Toshio Matsuda

Publications (123)409.04 Total impact

• Article: Effect of Overexpression of the Brain-Specific Na(+)/Ca(2+) Exchanger Splice Variant NCX1.5 on NO Cytotoxicity in HEK293 Cells.

  Yuki Ota, Takuya Kawanai, Ryo Watanabe, Akira Nishimura, Yukio Ago, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Nitric oxide (NO) induces cytotoxicity in neuronal and glial cells via activation of the Na(+)/Ca(2+) exchanger (NCX). This study examined the role of the predominant brain-specific NCX splice variant NCX1.5 in NO-induced cytotoxicity in the HEK293 cell expression system. Cells were transfected with the plasmid construct pcDNA3.1/V5-His containing full-length rat NCX1.5 cDNA. There was no difference in the cytotoxic effects of the NO donors sodium nitroprusside and S-nitroso-N-acetylpenicillamine between control and transfected cells. These results suggest that NO cytotoxicity is not dependent on NCX1.5.
  Journal of Pharmacological Sciences 03/2013; · 2.08 Impact Factor
• Article: Role of social encounter-induced activation of prefrontal serotonergic systems in the abnormal behaviors of isolation-reared mice.

  Yukio Ago, Ryota Araki, Tatsunori Tanaka, Asuka Sasaga, Saki Nishiyama, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Isolation-reared male rodents show abnormal behaviors such as hyperlocomotion, aggressive behaviors, deficits of prepulse inhibition, and depression- and anxiety-like behaviors, but the neurochemical mechanism for the effects of psychological stress in these animals is not fully understood. This study examined the effects of social interactions between isolation-reared mice and intruder mice on brain monoaminergic systems. A cage was divided in two compartments by a mesh partition to prevent direct physical interactions. The 20-min encounter with an intruder elicited a restless and hyperexcitable state (hyperactivity) in male, but not female, isolation-reared mice, whereas encounters with a sleeping intruder or a novel object did not. Although the encounter did not affect prefrontal neuronal-activity-marker c-Fos expression, dopamine (DA) levels, or serotonin (5-HT) levels in male group-reared mice or female isolation-reared mice, it increased prefrontal c-Fos expression, DA levels, and 5-HT levels in male isolation-reared mice. Furthermore, encounter-induced increases in c-Fos expression in the dorsal raphe nucleus and ventral tegmental area, but not nucleus accumbens shell, were much greater in isolation-reared than group-reared male mice. A 5-HT(1A) receptor agonist, a metabotropic glutamate 2/3 receptor agonist, and a gamma-aminobutyric acid A receptor agonist attenuated isolation-induced aggressive behaviors and encounter-induced hyperactivity, c-Fos expression in the prefrontal cortex and dorsal raphe nucleus, and increases in prefrontal 5-HT levels. These findings suggest that the prefrontal DA and 5-HT systems are activated by encounter stimulation in male isolation-reared mice and the encounter-induced activation of 5-HT system triggers the induction of some abnormal behaviors in male isolation-reared mice. Furthermore, this study implies that the encounter stimulation-induced signal has a pharmacological significance.Neuropsychopharmacology accepted article preview online, 20 February 2013; doi:10.1038/npp.2013.52.
  Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; · 6.99 Impact Factor
• Article: The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity.

  Kazuhiro Takuma, Yukio Ago, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: The plasma membrane Na+/Ca2+ exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na+ in one direction with that of Ca2+ in the opposite direction. This system contributes to the regulation of intracellular Ca2+ concentration via the forward mode (Ca2+ efflux) or the reverse mode (Ca2+ influx). We have previously demonstrated that the Ca2+ paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca2+ homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca2+ paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca2+ and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity.
  Current Protein and Peptide Science 02/2013; · 2.89 Impact Factor
• Article: The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses psychomotor abnormalities and recognition memory deficits in mice lacking the pituitary adenylate cyclase-activating polypeptide.

  Yukio Ago, Naoki Hiramatsu, Toshihiro Ishihama, Keisuke Hazama, Atsuko Hayata-Takano, Yasuhiro Shibasaki, Norihito Shintani, Hitoshi Hashimoto, Toshiyuki Kawasaki, Hirotaka Onoe, Shigeyuki Chaki, Atsuro Nakazato, Akemichi Baba, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric disorders. In this study, we examined the effects of the selective metabotropic glutamate 2/3 (mGlu2/3) receptor agonist MGS0028 on behavioral abnormalities in mice lacking the pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental model of psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder. We found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg). Similarly, MGS0028 improved hyperactivity and jumping behaviors, but did not reverse increased immobility times in the forced swim test in PACAP-deficient mice. These results suggest that MGS0028 may be a potential, novel treatment for psychiatric disorders.
  Behavioural pharmacology 02/2013; 24(1):74-77. · 2.85 Impact Factor
• Article: Effects of serotonin-norepinephrine reuptake inhibitors on locomotion and prefrontal monoamine release in spontaneously hypertensive rats.

  Masato Umehara, Yukio Ago, Kazumi Fujita, Naoki Hiramatsu, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Catecholamine neurotransmission in the prefrontal cortex plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). Recent clinical studies show that several serotonin-norepinephrine reuptake inhibitors have potential for treating ADHD. In this study, we examined the effects of acute treatment with serotonin-norepinephrine reuptake inhibitors on locomotion and the extracellular levels of monoamines in the prefrontal cortex in spontaneously hypertensive rats (SHR), an animal model of ADHD. Adolescent male SHR exhibited greater horizontal locomotion in an open-field test than male WKY control rats. Psychostimulant methylphenidate (0.3 and 1mg/kg), the selective norepinephrine reuptake inhibitor atomoxetine (1 and 3mg/kg), and serotonin-norepinephrine reuptake inhibitors duloxetine (10mg/kg), venlafaxine (10 and 30mg/kg) and milnacipran (30mg/kg) reduced the horizontal activity in SHR, but did not affect in WKY rats. The selective norepinephrine reuptake inhibitor reboxetine (10mg/kg) and the tricyclic antidepressant desipramine (10 and 30mg/kg) also reduced the horizontal activity in SHR, whereas the selective serotonin reuptake inhibitor citalopram (30mg/kg) did not. Microdialysis studies showed that atomoxetine, methylphenidate, duloxetine, venlafaxine, milnacipran, and reboxetine increased the extracellular levels of norepinephrine and dopamine in the prefrontal cortex in SHR. Citalopram did not affect norepinephrine and dopamine levels in the prefrontal cortex, although it increased the serotonin levels. Neither duloxetine nor venlafaxine increased the dopamine levels in the striatum. These findings suggest that serotonin-norepinephrine reuptake inhibitors, similar to methylphenidate and atomoxetine, have potential for ameliorating motor abnormality in the SHR model.
  European journal of pharmacology 01/2013; · 2.59 Impact Factor
• Article: Involvement of spinal 5-HT(1A) receptors in isolation rearing-induced hypoalgesia in mice.

  Naotaka Horiguchi, Yukio Ago, Kazuki Asada, Yuki Kita, Naoki Hiramatsu, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: RATIONALE: Isolation rearing in rodents causes not only abnormal behaviors which resemble the clinical symptoms of schizophrenia but also hypoalgesia in thermal nociception models. However, the mechanism of the hypoalgesia is not known. OBJECTIVES: The present study investigated the effect of isolation rearing on acute pain and the descending pain inhibitory pathways in mice. RESULTS: Rearing in isolation for 6 weeks from post-weaning reduced pain sensitivity in the hot plate test and acetic acid-induced writhing test. Isolation rearing also reduced the intraplantar capsaicin-induced licking behavior. Capsaicin increased c-Fos expression, a neuronal activity marker, in the spinal cord and primary somatosensory cortex both in group- and isolation-reared mice, but this effect did not differ between groups. On the other hand, c-Fos expression in the anterior cingulate cortex, periaqueductal gray matter, and rostral ventromedial medulla, but not in the spinal cord or somatosensory cortex, was enhanced by isolation rearing. Systemic administration of WAY100635 (serotonin (5-HT)(1A) receptor antagonist), but not of ketanserin (5-HT(2) receptor antagonist), prazosin (α(1)-adrenoceptor antagonist), or yohimbine (α(2)-adrenoceptor antagonist), attenuated isolation rearing-induced hypoalgesia in capsaicin-induced licking behavior. Attenuation of isolation rearing-induced hypoalgesia was also observed following the intrathecal injection of WAY100635. Naloxone, an opioid receptor antagonist, did not affect the hypoalgesia in isolation-reared mice. CONCLUSIONS: These findings suggest that isolation rearing causes hypoalgesia in mouse models of acute pain and imply that the spinal 5-HT(1A) receptor activation probably through descending serotonergic inhibitory pathway is involved in isolation rearing-induced hypoalgesia.
  Psychopharmacologia 12/2012; · 4.08 Impact Factor
• Article: Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice.

  Yukio Ago, Koji Yano, Ryota Araki, Naoki Hiramatsu, Yuki Kita, Toshiyuki Kawasaki, Hirotaka Onoe, Shigeyuki Chaki, Atsuro Nakazato, Hitoshi Hashimoto, Akemichi Baba, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists have an antidepressant-like effect, but the exact mechanism still remains unclear. This study examined the effects of mGlu2/3 receptor antagonists in chronic corticosterone-treated mice which could be used as an animal model of depression. In the forced swim test, the mGlu2/3 receptor antagonists MGS0039 (1.0 mg/kg, i.p.) and LY341495 (0.3 mg/kg, i.p) significantly reduced the increased immobility time of mice pretreated with corticosterone (20 mg/kg, s.c.) for 21 days, while desipramine (30 mg/kg, i.p.) and fluoxetine (30 mg/kg, i.p.) did not. The antidepressant-like effect of LY341495 was not blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist NBQX (10 mg/kg, i.p.). Systemic administration of LY341495 did not affect basal release of glutamate, dopamine or serotonin in the prefrontal cortex of the control or chronic corticosterone-treated mice. Chronic corticosterone markedly enhanced high K(+)-induced release of dopamine, but not serotonin or glutamate, in the prefrontal cortex. This neurochemical change was blocked by systemic administration of MGS0039 and LY341495, but not desipramine or fluoxetine. These results suggest that chronic corticosterone-treated mice could be used as an animal model of treatment-resistant depression. This study also suggests that the prefrontal dopaminergic system is involved in the antidepressant-like effect of mGlu2/3 receptor antagonists in the chronic corticosterone-induced depression model.
  Neuropharmacology 09/2012; 65C:29-38. · 4.81 Impact Factor
• Article: Galantamine increases hippocampal insulin-like growth factor 2 expression via α7 nicotinic acetylcholine receptors in mice.

  Yuki Kita, Yukio Ago, Erika Takano, Asako Fukada, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: RATIONALE AND OBJECTIVE: Galantamine, a drug for the treatment of Alzheimer's disease, has neuroprotection in several experimental models and stimulates adult neurogenesis in the rodent brain, but the exact mechanism remains unclear. This study examined whether galantamine affects the expression of neurotrophic/growth factors in the mouse hippocampus and prefrontal cortex. METHODS: Nine-week-old male ddY mice were used. The mRNA levels of neurotrophic/growth factors were analyzed by a real-time quantitative PCR. The protein levels of insulin-like growth factor 2 (IGF2) were analyzed by Western blotting. RESULTS: Acute administration of galantamine (0.3-3 mg/kg, i.p.) increased IGF2 mRNA levels in the hippocampus, but not in the prefrontal cortex, in time- and dose-dependent manner. Galantamine (3 mg/kg, i.p.) caused a transient increase in fibroblast growth factor 2 mRNA levels and a decrease in brain-derived neurotrophic factor mRNA levels in the hippocampus, while it did not affect the mRNA levels of other neurotrophic/growth factors. The galantamine-induced increase in the hippocampal IGF2 mRNA levels was blocked by mecamylamine, a nonselective nicotinic acetylcholine (ACh) receptor (nAChR) antagonist, and methyllycaconitine, a selective α7 nAChR antagonist, but not by telenzepine, a preferential M(1) muscarinic ACh receptor antagonist. Moreover, the selective α7 nAChR agonist PHA-543613 increased the IGF2 mRNA levels, while donepezil, an acetylcholinesterase inhibitor, did not. Galantamine also increased hippocampal IGF2 protein, which was blocked by methyllycaconitine. CONCLUSIONS: These findings suggest that galantamine increases hippocampal IGF2 levels via α7 nAChR activation in mice and imply that the effect may contribute to its neuroprotection or neurogenesis.
  Psychopharmacologia 08/2012; · 4.08 Impact Factor
• Article: Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with (11)C-labeled 20-HETE synthase-specific inhibitor.

  Toshiyuki Kawasaki, Toshiyuki Marumo, Keiko Shirakami, Tomoko Mori, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Shigeyuki Chaki, Atsuro Nakazato, Yukio Ago, Hitoshi Hashimoto, Toshio Matsuda, Akemichi Baba, Hirotaka Onoe
  [show abstract] [hide abstract]
  ABSTRACT: 20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.
  Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2012; 32(9):1737-46. · 5.46 Impact Factor
• Article: Effect of prenatal valproic acid exposure on cortical morphology in female mice.

  Yuta Hara, Yuko Maeda, Shunsuke Kataoka, Yukio Ago, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.
  Journal of Pharmacological Sciences 03/2012; 118(4):543-6. · 2.08 Impact Factor
• Article: Neuronal nitric oxide synthase inhibition attenuates the development of L-DOPA-induced dyskinesia in hemi-Parkinsonian rats.

  Kazuhiro Takuma, Tatsunori Tanaka, Tsuyoshi Takahashi, Naoki Hiramatsu, Yuki Ota, Yukio Ago, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Long-term treatment with the dopamine precursor levodopa (l-DOPA) frequently induces dyskinesia in Parkinson's disease patients, which is a major complication of this therapy. Previous studies using animal models show that repeated administration of l-DOPA results in alterations of some signaling molecules, including ΔFosB, phospho-DARPP32 and phosoho-GluA1 (also referred to as GluR1 or GluR-A) AMPA receptor subunits. Moreover, an in vivo microdialysis study showed that l-DOPA increases nitric oxide (NO) production in the striatum. However, it is not known whether NO is involved in the development of dyskinesia. The present study examined the effects of NOS inhibitors on the development of l-DOPA-induced dyskinesia in the rats. Dyskinesia symptoms were triggered by daily administration of l-DOPA for 3-4weeks in unilateral 6-hydroxydopamine lesioned rats. Repeated treatments, 30min prior l-DOPA administration, of the nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester, and the nNOS inhibitor 7-nitroindazole, but not the inducible NOS inhibitor aminoguanidine, attenuated the development of l-DOPA-induced dyskinesia. In agreement with the behavioral analysis, 7-nitroindazole reduced the l-DOPA-induced increases in ΔFosB, phospho-DARPP32 and phospho-GluA1 AMPA receptor subunit levels in the striatum of 6-hydroxydopamine-lesioned rats. Furthermore, aminoguanidine did not affect ΔFosB or phospho-GluA1 AMPA receptor subunit levels. These findings suggest that nNOS-derived NO is involved in the development of l-DOPA-induced dyskinesia through a post-synaptic mechanism.
  European journal of pharmacology 03/2012; 683(1-3):166-73. · 2.59 Impact Factor
• Article: Lithium attenuates methamphetamine-induced hyperlocomotion and behavioral sensitization via modulation of prefrontal monoamine release.

  Yukio Ago, Tatsunori Tanaka, Yuki Kita, Hokuto Tokumoto, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Lithium attenuates psychostimulant-induced hyperactivity and behavioral sensitization, but the exact mechanisms are not known. Previous studies show that lithium has neuromodulatory effects on monoamine systems. The present study was aimed to clarify whether prefrontal monoaminergic neurotransmission is involved in the effect of lithium on methamphetamine (METH)-induced behaviors in mice. Lithium attenuated METH-induced hyperactivity and METH-induced increase in extracellular dopamine (DA), but not serotonin (5-HT), levels in the prefrontal cortex. Chronic METH caused behavioral sensitization and enhancement of METH-induced increase in prefrontal 5-HT release (neurochemical sensitization). Co-administration of lithium with METH attenuated behavioral sensitization and neurochemical sensitization. Chronic METH also reduced the 5-HT(1A) receptor agonist osemozotan-induced decrease in prefrontal 5-HT release (desensitization of presynaptic 5-HT(1A) autoreceptor), and this effect was reversed by co-administration of lithium. These results suggest that lithium attenuates acute METH-induced hyperactivity and chronic METH-induced behavioral sensitization via modulation of prefrontal release of DA and 5-HT, respectively. The present study also suggests that a 5-HT(1A) receptor-mediated mechanism is involved in the effect of lithium on chronic METH-induced behavioral sensitization.
  Neuropharmacology 03/2012; 62(4):1634-9. · 4.81 Impact Factor
• Source

  Available from: Yukio Ago

  Article: The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses isolation rearing-induced abnormal behaviors in mice.

  Yukio Ago, Ryota Araki, Koji Yano, Toshiyuki Kawasaki, Shigeyuki Chaki, Atsuro Nakazato, Hirotaka Onoe, Hitoshi Hashimoto, Akemichi Baba, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Isolation-induced abnormal behaviors are useful animal models for assessing potential anti-psychotic drugs. This study examined the effect of MGS0028, a selective metabotropic glutamate 2/3 receptor agonist, on abnormal behaviors such as hyperactivity, aggression, and deficits of prepulse inhibition in isolation-reared mice. MGS0028 attenuated hyperactivity and aggressive behaviors in isolation-reared mice. The agonist also reversed isolation rearing-induced deficits of prepulse inhibition. On the other hand, MGS0028 did not affect locomotor activity and prepulse inhibition in group-reared mice. These results suggest that the metabotropic glutamate 2/3 receptor agonist, MGS0028, is a potential compound for the treatment of psychiatric disorders.
  Journal of Pharmacological Sciences 02/2012; 118(2):295-8. · 2.08 Impact Factor
• Article: [Pharmacological profiles of galantamine: the involvement of muscarinic receptor].

  Toshio Matsuda, Yukio Ago, Kazuhiro Takuma
  [show abstract] [hide abstract]
  ABSTRACT: Galantamine, currently used in Japan for the treatment of Alzheimer's disease, may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder and alcohol abuse. It is a rather weak acetylcholinesterase inhibitor in vitro, but has additional allosteric potentiating effects at nicotinic receptors. We have found that galantamine increased acetylcholine levels in the brain. This suggests that the pharmacological effects of galantamine are mediated by not only nicotinic receptors but also muscarinic receptors. We found that galantamine, but not donepezil, improved prepulse inhibition (PPI) deficits in isolation-reared mice, although both drugs improved PPI deficits in an apomorphine model. The difference in the effects on PPI deficits between galantamine and donepezil may be explained by the effects on muscarinic receptors. This review summarizes the pharmacological profiles of galantamine, focusing on the importance of muscarinic receptors.
  Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 02/2012; 32(1):1-8.
• Article: Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid.

  Shunsuke Kataoka, Kazuhiro Takuma, Yuta Hara, Yuko Maeda, Yukio Ago, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4-8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.
  The International Journal of Neuropsychopharmacology 11/2011; · 4.58 Impact Factor
• Article: SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease.

  Yukio Ago, Toshiyuki Kawasaki, Tetsuaki Nashida, Yuki Ota, Yana Cong, Mari Kitamoto, Teisuke Takahashi, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.
  Neuropharmacology 09/2011; 61(8):1441-51. · 4.81 Impact Factor
• Source

  Available from: Yukio Ago

  Article: Preventive effects of an enriched environment on rodent psychiatric disorder models.

  Kazuhiro Takuma, Yukio Ago, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: Interplay between genetic and environmental factors plays a key role in psychiatric disorders, as well as other brain diseases, cancer, and metabolic syndrome. In accordance with epidemiological findings, animal studies have pointed out the importance of a variety of environmental factors, such as viral infection during pregnancy or infancy, early parental loss or separation, and physical or sexual abuse in early life, in the etiology of psychiatric disorders. Conversely, positive effects of environmental factors against the pathogenesis of psychiatric disorders are also demonstrated, in which most of the animals are exposed to an "enriched environment". This review summarizes recent progress of research in this field focusing on the preventive effects of an "enriched environment" against the expression of behavioral abnormalities in rodent models of psychiatric disorders.
  Journal of Pharmacological Sciences 09/2011; 117(2):71-6. · 2.08 Impact Factor
• Article: Molecular and functional characterization of the human platelet Na(+) /Ca(2+) exchangers.

  Diane E Roberts, Toshio Matsuda, Ratna Bose
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND AND PURPOSE The Na(+) /Ca(2+) exchanger is a bi-directional transporter that plays an important role in maintaining the concentration of cytosolic Ca(2+) ([Ca(2+) ](i) ) of quiescent platelets and increasing it during activation with some, but not all, agonists. There are two classes of Na(+) /Ca(2+) exchangers: K(+) -independent Na(+) /Ca(2+) exchanger (NCX) and K(+) -dependent Na(+) /Ca(2+) exchanger (NCKX). Platelets have previously been shown to express NCKX1. However, initial studies from our laboratory suggest that NCX may also play a role in platelet activation. The objective of this study was to determine if the human platelet expresses functional NCXs. EXPERIMENTAL APPROACH RT-PCR, DNA sequencing and Western blot analysis were utilized to characterize the human platelet Na(+) /Ca(2+) exchangers. Their function during quiescence and collagen-induced activation was determined by measuring [Ca(2+) ](i) with calcium-green/fura-red in response to: changes in the Na(+) and K(+) gradient, NCX pharmacological inhibitors (CBDMB, KB-R7943 and SEA0400) and antibodies specific to extracellular epitopes of the exchangers. KEY RESULTS Human platelets express NCX1.3, NCX3.2 and NCX3.4. The NCXs operate in the Ca(2+) efflux mode in resting platelets and also during their activation with thrombin but not collagen. Collagen-induced increase in [Ca(2+) ](i) was reduced with the pharmacological inhibitors of NCX (CBDMB, KB-R7943 or SEA0400), anti-NCX1 and anti-NCX3. In contrast, anti-NCKX1 enhanced the collagen-induced increase in [Ca(2+) ](i) . CONCLUSIONS AND IMPLICATIONS Human platelets express K(+) -independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. During collagen activation, NCX1 and NCX3 transiently reverse to promote Ca(2+) influx, whereas NCKX1 continues to operate in the Ca(2+) efflux mode to reduce [Ca(2+) ](i) .
  British Journal of Pharmacology 07/2011; 165(4):922-36. · 4.41 Impact Factor
• Article: Donepezil, but not galantamine, blocks muscarinic receptor-mediated in vitro and in vivo responses.

  Yukio Ago, Ken Koda, Yuki Ota, Yuki Kita, Asako Fukada, Kazuhiro Takuma, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: We have found that galantamine, but not donepezil, reversed isolation rearing-induced deficits of prepulse inhibition (PPI) via an activation of muscarinic M1 receptors. To explain this difference, the present study examined the effects of these acetylcholinesterase inhibitors on muscarinic receptor-mediated responses in in vitro and in vivo systems. Ca(2+) -imaging study showed that donepezil, but not galantamine, blocked a muscarinic agonist carbachol-induced increase in intracellular Ca(2+) levels in SH-SY5Y cells. Moreover, a microdialysis study showed that intraperitoneal administration of donepezil, but not galantamine, attenuated a preferential M1 receptor agonist Ndesmethylclozapine-induced increase in dopamine release in mouse cerebral cortex. These results suggest that donepezil, but not galantamine, has an ability to block muscarinic receptor function and imply that the differential effects may be responsible for the difference in the effects on isolation rearing-induced deficits of PPI between these drugs. Synapse, 2011. © 2011 Wiley-Liss, Inc.
  Synapse 07/2011; 65(12):1373-7. · 2.94 Impact Factor
• Article: The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide-induced cytotoxicity in SH-SY5Y cells.

  Tetsuaki Nashida, Kazuhiro Takuma, Sayoko Fukuda, Toshiyuki Kawasaki, Teisuke Takahashi, Akemichi Baba, Yukio Ago, Toshio Matsuda
  [show abstract] [hide abstract]
  ABSTRACT: The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway.
  Neurochemistry International 06/2011; 59(1):51-8. · 2.86 Impact Factor