Masaki Takahashi

Aoyama Gakuin University, Edo, Tōkyō, Japan

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Publications (27)61.62 Total impact

  • Erika Sawano · Masaki Takahashi · Takayuki Negishi · Tomoko Tashiro ·
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    ABSTRACT: Thyroid hormone (TH) plays essential roles in normal brain development mainly by regulating gene expression through binding to specific nuclear receptors which serve as transcription factors. Previous studies showed that perinatal deficiency of TH or impairment of its signaling severely affect brain development, especially the development of the γ-aminobutyric acid (GABA) system, but cellular and molecular targets of the hormone are only partly uncovered. In the present study, we focused on the developing rat hippocampus which was confirmed to be one of the regions highly sensitive to TH status, and found two new targets of the hormone among the pre- and post-synaptic components of the GABAergic system. One was glutamic acid decarboxylase 65 (GAD65), the protein level of which was reduced to less than 50% of control in the hippocampus of hypothyroid rats (obtained by administering 0.025% methimazole in drinking water to pregnant dams from gestational day 15 until 4 weeks postpartum) and recovered to control levels by daily thyroxine-replacement after birth. Reduction in GAD65 protein was correlated immunohistochemically with a 37% reduction in the number of GAD65-positive cells as well as a reduction in GAD65-positive processes. In contrast, the other GAD isotype, GAD67, was not affected by TH status. A subpopulation of GABAergic neurons containing parvalbumin was also confirmed to be highly dependent on TH status. The second target of thyroid hormone was neuron-specific K(+)/Cl(-) co-transporter, KCC2, which is responsible for switching of GABA action from excitatory to inhibitory. In the euthyroid hippocampus, a sharp rise of kcc2 expression was observed at postnatal day (PND)10 which was followed by a large increase in KCC2 protein at PND15. This transient rise in kcc2 expression was completely suppressed by hypothyroidism, resulting in nearly 80% reduction in KCC2 protein at PND15. These results indicate that the development of GABAergic terminals and the excitatory to inhibitory maturation of GABA signaling are strongly dependent on TH.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 09/2013; 31(8). DOI:10.1016/j.ijdevneu.2013.09.007 · 2.58 Impact Factor
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    ABSTRACT: An incident of poisoning occurred in Japan in 2003 when high-level contamination with arsenic, mainly diphenylarsinic acid (DPAA), was found in well water. People using this water particularly experienced cerebellar symptoms. In the present study, we investigated the adverse effects of DPAA on the cerebellum in vitro and in vivo to understand the biological mechanisms that cause cerebellar symptoms. Comprehensive gene expression analyses in primary cultured ratcerebellar cells exposed to 10 μM DPAA for 24 hours indicated significant alterations in the mRNA expression of genes encoding antioxidative stress proteins (heme oxigenase 1 and heat shock protein72) and neuroactive and vasoactive peptides (neuropeptide Y, adrenomedullin, monocyte chemoattractant protein 1, and fibroblast growth factor 2). Further analyses of proteins revealed that cultured cerebellar astrocytes expressed these antioxidative stress proteins and peptides in response to exposure to DPAA. In addition, these adverseeffects were also observed in the cerebellum exposed in vivo to DPAA (100 mg/L) for 21 days. These results suggested that cerebellarastrocytes irregularly secrete neuroactive and vasoactive peptidesagainst DPAA-induced oxidative stress, which leads to abnormal neural functions and disrupted cerebellar autoregulation dynamics and results in the onset of cerebellar symptoms.
    Journal of Neuropathology and Experimental Neurology 05/2012; 71(6):468-79. DOI:10.1097/NEN.0b013e3182561327 · 3.80 Impact Factor

  • Neuroscience Research 12/2010; 68:e417-e418. DOI:10.1016/j.neures.2010.07.1851 · 1.94 Impact Factor
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    ABSTRACT: The patient was a 69-year-old woman with a family history of type 2 diabetes. Her body mass index was 31.5. She was diagnosed as type 2 diabetes 32 years previously, and treated with insulin for 8 years. She had no episode of weight loss. She was hospitalized with diabetic ketoacidosis for the first time. Her GAD antibodies were not detected. However, ICA antibodies and insulin antibodies were positively detected. She was diagnosed with type 1 diabetes. Interestingly, her diabetes state was controlled to the same level after recovery from ketoacidosis.
    Internal Medicine 01/2010; 49(5):393-5. DOI:10.2169/internalmedicine.49.2843 · 0.90 Impact Factor
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    ABSTRACT: We performed a receiver operator characteristic (ROC) curve analysis of 3915 men and 2032 women. Subjects who were diagnosed with two or more factors among high blood pressure, hyperglycaemia or high triglyceride and/or low HDL were classified as the metabolic syndrome group. By performing a ROC curve analysis, we have determined the cut-off point of waist circumference (WC) and BMI to define metabolic syndrome and further calculated the sensitivity and specificity of these two factors for the diagnosis. Cut-off point for the diagnosis of metabolic syndrome was 85 cm (men) and 80 cm (women) in WC and 24 (men) and 23 (women) in BMI. By combining these two factors, the sensitivity for the diagnosis increased to more than 80%. We conclude that it is beneficial to combine both WC and BMI for diagnosis of metabolic syndrome.
    Endocrine Journal 10/2009; 56(9):1079-82. DOI:10.1507/endocrj.K09E-197 · 2.00 Impact Factor
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    ABSTRACT: Clostridium infections are rare but frequently associated with malignancy, and mortality approaches 100% if care is not rendered within 12 to 24 h. These infections are associated with various medical problems including diabetes mellitus. In this report, we describe a unique case of sepsis and a gas-forming splenic abscess caused by Clostridium septicum in a type 2 diabetes patient which was treatable solely with antibiotics.
    Journal of diabetes and its complications 04/2009; 24(2):142-4. DOI:10.1016/j.jdiacomp.2009.02.001 · 3.01 Impact Factor
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    ABSTRACT: Polychlorinated biphenyls (PCBs), major environmental hormonally active agents, are metabolized into hydroxylated PCBs in the liver to facilitate excretion. Some of hydroxylated PCBs also have potencies disturbing endogenous hormonal activities at least in vitro. Hormonal activities of hydroxylated PCBs raise a possibility of their interfering with normal brain development which is strictly regulated by endogenous hormones. We investigated whether and how prenatal exposure to a congener of hydroxylated PCBs (4-OH-2',3,3',4',5'-penta CB; 4-OH-PCB106) having activities to disrupt thyroid hormone-dependent signals in vitro could perturb normal gene expression in the developing brain in vivo. Pregnant rats were exposed to 4-OH-PCB106 subcutaneously at the dose of 1.0mg/(kgday) from day 7 of gestation to postnatal day 1. Then three brain regions (cerebral cortex, hippocampus and striatum) were obtained from offspring on postnatal day 1 and subjected to further gene expression analyses. Comprehensive analyses of mRNA expression by oligo DNA microarrays and subsequent validations by quantitative RT-PCR revealed that prenatal exposure to 4-OH-PCB106 affected mRNA expression of glutamate receptors as well as that of thyroid hormone-responsive genes in region-specific manners. Concomitantly 4-OH-PCB106 exposure increased mRNA expression of genes related to exocytosis in the three brain regions. These results raise the possibility that prenatal exposure to some hydroxylated PCBs with thyroid hormone-disrupting potencies leads to abnormal brain development via perturbations on the expression of genes involved in glutamatergic neurotransmission.
    Toxicology 03/2009; 257(1-2):17-24. DOI:10.1016/j.tox.2008.12.003 · 3.62 Impact Factor
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    Masaki Takahashi · Takayuki Negishi · Tomoko Tashiro ·
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    ABSTRACT: Despite the indispensable role thyroid hormone (TH) plays in brain development, only a small number of genes have been identified to be directly regulated by TH and its precise mechanism of action remains largely unknown, partly because most of the previous studies have been carried out at postnatal day 15 or later. In the present study, we screened for TH-responsive genes in the developing mouse cerebellum at postnatal day 4 when morphological alterations because of TH status are not apparent. Among the new candidate genes selected by comparing gene expression profiles of experimentally hypothyroid, hypothyroid with postnatal thyroxine replacement, and control animals using oligoDNA microarrays, six genes were confirmed by real-time PCR to be positively (orc1l, galr3, sort1, nlgn3, cdk5r2, and zfp367) regulated by TH. Among these, sort1, cdk5r2, and zfp367 were up-regulated already at 1 h after a single injection of thyroxine to the hypothyroid or control animal, suggesting them to be possible primary targets of the hormone. Cell proliferation and apoptosis examined by BrdU incorporation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay revealed that hypothyroidism by itself did not enhance apoptosis at this stage, but rather increased cell survival, possibly through regulation of these newly identified genes.
    Journal of Neurochemistry 03/2008; 104(3):640-52. DOI:10.1111/j.1471-4159.2007.05049.x · 4.28 Impact Factor
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    ABSTRACT: Activity-dependent gene expression is one of the key mechanisms of synaptic plasticity that form the basis of higher order functions such as learning and memory. In the present study, we surveyed for activity-dependent genes by analyzing gene expression changes accompanying reversible inhibition of synaptic activity by tetrodotoxin (TTX) using two types of DNA microarrays; our focused oligo DNA microarray "Synaptoarray" and the commercially available high-density array. Cerebral cortical cells from E18 rat embryos were cultured for 14 days to ensure synaptogenesis, then treated with 1 muM TTX for 48 hr without detectable effect on cell viability. Synaptic density estimated by the amount of Synapsin I and Synaptotagmin I was decreased 21-24% by TTX treatment, but recovered to the control level 48 hr after TTX withdrawal. Comparison of gene expression profiles by competitive hybridization of fluorescently labeled cRNA from TTX-treated and control cells showed an overall downregulation of the genes on the Synaptoarray by TTX-treatment with different recovery rates after TTX withdrawal. With 16 representative genes, microarray data were validated by real-time PCR analysis. Genes most severely downregulated by TTX and upregulated above the control level at 5 hr after TTX withdrawal were munc13-1 (involved in docking and priming of synaptic vesicles) and Shank2 (involved in the postsynaptic scaffold). In addition, comprehensive screening at 5 hr after TTX withdrawal using high density arrays resulted in additional identification of Rgs2, a regulator of trimeric G-protein signaling, as an activity-dependent gene. These three genes are thus likely to be key factors in the regulation of synaptic plasticity. (c) 2007 Wiley-Liss, Inc.
    Journal of Neuroscience Research 08/2007; 85(11):2385-99. DOI:10.1002/jnr.21391 · 2.59 Impact Factor
  • Nobuyuki Kimura · Masaki Takahashi · Tomoko Tashiro · Keiji Terao ·
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    ABSTRACT: Astrocytes, the most abundant type of glia in the brain, are considered to play a key role in Alzheimer's disease (AD) pathologies. In a cell culture study, we have previously shown that astroglial responses against amyloid beta (Abeta) occur before obvious neuronal damage could be detected, suggesting the possibility that astrocytes might be an attractive therapeutic target for treating AD. In the present study, we investigated astroglial gene expression changes in response to Abeta to elucidate further the role of astrocytes in Abeta toxicity. By using real-time PCR and ELISA analyses, we found that Abeta rapidly induced astrocytes to produce brain-derived neurotrophic factor (BDNF). Abeta42 was more effective than Abeta40 in increasing astroglial BDNF production. Moreover, BDNF treatment rescued the neuronally differentiated human neuroblastoma cells from neuritic degeneration caused by Abeta toxicity. This is the first study to demonstrate that astrocytes are capable of increasing the production of a particular neurotrophic factor in response to Abeta. Our findings also identify BDNF as a potential therapeutic agent for preventing Abeta-related neuritic degeneration.
    Journal of Neuroscience Research 09/2006; 84(4):782-9. DOI:10.1002/jnr.20984 · 2.59 Impact Factor
  • Article: P3-342
    Nobuyuki Kimura · Masaki Takahashi · Tomoko Tashiro · Keiji Terao ·

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    ABSTRACT: Use of DNA microarrays in neuroscience have been limited to rough screening purposes, mainly because the reliability and sensitivity of available arrays are not high enough. Because only a few hundred to one thousand genes are usually found to change expression levels in most experiments, we attempted to develop a more quantitative array by the following strategies: 1) limit the genes to those relevant to the experimental system, 2) design oligonucleotide probes of specified molecular properties so that more stringent hybridization conditions can be employed, 3) place six spots per probe on one slide and use multiple normalization genes, and 4) use a new type of gold-coated slide with higher S/N ratio. Genes involved in the construction and functioning of the synapse were selected from the literature as well as experimentally by comparing cerebella from hypothyroid and control mice at postnatal day 15 (P15). Although the number of genes covered was not yet large (172 genes), the custom array "Synaptoarray" thus constructed was capable of detecting +/-20% difference in gene expression ratios. Analysis of the postnatal development of the mouse cerebellum by using Synaptoarray demonstrated a general expression pattern with a peak at P7, followed by a decline at P15 and a partial recovery after P21. P10 clearly marked the end of the initial growth stage and a major transcriptional turning point in this system. This result suggests that such a custom array should be useful in monitoring perturbations to the normal developmental program.
    Journal of Neuroscience Research 06/2005; 80(6):777-88. DOI:10.1002/jnr.20533 · 2.59 Impact Factor
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    M Nara · Masaki Takahashi · Tsugiyasu Kanda · Younosuke Shimomura · Isao Kobayashi ·
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    ABSTRACT: NARA, MAKOTO, MASAKI TAKAHASHI, TSUGIYASU KANDA, YOUNOSUKE SHIMOMURA, ISAO KOBAYASHI. Running exercise improves metabolic abnormalities and fat accumulation in sucrose-induced insulin-resistant rats. Insulin resistance and hyperinsulinemia are observed in rats fed a high sucrose diet. Insulin resistance is thought to be related to abnormal fat distribution. We previously reported the metabolic characteristics and the fat distribution in rats with sucrose-induced insulin resistance. This study was designed to examine the effects of exercise in these rats. The rats were divided into three groups: those receiving a starch-based diet (control), those receiving a high-sucrose diet (sucrose fed), and those receiving a high-sucrose diet and wheel-running exercise (exercised). Animals were killed after 4 weeks or 12 weeks. After 4 weeks, the three groups did not differ with respect to gain in adipose tissues. The portal vein (PV) insulin concentration was significantly increased in the sucrose-fed and the exercised rats compared with the control rats. The inferior vena cava (IVC) glucose concentration and the PV free fatty acid (FFA) were significantly lower in the exercised rats than in the sucrose-fed rats. After 12 weeks, the exercised rats had significantly lower mesenteric fat (MS) and subcutaneous fat (SC) and a lower MS:SC ratio than the sucrose-fed rats. The glucose levels in IVC, PV, and FFA in PV were significantly reduced in the exercised rats as compared with the sucrose-fed rats. These findings suggest that long-term exercise improves insulin resistance by reducing the accumulation of MS as well as SC. It is also suggested that short-term exercise improves glucose metabolism without change of fat accumulation.
    Obesity research 07/1997; 5(4):348-53. DOI:10.1002/j.1550-8528.1997.tb00563.x · 4.95 Impact Factor
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    ABSTRACT: High sucrose intake is generally thought to be a risk factor for obesity and insulin resistance. We examined the effects of feeding sucrose on fat accumulation and insulin release in male rats. Six-week-old male Wistar rats were maintained on a high sucrose diet for 4 or 12 weeks. Control rats were fed a diet based on starch. No significant difference in daily caloric intake or weight gain existed between the two dietary groups. There was no difference between the two dietary groups in the gain of abdominal subcutaneous fat (SC) at 4-week. In contrast, rats fed the high sucrose diet had significantly more mesenteric fat (MES) than controls (p < 0.01). At 12 weeks, rats fed the high sucrose diet had significantly more SC and MES than controls (SC: p < 0.05, MES: p < 0.01). Basal immunoreactive insulin (IRI) concentrations in the portal vein (PV) of rats fed the high sucrose diet was significantly higher compared to those of controls (4 wk: p < 0.05, 12 wk: p < 0.05). No difference between the two dietary groups in basal IRI concentrations in the inferior vena cava (IVC) existed at 4 weeks; whereas at 12 weeks, the basal IRI concentrations in the IVC in rats fed the high sucrose diet were significantly higher than in controls (p < 0.05). The mesenteric and subcutaneous fat accumulations were closely related to hyperinsulinemia in the portal vein and inferior vena cava, respectively. Twelve weeks of high sucrose feeding caused accumulation of abdominal adipose tissue with marked hyperinsulinemia and hyperlipidemia. Our study is the first to demonstrate that abdominal fat induced by high sucrose intake in male rats is accompanied by an abnormal metabolic state similar to an insulin-resistant state.
    Obesity research 11/1996; 4(6):561-8. DOI:10.1002/j.1550-8528.1996.tb00270.x · 4.95 Impact Factor
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    ABSTRACT: This study was undertaken to investigate changes in feeding behavior and ambulatory activity, in rats with D-galactosamine (D-GAL)-induced hepatic failure. D-GAL was administered (1000 mg/kg) IP at 1800, just before the dark phase. The first significant decrease of ambulatory activity in rats with hepatic failure was observed between 0000 and 0300 h. A significant increase in drinking behavior was observed between 1800 and 2100 h, and a significant decrease was observed between 2100 and 0300 h. A significant decrease in food intake occurred between 1800 and 2400 h. Thereafter, there was no difference in food intake. In conclusion, we demonstrated significant changes in ambulatory activity, drinking behavior and food intake produced by D-GAL. A wide variation in systems, including monoamine turnover, and amino acid disturbance could be expected in these animals, and such changes might also have contributed to the results observed.
    Physiology & Behavior 06/1992; 51(5):1029-33. DOI:10.1016/0031-9384(92)90087-I · 2.98 Impact Factor
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    ABSTRACT: Since the peripheral prostaglandin synthetizing system may at least partly involved in the anorexia that follows central interleukin-1 beta (IL-1) administration, this study was undertaken to investigate the effect of ibuprofen (ip), selective cyclooxygenase blocker and AA 861, selective lipoxygenase inhibitor, on changes of food and water intake by a single injection of IL-1 (2 micrograms/rat, ip). We demonstrated that food and water intake were suppressed by peripheral administration of IL-1. Throughout the entire observation periods, suppressed food intake was partially restored to control levels by ibuprofen, while water intake completely restored. In addition, no significant differences about water/food intake were observed in the IL-1 + ibuprofen-treated groups, respectively. In the next experiment, IL-1 induced anorexia was also partially restored to the control level following pretreatment with AA 861. These results may suggest that other mechanism including lipoxygenase blocker besides prostaglandin production may be involved in IL-1 induced anorexia.
    Life Sciences 02/1992; 51(18):1419-26. DOI:10.1016/0024-3205(92)90536-X · 2.70 Impact Factor
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    ABSTRACT: This study was undertaken to investigate changes in ambulatory and drinking behavior, using the Gunma University-type special apparatus for continuous and direct measurement of ambulation and drinking in streptozotocin-induced diabetic rats (STZ, 60 mg/kg). Ambulatory activity of diabetic rats was significantly less than that of control rats during the dark phase but not during the light phase. Ambulatory activity of diabetic rats was also significantly less from 0900 to 1000 hr, but significantly more from 1400 to 1500 hr and 1700 to 1800 hr than that of control rats. On the other hand, there was significant increase in drinking behavior from DM-1W to DM-4W rats throughout the experimental time. Since diabetic animals are very sick, a wide variety of metabolic systems, including dopamine turnover, would be expected to be altered in these animals, and such alterations could also contribute to the results observed. Further studies are in progress to determine whether these abnormalities will be normalized by insulin administration.
    Physiology & Behavior 07/1990; 47(6):1153-5. DOI:10.1016/0031-9384(90)90366-C · 2.98 Impact Factor
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    ABSTRACT: The present studies were undertaken to investigate whether or not decreased ambulatory activity, including abnormal feeding behavior in diabetic rats, will be simultaneously normalized by insulin administration. To do this, we used the Gunma University-type automatic apparatus for continuous and direct measurement of ambulation and drinking. In this study, 3 U NPH insulin were administered at 1800, just before the dark phase, and 2 U were administered at 0600, just before the light phase. With these insulin doses, we found that 5 weeks were needed to normalize ambulatory activity, 4 weeks were necessary for food intake, 6 weeks for drinking and 2 weeks for body weight. Since ambulatory activity is reported to be related to changes in dopamine turnover, further studies are in progress to determine whether or not dopamine turnover is normalized when there is no difference in ambulatory activity due to insulin replacement.
    Physiology & Behavior 05/1990; 47(4):731-4. DOI:10.1016/0031-9384(90)90086-J · 2.98 Impact Factor
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    ABSTRACT: We report an adolescent patient with Prader-Willi syndrome accompanying suppressible hypergonadotropism. The subject is an 18-year-old female. She was obese (body mass index: 35.7) and hypomyotonic with mental retardation. On endocrinological examination, a high serum LH concentration and hyperresponsiveness of luteinizing hormone (LH) to intravenously administered LH-Releasing Hormone (LH-RH) were observed, while the basal follicle stimulating hormone level was within the normal range. In addition, serum dehydroxyepiandrosterone sulfate (DHEA-S) was also increased. Following 2 mg dexamethasone administration for 7 days, serum LH and DHEA-S were almost normalized and hyperresponse of LH to LH-RH completely disappeared. The present study provides evidence that altered responsiveness to adrenal steroid may be involved in the establishment of hypergonadotropinism in an adolescent patient with Prader-Willi syndrome.
    Endocrinologia japonica 03/1990; 37(1):165-9. DOI:10.1507/endocrj1954.37.165
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    ABSTRACT: We attempted to determine the significance of ambulatory activity as a cause of overweight in ovariectomized rats. Drinking and ambulation were measured continuously and directly for periods up to 12 months in special apparatus developed at Gunma University. In older rats, ambulatory activity decreased much more in the ovariectomy group than in the control group. There was no difference in food intake between the ovariectomized and the control group. After 2 months, the ovariectomy group increased body weight more than the control group despite no difference in food intake. The decrease in ambulatory activity was consistent in the ovariectomy group, regardless of any differences in age and body weight. These results indicate that decrease of energy expenditure by gradual decrease in ambulatory activity may be an important factor as a cause of overweight in ovariectomized, obese rats.
    Physiology & Behavior 02/1990; 47(1):155-9. DOI:10.1016/0031-9384(90)90055-9 · 2.98 Impact Factor

Publication Stats

299 Citations
61.62 Total Impact Points


  • 2005-2013
    • Aoyama Gakuin University
      • • Department of Science and Engineering
      • • Department of Chemistry and Biological Science
      Edo, Tōkyō, Japan
  • 2009-2010
    • Hidaka Hospital
      Takasaki, Gunma, Japan
  • 1990-1997
    • Gunma University
      • • Department of Clinical Laboratory Medicine
      • • School of Medicine
      Maebashi, Gunma, Japan