that after the initial decline in CBF with MCA occlusion, hyperglycemia led to a further progressive reduction during ischemia. Blood-brain barrier transport measured by permeability surface area (PS) product for glutamine was reduced in both normoglycemic and hyperglycemic rats. However, the decline was greater in the hyperglycemic rats. Hyperglycemia induces progressive cerebrovascular changes and affects blood-brain barrier transport during focal cerebral ischemia. These changes may contribute to the adverse effects of hyperglycemia in stroke.

Animals↗
PubMed1998

Immunohistochemical study of clathrin in distal myopathy with rimmed vacuoles.

Clathrin-coated vesicles are involved in three receptor-mediated intracellular transport pathways: export from the Golgi apparatus, transfer of lysosomal enzymes from the Golgi apparatus to lysosomes, and endocytosis at the plasma membrane. Seeking evidence of transport abnormalities in distal myopathy with rimmed vacuoles (DMRV), we performed immunohistochemistry for clathrin in muscle biopsy specimens from patients with this disorder or other neuromuscular disorders, and also in control muscle samples resected in orthopedic procedures. While most myofibers from control muscle did not stain for clathrin, some fibers revealed finely granular sarcoplasmic staining. In specimens from patients with Duchenne and Becker muscular dystrophy, amyotrophic lateral sclerosis, peripheral neuropathy, and DMRV, numerous clathrin-positive granules were often scattered through the sarcoplasm and seen to a lesser extent in subsarcolemmal regions. Quantitative immunohistochemical assessment showed more reactivity for clathrin in DMRV than in controls and other diseased muscles, particularly in atrophic fibers and type 2 fibers. Not all strongly clathrin-positive muscle fibers contained rimmed vacuoles, although most fibers with vacuoles were clathrin positive. The result suggests that the lysosome system is activated and receptor-mediated intracellular transport pathways function appropriately in the muscles of DMRV patients.

Adolescent↗
PubMed1998

Effects of niravoline (RU 51599), a selective kappa-opioid receptor agonist on intracranial pressure in gradually expanding extradural mass lesion.

It has recently been reported that kappa-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and animals. We investigated the effect of niravoline (RU 51599), a selective kappa-opioid receptor agonist in the treatment of intracranial hypertension. Acute intracranial hypertension was induced in cats by continuous inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 3 h. At this point, inflation was discontinued and the balloon remained expanded for an additional hour after which it was deflated. In the post-deflation period, monitoring continued for 1 h. The control group (n = 8) received ringer's lactate solution only, while the treatment group (n = 8) received an intravenous (IV) injection of 1.0 mg/kg of niravoline, every hour at the beginning of balloon inflation, during balloon inflation, in post-inflation, and at deflation time (5 doses). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), blood gases, pupil size, serum electrolytes, and osmolality were measured in both groups. Brain water content was determined in a separate group of cats at the end of a 3-h extradural brain compression. Compared to the untreated group, the niravoline-treated group had a significantly lower ICP and higher CPP at the 2 and 3 h during balloon inflation, in post-inflation, and in post-deflation periods. Brain water content was significantly reduced in niravoline-treated animals. No significant change was observed in serum osmolality throughout the experiment. Our results indicate that the mechanism by which niravoline reduces ICP is partly via a reduction in brain water content. Also, the current findings suggest that in clinical situations in which ICP is elevated due to the pressure of an extradural mass, niravoline may effectively reduce ICP while maintaining adequate CPP until the mass is removed.

Animals↗
PubMed1998

Specific inhibition of apoptosis after cold-induced brain injury by moderate postinjury hypothermia.

OBJECTIVE: Apoptosis of neuronal cells plays a key role in many developmental and pathological processes of the central nervous system. Deoxyribonucleic acid (DNA) of cells undergoing apoptosis is cleaved by an endonuclease into oligonucleosoma-sized fragments. These fragments can be labeled using in situ terminal deoxynucleotidyl transferase so that the apoptotic cells can be visualized by in situ apoptotic staining. The model of cold-induced rat brain edema was used to further examine this hypothesis. The protective effect of hypothermia was also studied in this model of cold-induced brain injury. METHODS: Using a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate-biotin nick end labeling technique, the neuronal cells with DNA fragmentation in different regions of the brains of rats subjected to cold-induced brain injury were detected. The internucleosomal fragments of DNA in apoptotic cells were examined using agarose gel electrophoresis. The animals were randomly divided into three groups: 1) sham (n = 8); 2) cold-induced brain injury, killed at 12, 24, 48, 72, and 168 hours after cold lesion (n = 10 for each time point); 3) hypothermia, both mean temporalis and rectal temperatures were reduced by surface cooling to 32 degrees C (standard deviation, 0.1 degrees C) for 3, 6, and 12 hours (n = 10 for each time point) beginning 1 hour after cold-induced brain injury. RESULTS: The apoptotic cells were detectable for up to 72 hours after the initial brain injury and reached a peak at approximately 24 to 48 hours, with a mean peak value of 24.29 +/- 5.26, 15.37 +/- 4.10, 15.81 +/- 3.56, 13.94 +/- 2.48, 10.46 +/- 2.23, and 7.68 +/- 2.48% in the cortex, subcortex, white matter, CA1, CA3, and dentate gyrus, respectively, and had a significant increase, compared with the control value (mean +/- standard error, P < 0.01). Agarose gel electrophoresis of DNA extracted from cortex and hippocampus containing apoptotic cells revealed a "DNA ladder" at 180- to 200-base pair intervals. In animals subjected to the same brain injury that underwent 32 degrees C hypothermia, the numbers of apoptotic cells were reduced evidently and DNA fragmentation was inhibited. CONCLUSION: The data suggest that apoptosis occurs after cold-induced brain injury and that DNA fragmentation may be associated with apoptotic cell death. Moderate hypothermia shows specific effect on inhibition of apoptotic cell death and cellular DNA fragmentation after cold-induced brain injury in rats.

Animals↗
PubMed1998

Neurotoxicity of Clostridium perfringens epsilon-toxin for the rat hippocampus via the glutamatergic system.

The neurotoxicity of epsilon-toxin, one of the major lethal toxins produced by Clostridium perfringens type B, was studied by histological examination of the rat brain. When the toxin was injected intravenously at a lethal dose (100 ng/kg), neuronal damage was observed in many areas of the brain. Injection of the toxin at a sublethal dose (50 ng/kg) caused neuronal damage predominantly in the hippocampus: pyramidal cells in the hippocampus showed marked shrinkage and karyopyknosis, or so-called dark cells. The dark cells lost the immunoreactivity to microtubule-associated protein-2, a postsynaptic somal and dendric marker, while acetylcholinesterase-positive fibers were not affected. Timm's zinc staining revealed that zinc ions were depleted in the mossy layers of the CA3 subfield containing glutamate as a synaptic transmitter. The cerebral blood flow in the hippocampus was not altered significantly before or after administration of the toxin, as measured by laser-Doppler flowmetry, excluding the possibility that the observed histological change was due to a secondary effect of ischemia in the hippocampus. Prior injection of either a glutamate release inhibitor or a glutamate receptor antagonist protected the hippocampus from the neuronal damage caused by epsilon-toxin. These results suggest that epsilon-toxin acts on the glutamatergic system and evokes excessive release of glutamate, leading to neuronal damage.

Animals↗
PubMed1998

Proteasomes in distal myopathy with rimmed vacuoles.

In a previous report we suggested that muscle fibers in distal myopathy with rimmed vacuoles (DMRV) were degraded by both lysosomal proteolysis (cathepsins) and Ca2+-dependent, nonlysosomal proteolysis (calpain). Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, we examined the role of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in this myopathy. Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak. Quantitative analysis showed more reactivity for proteasomes in DMRV muscles and, to a lesser extent, in muscles from muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis patients. In DMRV, proteasomes often were located within or on the rim of rimmed vacuoles, and in the cytoplasm of atrophic fibers. Ubiquitin accumulation was marked within rimmed vacuoles and was seen less extensively in the cytoplasm of atrophic fibers. The latter proteins colocalized well. In other diseased muscles, proteasomes and ubiquitin showed a positive reaction in the atrophic or necrotic fibers. The results indicate increased proteasome and ubiquitin in these muscle fibers as well as in other diseased muscle fibers. We suggest that the ATP-ubiquitin-proteasome proteolytic pathway as well as the nonlysosomal calpain and the lysosomal proteolytic pathway may participate in the muscle fiber degradation in DMRV.

Adenosine Triphosphate↗
PubMed1998

Spinal cord hemangioblastoma presenting with subarachnoid hemorrhage.

A 41-year-old man presented with subarachnoid hemorrhage (SAH) caused by a cervical spinal cord hemangioblastoma. There were no features to distinguish the SAH from that due to an intracranial lesion. The diagnosis was established by cerebral angiography, computed tomography, and magnetic resonance imaging. The tumor was located in the right dorsolateral aspect of the cervical spinal cord. Hemilaminectomy was performed, and the tumor was completely removed. No postoperative neurological deficit was observed. The possibility of a spinal origin for SAH should be considered if no cranial origin can be detected.

Adult↗
PubMed1998

[Incidence of mutation and deletion in topoisomerase II mRNA of etoposide and m-AMSA resistant cell lines].

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to ETP or m-AMSA. Subsequently, a population of cells from each subline was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. The frequency and nature of mutations in topo II in the drug selected cell lines have been evaluated. In order to screen a large number of cell lines, an RNase protection assay was developed. Fragments covering the entire coding sequence of topo II was isolated after PCR amplification and subcloned in pGEM3Z vector. Using this approach, mismatches was observed in 13.6% of resistant cell lines (12% of resistant cell lines exposed to lower drug concentrations and 18.8% of resistant cell lines exposed to higher drug concentrations). Our findings suggest that mutations of topo II gene seem to be an important and frequent mechanism of resistance to topo II inhibitors.

Amsacrine↗
PubMed1998

[Vasopressin and blood-brain barrier].

Arginine vasopressin (AVP) has been known to exert antidiuretic action at the kidney and some neuroactive effects. In order to examine the neural effect of AVP, it is essential to clarify the mechanism of BBB transport from intraluminal side to brain. Recent basic experimental data show the most possible mechanism for the transport of peripheral AVP across the BBB is binding of V1 receptor of AVP at the capillary luminal membrane and consequently transports AVP to neuronal cell and changes in permeability of amino acid, ion and water at the BBB. An increase in peripheral AVP results in suppression of amino acid permeability and increases in transport of sodium, potassium ions and water. Our data indicate that intraventricular or venous administration of V1 receptor antagonist significantly reduces the permeabiltiy of water, electrolites and plasma from capillary to brain in experimental brain edema. V1 receptor antagonist may become new tool for the treatment of brain edema.

Animals↗
PubMed1997

Acute effects of tetrahydrobiopterin on the dynamic characteristics and adaptability of of vestibulo-ocular reflex in normal and flocculus lesioned rabbits.

The acute effects of (6R)-5,6,7,8-tetrahydro-L-biopterin (R-THBP) on the dynamic characteristics of horizontal vestibulo-ocular reflex (HVOR) were examined in chronically prepared alert pigmented rabbits. The HVOR gain was measured by 10 degrees-0.1 Hz sinusoidal oscillation of the turntable in darkness. In control rabbits, intramuscular injection of R-THBP (10 mg/kg) induced an increase of HVOR gain by 0.1-0.2, which lasted for 1-3 h. Sustained 10 degrees-0.1 Hz sinusoidal oscillation of the turntable and screen in the reversed direction induced an adaptive increase of HVOR gain by 0.2 in 3 h, which was not affected by applications of R-THBP. In flocculus lesioned rabbits, the HVOR gain reduced by 23%, and applications of R-THBP no longer induced a HVOR gain increase. These experimental observations suggested that the R-THBP affected on the HVOR dynamics within the cerebellar flocculus or its related neural areas.

Animals↗
PubMed1997

Differences of the primate flocculus and ventral paraflocculus in the mossy and climbing fiber input organization.

Potential sources of cerebellar cortical afferent fibers were identified in the vestibular ganglion, medulla oblongata, pons, and cerebellar nucleus of seven anesthetized Macaca fuscata after local injections of wheat germ agglutinin-conjugated horseradish peroxidase or Fast Blue into the flocculus (FL) or ventral paraflocculus (VP). There were differences in the sources of mossy fibers to the FL and VP. Labeled neurons, after injections into the FL, were located mainly in the ipsilateral vestibular ganglion, bilaterally in the vestibular and prepositus hypoglossal nuclei, nucleus reticularis tegmenti pontis, and the central part of the mesencephalic reticular formation including the raphe nuclei. Labeled neurons were rarely seen in the pontine nuclei after injections into the FL. By contrast, after injections into the VP, numerous labeled neurons were located in the contralateral pontine nuclei, but relatively few in the vestibular nuclei bilaterally. Sources of climbing fibers to the FL and VP were completely contralateral to the injection side. After the injection into the FL and VP, labeled neurons were located in the dorsal cap, ventrolateral outgrowth, and ventral part of the medial accessory olivary nucleus. The projections from these three olivary areas were generally consistent with a zonal pattern of terminations in the FL and VP. The present results are consistent with a hypothesis that the FL is mainly involved in the control of vestibulo-ocular reflex and that the VP is mainly involved in the control of smooth pursuit eye movements.

Afferent Pathways↗
PubMed1997

Prooxidant activity of caffeic acid, dietary non-flavonoid phenolic acid, on Cu2+-induced low density lipoprotein oxidation.

The effects of caffeic acid (CA) and chlorogenic acid (CHA), an ester of caffeic acid with quinic acid, were studied on isolated human Cu2+-induced low density lipoprotein (LDL) oxidation in initiation and propagation phases by measuring the formation of thiobarbituric acid reactive substances (TBARS), detecting conjugated diene and investigating the electrophoretic mobility change of LDL. Both non-flavonoids exhibited prooxidant and antioxidant activities depending on the LDL oxidation phases. CA and CHA (0.1 microM or more) enhanced LDL oxidation in the propagation phase. In agreement with previous findings, 0.5 microM CA and CHA inhibited LDL oxidation in the initiation phase. When 0.5 microM CA was added at 0 min, the duration of inhibition was about 60 min. Yet, after >9 min incubation with Cu2+, 0.5 microM CA accelerated LDL oxidation. The acceleration ratios were modified depending on the oxidation process and the concentration of added CA in the propagation phase. The maximum acceleration ratio was about 5 on addition of 2-5 microM CA, attained after 40 min incubation with Cu2+. Even in the propagation phase, an elevated concentration of CA inhibited oxidation; after 20 min incubation with Cu2+, CA at >3 microM functioned as an inhibitor. Further studies must be performed in order to clarify the counteracting deleterious prooxidant conditions of these widespread natural dietary compounds.

Antioxidants↗