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Biomedical subjects

S Morinobu

Publications and source records attributed to S Morinobu.

At least 19 recordsLinked to original sources
PubMed2004

Reduction in levels of amphiphysin 1 mRNA in the hippocampus of aged rats subjected to repeated variable stress.

Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.

Aging↗
PubMed2003

Lithium, but not valproate, induces the serine/threonine phosphatase activity of protein phosphatase 2A in the rat brain, without affecting its expression.

Protein phosphatase 2A (PP2A) regulates protein kinase cascades and thus plays an important role in the regulation of cell growth, gene expression and development. We examined the influence of lithium and valproate on the expression of PP2A and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus. Western blot and immunohistochemical analyses demonstrated that neither lithium nor valproate treatment had an effect on the levels of PP2A immunoreactivity in these brain regions. However, administration of lithium for 1 or 14 days significantly upregulated the activity of PP2A in the frontal cortex. Similarly, lithium administration tended to increase the activity of PP2A in the hippocampus. In contrast, neither a single nor repeated administration of valproate affected the activity of PP2A in these brain regions. These findings indicate that lithium, but not valproate, upregulated the activity of PP2A in the rat brain. It is suggested that the changes in neuronal functions induced by PP2A may be, at least in part, associated with the therapeutic action of lithium.

Animals↗
PubMed2003

Attenuated left prefrontal activation during a verbal fluency task in patients with depression.

Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.

Brain Mapping↗
PubMed2002

Differential changes in messenger RNA expressions and binding sites of neuropeptide Y Y1, Y2 and Y5 receptors in the hippocampus of an epileptic mutant rat: Noda epileptic rat.

The anti-convulsive effects of neuropeptide Y have been suggested in several animal models of epilepsy. We have found the sustained increase of neuropeptide Y contents and the seizure-induced elevation of hippocampal messenger RNA in a novel spontaneous epileptic mutant rat: Noda epileptic rat. In the present study, we investigated the change of neuropeptide Y Y1 and Y2 receptor messenger RNA expressions and binding sites in the hippocampus following a spontaneous generalized tonic-clonic seizure of Noda epileptic rat. Furthermore, the binding sites of a more recently isolated receptor subtype, neuropeptide Y Y5 receptors, were also evaluated by receptor autoradiography. A marked elevation of neuropeptide Y immunoreactivity in the mossy fiber, and Y2-receptor up-regulation in the dentate gyrus were observed in the hippocampus of Noda epileptic rat, which coincided with the previous results of the other epileptic models. In contrast, Y1-receptor down-regulation was not found after a spontaneous seizure of Noda epileptic rat while this occurs in kindling and after kainic acid-induced seizures. [125I][Leu31, Pro34]peptide YY/BIBP 3226-insensitive (Y5 receptor) binding sites in CA1 stratum radiatum were significantly decreased following a spontaneous seizure of Noda epileptic rat. The present results suggest that a spontaneous seizure of Noda epileptic rat induces significant changes in neuropeptide Y-mediated transmission in the hippocampus via Y2 and Y5 receptors, but not Y1 receptors. Therefore, specific subset of neuropeptide Y receptor subtypes might be involved in the epileptogenesis of Noda epileptic rat.

Animals↗
PubMed2002

Cognitive dysfunction in recovered depressive patients with silent cerebral infarction.

In this study, we characterized cognitive functioning in patients with major depression and silent cerebral infarction (SCI), as detected by magnetic resonance imaging (MRI), after they had recovered from depression. Thirty-five patients with unipolar depression who experienced the onset of depression after the age of 50 underwent MRI and were classified as SCI(+) (n = 17) or SCI(-) (n = 18). The Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Uchida-Kraepelin psychodiagnostic test were administered after the patients had recovered from depression. In addition, the intelligence quotient (IQ) and mental speed of the patients in the two groups were compared. The total, verbal and performance IQ scores, as determined by the WAIS-R, were significantly lower in the SCI(+) group than in the SCI(-) group. The mental speed of patients in the SCI(+) group, as assessed by the Uchida-Kraepelin psychodiagnostic test, was almost half that of the SCI(-) group. Our findings provide further evidence that a comprehensive impairment of cognitive functioning, especially a severe reduction in mental speed, remains after recovery from depression in patients with major depression and SCI.

Aged↗
PubMed2001

Effect of beta-estradiol on voltage-gated Ca(2+) channels in rat hippocampal neurons: a comparison with dehydroepiandrosterone.

We investigated the effects of beta-estradiol, dehydroepiandrosterone and dehydroepiandrosterone sulfate on intracellular calcium concentration ([Ca(2+)](i)) increases induced by gamma-aminobutyric acid (GABA), high K(+) and N-methyl-D-aspartate acid (NMDA) in cultured hippocampal neurons. Acute treatment with beta-estradiol, dehydroepiandrosterone and dehydroepiandrosterone sulfate inhibited the GABA-induced [Ca(2+)](i) increases to the similar extent. Tamoxifen, an estrogen receptor antagonist, did not block the inhibitory effects of beta-estradiol. On the other hand, GABA type A (GABA(A)) receptor antagonists, picrotoxin and bicuculline, blocked the GABA-induced [Ca(2+)](i) increases. Previously, we demonstrated that GABA- and high K(+)-induced [Ca(2+)](i) increases were commonly mediated by voltage-gated calcium channels (VGCCs). Therefore, we examined the effects of these steroids on the high K(+)-induced [Ca(2+)](i) increases. The inhibitory effect of beta-estradiol on the high K(+)-induced [Ca(2+)](i) increases was much greater than that of dehydroepiandrosterone and dehydroepiandrosterone sulfate. beta-Estradiol inhibited the NMDA-induced [Ca(2+)](i) increases with an IC(50) of 51.8 microM and NMDA responses were reduced to half in the presence of 10 micro M nifedipine, indicating that the NMDA-induced [Ca(2+)](i) increases also involved VGCCs. Further, we examined the inhibitory effect of beta-estradiol on the high K(+)-induced [Ca(2+)](i) increases in the presence of a N-type VGCCs antagonist, 1 microM omega-conotoxin, or a L-type VGCCs antagonist, 10 microM nifedipine. The IC(50) value of beta-estradiol alone (45.5 microM) was similar to that of omega-conotoxin (33.1 microM), while the value combined with nifedipine was reduced to 2.2 microM. beta-Estradiol also abolished the positive modulatory effect of L-type VGCCs agonist, 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid methyl ester (Bay K 8644). Our results showed that the inhibitory mechanism of beta-estradiol is different from that of dehydroepiandrosterone and dehydroepiandrosterone sulfate and beta-estradiol may act primarily at L-type VGCCs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Influence of restraint stress on the expression and the serine/threonine phosphatase activity of calcineurin in the rat brain.

To investigate the role of calcineurin (CaN) in the pathogenesis of stress-related psychiatric disorders, we examined the expression of CaN A mRNA and the serine/threonine phosphatase activity of CaN in the rat brain following various restraint stress paradigms. Northern blot analysis revealed no significant changes in the levels of CaN A mRNA expression, in either the frontal cortex or the hippocampus, in response to a single restraint stress for either 15, 45, or 90 min. In addition, no significant change in the levels of CaN A mRNA was found 3 or 6 h after a single restraint stress for 90 min. In situ hybridization analysis revealed that a single restraint stress for 45 min had no influence on CaN A mRNA expression in the CA1 and CA3 pyramidal cell layers or in the dentate gyrus granule cell layer of the hippocampus. However, serine/threonine phosphatase activity was significantly increased in both regions in response to a single restraint stress for either 45 or 90 min. These results demonstrate that the single restraint stress paradigms used in this study increase the activity of CaN without any changes in the expression of CaN, suggesting that the activation of calmodulin and the increased levels of heat shock proteins in response to the restraint stress may upregulate the activity of CaN in the rat brain.

Animals↗
PubMed2001

Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.

RATIONALE: Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved. OBJECTIVE: We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF. METHODS: Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. RESULTS: Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.

Administration, Oral↗
PubMed2001

Characterization of 5-HT2A receptor desensitization and the effect of cycloheximide on it in C6 cells.

Effect of prolonged pretreatment with serotonin (5-HT) on 5-HT2A receptor desensitization was examined by the measurement of intracellular calcium ([Ca2+]i) mobilization in C6 cells. 5-HT-induced desensitization of [Ca2+]i mobilization was in a time and dose dependent manner and reached a plateau after 3 hr. After 1 and 3 hr 5-HT pretreatment, 5-HT concentration in the medium little changed. 5-HT pretreatment with cycloheximide, a protein synthesis inhibitor, produced an enhancement of the desensitization for 3 and 6 hr pretreatment. However, 5-HT pretreatment for 3 and 6 hr caused no marked change in the 5-HT2A receptor mRNA level or Galphaq/11 protein in this study, suggesting that 5-HT may decrease 5-HT-induced [Ca2+]i mobilization independent of 5-HT2A receptor mRNA or G-proteins. Endothelin-1-induced [Ca2+]i mobilization did not alter after 5-HT and/or cycloheximide pretreatment. These results showed that activation of the 5-HT2A receptor induced homologous desensitization and pretreatment with 5-HT and/or cycloheximide did not change the efficacy of the second messenger pathway from Gq to a [Ca2+]i rise.

Animals↗
PubMed2001

Nucleotide sequence analysis of the binding site on the inositol 1,4,5-trisphosphate type-1 receptor in bipolar disorder -- a negative study.

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.

Adult↗
PubMed2001

Modulation of serotonin2A receptor function in rats after repeated treatment with dexamethasone and L-type calcium channel antagonist nimodipine.

1. It has been conceivable that the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity plays an important role in the pathophysiology of depression. In the present study, we have investigated the effect of repeated treatment with dexamethasone on serotonin (5-HT) 1A, 5-HT2A and alpha1-adrenergic receptors in the rat frontal cortex. Moreover, several studies have suggested the effectiveness of L-type calcium channel antagonist nimodipine for the treatment of depression. We also investigated the effect of repeated treatment with nimodipine on 5-HT2A receptor in rats with repeated dexamethasone treatment. 2. Repeated treatment with dexamethasone (1 mg/kg/day for 14 days) increased the density of 5-HT2A receptor, but not 5-HT1A and alpha1-adrenergic receptors in the rat frontal cortex. 3. The density of 5-HT2A receptor in the rat frontal cortex was significantly increased 1 day after repeated treatment with dexamethasone, but was not increased 7 or 14 days after repeated treatment. Wet dog shakes (WDS) induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A receptor agonist, in rats were significantly enhanced 1, 7 and 14 days after repeated treatment with dexamethasone, although the frequency of WDS gradually decreased after repeated treatment. 4. Repeated treatment with nimodipine (5 mg/kg/day for 14 days) attenuated DOI-induced WDS enhanced by repeated treatment with dexamethasone (1 mg/kg/day for 14 days), however, it did not change the density of 5-HT2A receptor. Repeated treatment with dexamethasone decreased locomotor activity and body weight, but repeated treatment with nimodipine did not recover these parameters. 5. The results of the present study suggest that repeated treatment with dexamethasone may selectively increase the 5-HT2A receptor in the rat frontal cortex and affect 5-HT2A receptor-mediated signal transduction. In addition, the intracellular calcium homeostasis by blocking calcium influx through L-type calcium channel may play an important role in the regulation of the 5-HT2A receptor function by dexamethasone.

Animals↗
PubMed2001

Antidepressant drug treatments induce glial cell line-derived neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells.

Modulation of neurotrophic factors to protect neurons from damage is proposed as a novel mechanism for the action of antidepressants. However, the effect of antidepressants on modulation of glial cell line-derived neurotrophic factor (GDNF), which has potent and widespread effects, remains unknown. Here, we demonstrated that long-term use of antidepressant treatment significantly increased GDNF mRNA expression and GDNF release in time- and concentration-dependent manners in rat C6 glioblastoma cells. Amitriptyline treatment also increased GDNF mRNA expression in rat astrocytes. GDNF release continued for 24 h following withdrawal of amitriptyline. Furthermore, following treatment with antidepressants belonging to several different classes (amitriptyline, clomipramine, mianserin, fluoxetine and paroxetine) significantly increased GDNF release, but which did not occur after treatment with non-antidepressant psychotropic drugs (haloperidol, diazepam and diphenhydramine). Amitriptyline-induced GDNF release was inhibited by U0126 (10 microM), a mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89 (1 microM), a protein kinase A inhibitor, calphostin C (100 nM), a protein kinase C inhibitor and PD 169316 (10 microM), a p38 mitogen-activated protein kinase inhibitor. These results suggested that amitriptyline-induced GDNF synthesis and release occurred at the transcriptional level, and may be regulated by MEK/MAPK signalling. The enhanced and prolonged induction of GDNF by antidepressants could promote neuronal survival, and protect neurons from the damaging effects of stress. This may contribute to explain therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.

Amitriptyline↗
PubMed2001

Clinical features and treatment response of patients with major depression and silent cerebral infarction.

Previously, we reported a relationship between silent cerebral infarction (SCI), as detected by magnetic resonance imaging (MRI), and late onset major depression. In the present study, we clarify the clinical features of the depressive phase of patients with major depression and SCI, and their response to antidepressant pharmacotherapy. Using clinical charts, we retrospectively examined patients with depression, who were first admitted for antidepressant pharmacotherapy. All patients were classified according to the MRI findings and the age on admission (older or younger than 50 years) into either the young SCI(-) group (n = 23), the elderly SCI(-) group (n = 27) or the elderly SCI(+) group (n = 20).The characteristics of the clinical features were evaluated at the time of admission, after 2 weeks of treatment and at the time of discharge using the Hamilton rating scale for depression (HAMD). These data were compared between each patient group. No differences in the clinical features, as evaluated by HAMD, were observed between the three groups at the time of admission. However, the mean length of treatment was significantly longer and the treatment response, as evaluated by the total HAMD score, was significantly worse in the elderly SCI(+) group than in the other two groups, when examined after 2 weeks of treatment and at the time of discharge. The elderly SCI(+) group demonstrated higher scores in feelings of guilt, suicide, retardation and hypochondriasis than the young SCI(-) group and the elderly SCI(-) group after two weeks of treatment, and higher scores in early insomnia, late insomnia, somatic anxiety and hypochondriasis at the time of discharge. Our findings suggest that while the presence of SCI does not affect the clinical features observed at the time of admission, it does affect the treatment response to antidepressant pharmacotherapy.

Adult↗
PubMed2000

Course and outcome of depressive episodes: comparison between bipolar, unipolar and subthreshold depression.

It is pragmatically important to know the comparative prognoses of bipolar, unipolar and subthreshold depressions after they present to clinical attention. Previous studies focusing on bipolar and/or unipolar depressions have questionable generalizability because of overrepresentation of inpatients and/or refractory patients, and no study has yet focused on the length of subthreshold depression. The Group for Longitudinal Affective Disorders Study (GLADS) in Japan is conducting a prospective, serial follow-up study of broadly defined mood disorder patients, who had not received treatment for their index episode before study entry. The median time to recovery for bipolar depression was 2.0 months (95%CI: 0.9-3.1), that for unipolar depression 3.0 (2.5-3.6), and that for subthreshold depression 3.2 (0-12.3). Survival analyses revealed no statistically significant difference among the three. Neither was the total time unwell significantly different among the three: on average, these patients were symptomatic with two or more significant affective symptoms for 9.5 (8.0-10.9) months out of the initial 24 months of follow-up. The bipolar depressed patients tended to present with graver functional impairment at intake, but thereafter there was no statistically significant difference in the global functioning of these three diagnostic subgroups. In our sample, patients with depressive disorder not otherwise specified appeared to suffer both symptomatologically and functionally as much as patients with major mood disorders.

Acute Disease↗
PubMed2000

Characterization of audiogenic-like seizures in naive rats evoked by activation of AMPA and NMDA receptors in the inferior colliculus.

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic-clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fos in the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fos mRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fos mRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fos mRNA in the IC induced by AMPA-induced seizures but did not suppress c-fos mRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fos mRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.

Acoustic Stimulation↗
PubMed2000

Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus.

The influence of two selective phosphodiesterase 4 (PDE4) inhibitors, rolipram and Ro 20-1724, on the induction of BDNF mRNA by antidepressant treatment was examined. Coadministration of rolipram or Ro 20-1724 with an antidepressant (either desipramine or Org 4428) for 21 d resulted in a significant induction of BDNF mRNA in hippocampus relative to administration of vehicle. Coadministration of a PDE4 inhibitor with an antidepressant for 7 or 14 d also increased levels of BDNF mRNA. In contrast, acute coadministration did not influence levels of BDNF mRNA. In situ hybridization analysis demonstrated that the induction of BDNF mRNA in response to the repeated coadministration paradigm occurs in the dentate gyrus granule and CA1 and CA3 pyramidal cell layers of hippocampus. These findings demonstrate that coadministration shortens the time required for the upregulation of BDNF mRNA, supporting the possibility that this treatment may provide an effective therapy for major depression.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Identification of a novel splice variant of heat shock cognate protein 70 after chronic antidepressant treatment in rat frontal cortex.

In this study, we identified a novel splice variant of 70-kDa heat shock cognate protein (HSC70), while screening differentially expressed molecules in rat brain after chronic antidepressant treatment. This clone, named HSC49, lacked 470 bp of nucleotides of rat HSC70. HSC49 encoded 442 amino acid residues with a calculated molecular mass of 48.6 kDa. DNA sequence analysis revealed that HSC49 lacked the entire Exon 7 and Exon 8 of the HSC70 gene. Chronic treatment with antidepressant, imipramine or sertraline, induced a 38.5 or 22.5% increase in mRNA levels in rat frontal cortex, respectively, when compared to controls. Western blot analysis also revealed that the protein expression of HSC49 was increased after antidepressant treatment. Our data suggest that HSC49 may be one of the common molecules induced after chronic antidepressant treatment.

Alternative Splicing↗