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Biomedical subjects

Mitsuhiro Yoshioka

Publications and source records attributed to Mitsuhiro Yoshioka.

At least 37 records · Page 2Linked to original sources
PubMed2004

Expression of endothelin receptors in the brain of SHR-SP and effects of an endothelin blocker.

Increased levels of endothelin-1 have been demonstrated in the ischemic brain, and endothelin receptor antagonism has been shown to improve the outcome of cerebral ischemia. However, it remains unknown what the relative receptor distribution in the brain of the spontaneously hypertensive stroke-prone rat (SHR-SP) is and whether it is changed by endothelin antagonism. The present study aimed to investigate the expression of the two endothelin receptors in the frontal cortex of SHR-SP after 12 weeks of treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting from the prehypertensive stage (6 weeks old). A 50% increase in the endothelin-A receptor was found in the vehicle-treated brain of SHR-SP compared with that of the age-matched Wistar-Kyoto control, but endothelin antagonism reversed this upregulation completely. A 20% decrease in endothelin-B receptor was found in the vehicle-treated brain of SHR-SP compared with Wistar-Kyoto and was recovered by endothelin antagonism. This is the first study to explore the relative endothelin receptor distribution in the frontal cortex of SHR-SP at the typical hypertensive stage and changes resulting from long-term endothelin antagonism starting from the prehypertensive stage.

Age Factors↗
PubMed2004

Brain expression of VEGF and its receptors in SHR-SP and effects of an endothelin blocker.

Spontaneously hypertensive stroke-prone rats suffer spontaneous strokes partly as a result of abnormal cerebrovascular development. This model exhibits prehypertensive, typical hypertensive and malignant hypertensive stages. We had observed that vascular endothelial growth factor and its receptors, kinase domain region (KDR) and fms-like tyrosine kinase (Flt-1), were upregulated in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage. The current study therefore investigated whether the long-term treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting at the prehypertensive stage (6 weeks old) could reverse the upregulated vascular endothelial growth factor and its receptors; this upregulation is believed to be a compensatory adaptation for hypertension in the brain of spontaneously hypertensive stroke-prone rats. A 40% upregulation of vascular endothelial growth factor was observed in the brain of vehicle-treated spontaneously hypertensive stroke-prone rats compared with the age-matched genetic control, Wistar-Kyoto rat, and this upregulation was markedly reversed by endothelin antagonism. A similar change was found in KDR and Flt-1 expression. It is worth noting that the vascular endothelial growth factor/KDR signaling system was upregulated in the brain of spontaneously hypertensive stroke-prone rats treated with vehicle at the typical hypertensive stage, whereas the cerebral blood flow did not differ between Wistar-Kyoto and spontaneously hypertensive stroke-prone rats. We concluded that endothelin antagonism reversed the upregulated vascular endothelial growth factor and its receptors in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage, and it is suggested that endothelin antagonism can reverse the hypertension-induced neurovascular remodeling in the brain of these rats.

Age Factors↗
PubMed2004

[What is Helicobacter pylori?: associated diseases in human].

Helicobacter pylori (H. pylori) is a spiral gram-negative bacterium, characterized by positive urease, catalase and oxidase activity. The complete resolution of the full genome has elucidated the biological characteristics, the pathogenicity, and the bacterial evolution. The infection is acquired in childhood by oral-oral transmission in developed countries, probably an intra-familiar transmission. The infection has an association with chronic histological gastritis, peptic ulcer, gastric cancer and MALT lymphoma in the stomach. All patients with H. pylori infection have histological gastritis and most of them remain asymptomatic for life. Only a minority of the infected individuals occurs ulceration or gastric cancer. Cure of the infection prevents recurrence of peptic ulcer without persistent treatments against ulceration. Concerning gastric cancer, WHO concluded in 1994 that H. pylori is a definite carcinogen in humans on the basis of epidemiological studies. Evidences that the infection leads to the development of gastric cancer have been accumulated in animal models as well as in vitro experimental studies. Such clinical diversities are caused by variations of H. pylori pathogenicity, host susceptibility, environmental factors including foods and those interactions. At present, an eradication treatment of H. pylori, combined with a proton-pump inhibitor and two antibiotics (clarithromycin and amoxicillin) is restrictedly approved in the patients with gastric or duodenal ulcer by Japanese health care system.

Amoxicillin↗
PubMed2003

Involvement of GABAA receptors in the regulation of the prefrontal cortex on dopamine release in the rat dorsolateral striatum.

The characteristics of the prefrontal cortex regulation of dopamine release in the rat dorsolateral striatum were investigated in focusing on the corticostriatal pathway, using dual-probe microdialysis in combination with simple behavioral procedures. Intracortical perfusion of the GABA(A) receptor antagonist bicuculline (0.03 and 0.1 mM) increased the striatal dopamine release, whereas the GABA(A) receptor agonist muscimol (0.1 and 1 mM) reduced the release dose dependently. Co-perfusion of muscimol (0.01 mM), which did not by itself affect the dopamine release, completely prevented the glutamate (1 mM)-stimulated dopamine release and behavioral activities, including locomotion and rearing. Muscimol (0.01 mM) also prevented the N-methyl-D-aspartate (NMDA; 1 mM)-induced increases in glutamate, as well as dopamine levels. These findings suggest that the prefrontal cortex functionally regulates dopamine release in the dorsolateral striatum, which is mediated via GABA(A) receptors. This cortical GABAergic system underlying the prefrontal cortex regulatory mechanism appears to be associated with the corticostriatal pathway.

Animals↗
PubMed2003

Effects of repetitive transcranial magnetic stimulation on behavioral and neurochemical changes in rats during an elevated plus-maze test.

In transcranial magnetic stimulation (TMS) the regional electrical activity in the brain is influenced by a pulsed magnetic field. The rapidly changed magnetic field produces electrical currents that activate neurons. Repetitive TMS (rTMS) treatment can cause functional changes in the cortex. The present study clarified the effects of rTMS treatment on behavioral changes in rats, focusing on anxiety by using an elevated plus-maze (plus-maze) test. The effects of rTMS treatment on neurochemical changes during the plus-maze test were investigated by determining the extracellular levels of serotonin (5-HT) and dopamine (DA) in the prefrontal cortex by using in vivo microdialysis. Each rat received rTMS of the frontal brain for 3 days, during which 125 stimuli from five trains in a day were applied at 25 Hz for 1 s with 2-min intervals between trains. Three-day series of (chronic) rTMS treatment caused significant increases in the time spent in open arms and the number of entries into open arms of the plus-maze compared with non-treated and sham-treated rats, which were not observed in 1-day series of (acute) rTMS treatment. Chronic rTMS treatment suppressed the increases in 5-HT levels induced by the plus-maze test, but did not influence the elicited DA levels. These data suggest that chronic rTMS treatment of the frontal brain has anxiolytic effects in rats, which are related to the 5-HTergic neuronal system.

Analysis of Variance↗
PubMed2003

The serotonergic modulation of synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway.

The ability of the serotonergic (5-HTergic) system to affect the hippocampo-medial prefrontal cortex (mPFC) synaptic properties was examined in rats with lesions of 5-HTergic neurons. Intracerebroventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) resulted in selective depletion of 5-HT and 5-hydroxyindoleacetic acid in the cerebral cortex, hippocampus and raphe regions. The 5,7-DHT-lesioned rat had no changes in basal synaptic transmission in the hippocampo-mPFC pathway. Conversely, we observed the augmentation of short-term synaptic plasticity, i.e. paired-pulse facilitation, when compared with sham-operated rats in this pathway. The magnitude of long-term potentiation (LTP) was significantly augmented in 5,7-DHT-lesioned rats. This augmentation of hippocampo-mPFC LTP had a significant correlation with the degree of cortical 5-HT levels. These results suggest that the 5-HTergic system may modulate plastic properties at the hippocampal-mPFC synapses in vivo.

5,7-Dihydroxytryptamine↗
PubMed2003

Chemical bladder irritation provokes c-fos expression in the midbrain periaqueductal gray matter of the rat.

We investigated the topographical localization of c-fos expression in the midbrain periaqueductal gray matter (PAG) to detect nociception-induced neural activity in the PAG. In conscious female Wistar rats, c-fos expression was induced by continuous intravesical infusion of saline or 0.1% acetic acid. Number of c-fos protein (Fos)-positive cells was counted at each coronal section of the PAG as well as Barrington's nucleus. Fos-positive cells were also counted at L1 and L6 of the spinal cord, where most of the hypogastric and pelvic nerve afferent terminals project, respectively. Compared with saline infusion, acetic acid infusion provoked irritative bladder responses characterized by a marked increase in the frequency of bladder contractions, and induced a significant increase in the number of Fos-positive cells in both L1 and L6 of the spinal cord. Following acetic acid infusion, there was a significant increase in the number of Fos-positive cells in all coronal sections of the PAG compared with saline infusion, especially in the caudal part of the PAG. The increase in the number of Fos-positive cells was mainly observed in the ventrolateral and lateral parts of the caudal PAG, and in the dorsal part of the rostral PAG. However, there was no difference in the number of Fos-positive cells in Barrington's nucleus between saline and acetic acid infusion. In conclusion, nociception induced by chemical bladder irritation influences neural activity in the PAG. Implication of topographical difference in Fos expression in the PAG and its relevance to changes in bladder function remain to be elucidated.

Acetic Acid↗
PubMed2003

Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors.

A selective 5-HT reuptake inhibitor, fluvoxamine (10 and 30 mg/kg, i.p.) suppressed long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Fluvoxamine (30 mg/kg, i.p.)-induced suppression of LTP was completely reversed by the 5-HT(1A) receptor antagonist NAN-190 (0.5 mg/kg, i.p), but not by the 5-HT(4) receptor antagonist GR 113808 (20 microg/rat, i.c.v.) and the 5-HT(7) receptor antagonist DR 4004 (10 microg/rat, i.c.v.). These data suggest that the inhibitory effect of fluvoxamine on LTP induction is mediated via 5-HT(1A) receptors.

Animals↗
PubMed2003

Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity.

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somatoautonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs such as cisplatin is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestine and the brainstem. It is proposed that cytotoxic drugs evoke 5-HT release from the enterochromaffin (EC) cells in the intestinal mucosa and that the released 5-HT stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells seems to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The release of 5-HT from the EC cells, however, is regulated by polymodal mechanisms on autoreceptors or heteroreceptors. The precise role of 5-HT on the occurrence of vomiting has not been fully elucidated. The present review aims to describe the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagus nerve activity. Various methods for predicting emesis are also evaluated.

Antineoplastic Agents↗
PubMed2003

Coronary capillary network remodeling and hypofibrinolysis in aged obese diabetic rats: implications for increased myocardial vulnerability to ischemia.

Despite the known abnormalities of cardiac function in patients with overt non-insulin dependent diabetes mellitus (NIDDM) the temporal changes of coronary capillary network remodeling leading to potential microcirculatory dysfunction have not been elucidated. To this end, left ventricular subendocardial capillary network of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, characterized by hypertension, obesity, hyperglycemia, hyperinsulinemia and mild NIDDM, and control Long-Evans Tokushima (LETO) rats were investigated. Total capillary density in OLETF was significantly higher than that in LETO at 20 weeks, suggesting compensatory improvement of O2 transport at early stages of NIDDM. The increase in capillary density in OLETF was lost at 40 and 60 weeks due to the decreases of intermediate capillary portions and venular capillary portions. Although capillary domain area (area innervated by single capillary) in OLETF was lower than that in LETO at 20 weeks, the values were similar between OLETF and LETO at 40 and 60 weeks, suggesting that adaptive improvement in the capacity for 02 transport with a high perfusion was lost in late stages of NIDDM. Activity of plasma plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of proteo(fibrino)lysis, in OLETF was higher than that in LETO at 40 and 60 weeks, suggesting that increase of PAI-1 may downregulate compensatory adaptive capillary network remodeling by inhibiting proteolysis and angiogenesis in the cardiac interstitium. Loss of adaptive myocardial microcirculation may therefore contribute to increased vulnerability in ischemic injury and to cardiac dysfunction in NIDDM.

Animals↗
PubMed2003

Changes in synaptic properties in cortical-limbic communications induced by repeated treatments with fluvoxamine in rats.

There is evidence indicating that dysregulation of coordinated interactions of the cortical-limbic circuitry is associated with anxiety and mood disorders. Our previous study has reported that an enhancement of long-term plasticity in the "limbic-cortical" pathway produced by repeated treatments with fluvoxamine may be involved in the clinical effects of a selective serotonin (5-HT) reuptake inhibitor (SSRI). Here we assessed the effects of single and repeated treatments with fluvoxamine on the synaptic transmission and plasticity in the "cortical-limbic" pathway in vivo. The evoked potentials in the basolateral amygdaloid complex (BLA) by stimulation of the medial prefrontal cortex (mPFC) in halothane-anesthetized rats were recorded. Single administration of fluvoxamine (10 and 30 mg/kg, i.p.) enhanced the efficacy of synaptic transmission at the mPFC-BLA synapses dose-dependently. The enhanced synaptic efficacy induced by 30 mg/kg fluvoxamine was suppressed after long-term administration of fluvoxamine (30 mg/kg per day x 21 days, orally). Repeated treatments with fluvoxamine affected short-term, but not long-term, synaptic plasticity in the mPFC-BLA pathway. These findings indicate that the 5-HTergic system contributes to modulation of synaptic changes in this pathway. Our results also suggest that different changes in synaptic properties in cortical-limbic communications induced by repeated treatments with fluvoxamine may be associated with therapeutic effects of SSRI.

Animals↗
PubMed2003

Effects of acute repetitive transcranial magnetic stimulation on extracellular serotonin concentration in the rat prefrontal cortex.

Repetitive transcranial magnetic stimulation (rTMS) changes the function of the cortex. This study clarified the effects of acute rTMS treatment on extracellular serotonin (5-HT) concentrations in the rat prefrontal cortex (PFC) by using in vivo microdialysis methods. Each rat received acute rTMS treatment of the frontal brain at 500 stimuli from twenty trains applied at 25 Hz for 1 s at 1-min intervals between trains. Sham-treated rats received the same handling procedure and sound of the stimulator. Sham treatment increased the extracellular 5-HT levels compared with the non-treated group. However, rTMS treatment using the stimulation intensity of 110% motor threshold eliminated the increase in 5-HT levels induced by the sham treatment. Acute rTMS treatment of the frontal brain is related to the serotonergic neuronal system in the rat PFC, and it may have therapeutic implications for emotional disorders.

Animals↗
PubMed2003

[Behavioral and pharmacological studies of juvenile stroke-prone spontaneously hypertensive rats as an animal model of attention-deficit/hyperactivity disorder].

The present study was undertaken to evaluate juvenile stroke-prone spontaneously hypertensive rats (SHRSP) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Juvenile SHRSP showed significant increases in horizontal ambulatory activity and vertical rearing activity in the open field as compared with genetic control Wistar-Kyoto rats (WKY). Anxiety-related behavior assessed by elevated plus-maze as an index of impulsivity, the entries into open arms and the spent time in the open arms of SHRSP were significantly higher than those of WKY. Spontaneous alternation behavior requiring attention and working memory in the Y-maze was significantly impaired in male, but not female, SHRSP when compared with sex-matched WKY. Hippocampal long-term potentiation formation, a cellular model of learning and memory, was not impaired in SHRSP. Methylphenidate, a first choice psychostimulant for AD/HD, significantly alleviated the hyperactivity in SHRSP. However, intense impulsivity of SHRSP was not improved by methylphenidate. Methylphenidate dose-dependently and significantly ameliorated the impaired spontaneous alteration behavior in male SHRSP. These results suggest that juvenile male SHRSP manifest problematic behavior resembling ADHD, namely inattention, hyperactivity and impulsivity. Methylphenidate alleviates the behavioral symptoms of hyperactivity and inattention. Thus, juvenile male SHRSP might be a useful behavioral animal model of AD/HD, from behavioral and pharmacological perspectives.

Animals↗
PubMed2003

[Science in taking medicine].

It is a well-known fact that medicine plays an important role in treatment of several diseases. New development of many drugs led to not only benefits but also unexpected damage to human beings. In Japan, we are plunged into an aging society we have never experienced. We have far more opportunities to take medicine. Under these circumstances, it is very important for each one of us to learn how more reliable to take medicine to prevent unexpected side effects. In this citizen joint symposium, we focused on how to take medicine more logically and effectively from the viewpoint of patients. Participation in this symposium could hopefully help promoting our health care in Hokkaido.

Drug Therapy↗
PubMed2002

Differential characteristics of endogenous serotonin-mediated synaptic transmission in the hippocampal CA1 and CA3 fields of anaesthetized rats.

The characteristics of endogenous serotonin (5-HT)-mediated synaptic transmission were investigated in the hippocampal CA1 and CA3 fields of anaesthetized rats. Electrophysiological approaches were used to elucidate the effects of a selective 5-HT reuptake inhibitor, fluvoxamine, on synaptic transmission by determining the population spike amplitude (PSA). Fluvoxamine (10 or 30 mg/kg i.p.) increased the PSA in the CA1 and CA3 fields concentration dependently, whereby this facilitatory response was greater in the CA3 than in the CA1 field. Fluvoxamine (30 mg/kg i.p.)-induced increases in the PSA were augmented by the 5-HT(1A) receptor antagonist NAN 190 (0.5 mg/kg i.p.) and prevented by the 5-HT(4) receptor antagonist GR 113808 (20 micro g/rat i.c.v.) or by the 5-HT(7) receptor antagonist DR 4004 (10 micro g/rat i.c.v.) in the CA1 field. Thus, fluvoxamine-induced facilitatory effects appear to be mediated via 5-HT(1A) and 5-HT(4)/5-HT(7) receptors in an inhibitory and a stimulatory manner, respectively. In the CA3 field, excitability produced by fluvoxamine was abolished by either NAN 190 or DR 4004, but not by GR 113808, suggesting that 5-HT(1A) and 5-HT(7) receptors contribute to this facilitation. These findings were supported in part by the results obtained by exogenously applied 5-HT receptor agonists: the 5-HT(1A) receptor agonist tandospirone (10 mg/kg i.p.) decreased PSA in the CA1 field, whereas the 5-HT(4) receptor agonist SC 53116 (10 micro g/rat i.c.v.) increased it. In contrast, in the CA3 field, tandospirone increased PSA, whereas SC 53116 had no effect. Taken together, the present study revealed that characteristics of synaptic transmission mediated via 5-HT receptors differ between the CA1 and CA3 fields: in the CA1 field, three 5-HT receptors, 5-HT(1A), 5-HT(4) and 5-HT(7), are associated with the endogenous 5-HT-induced facilitation in an opposite and independent manner. In the CA3 field, at least two 5-HT receptors, i.e. 5-HT(1A) and 5-HT(7), are involved in this mediation in a facilitatory manner. 5-HT neurons may modulate pyramidal neuron responses to incoming stimuli by complex mechanisms involving these 5-HT receptors. In other words, the net effects resulting from the differential characteristics in the CA1 and CA3 fields may play an important role in the physiological functions of the hippocampus.

Action Potentials↗
PubMed2002

Changes in synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway induced by repeated treatments with fluvoxamine.

The present studies were conducted to examine the effects of single and repeated treatments with fluvoxamine, which is a selective serotonin reuptake inhibitor (SSRI), on the synaptic efficacy and synaptic plasticity in the rat hippocampo-medial prefrontal cortex (mPFC) pathway in vivo. It has been reported that the projections arising from the hippocampal structures to the mPFC are involved in the execution of higher cognitive functions in rats. The evoked potentials were recorded in the mPFC by stimulation of the CA1/subicular region of the ventral hippocampus in halothane-anesthetized rats. Single administration of fluvoxamine (10 and 30 mg/kg, i.p.) enhanced synaptic efficacy in the hippocampo-mPFC pathway in a dose-dependent manner. Although repeated treatments with fluvoxamine (30 mg/kg, i.p. after 30 mg/kg/dayx21 days, p.o.) caused an enhancement of synaptic efficacy, there was no significant difference between single and repeated treatments. The input/output characteristics showed hypersensitivity to stimulation intensity in the group with repeated fluvoxamine treatments. The establishment of long-term potentiation (LTP) in the hippocampo-mPFC pathway after a single administration of fluvoxamine was not different from that in the saline-injected group. On the other hand, the hippocampo-mPFC LTP was significantly augmented by repeated treatments with fluvoxamine when compared to a single treatment. These findings suggest that the serotonergic system could modulate the synaptic plasticity at hippocampal-mPFC synapses. The present study, furthermore, suggests that the enhancement of LTP in the hippocampo-mPFC pathway produced by repeated treatments with fluvoxamine may be implicated in the SSRI-induced therapeutic effect on psychiatric disorders.

Afferent Pathways↗
PubMed2002

Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats.

The effects of aniracetam, a cognition enhancer, on extracellular levels of glutamate (Glu), gamma-aminobutyric acid (GABA) and nitric oxide metabolites (NOx) were examined in the prefrontal cortex (PFC) and the basolateral amygdala (AMG) in stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal release of Glu, was lower in the AMG of SHRSP than in normotensive Wistar Kyoto rats, whereas no difference in GABA and NOx was noted. Aniracetam (100 mg/kg, p.o.) significantly increased the area under the curve of Glu levels in the PFC, but not in the AMG, of SHRSP. Aniracetam failed to exert any remarkable effects on GABA or NOx levels in either brain region. Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions.

Amino Acids↗