Koyama Y.,Osaka Ohtani University
Biomolecular Concepts | Year: 2013
In addition to their potent vasoconstriction effects, endothelins (ETs) show multiple actions in various tissues including the brain. The brain contains high levels of ETs, and their production is stimulated in many brain disorders. Accumulating evidence indicates that activation of brain ET receptors is involved in several pathophysiological responses in damaged brains. In this article, the roles of brain ET systems in relation to brain disorders are reviewed. In the acute phase of stroke, prolonged vasospasm of cerebral arteries and brain edema occur, both of which aggravate brain damage. Studies using ET antagonists show that activation of ET A receptors in the brain vascular smooth muscle induces vasospasm after stroke. Brain edema is induced by increased activity of vascular permeability factors, such as vascular endothelial growth factor and matrix metalloproteinases. Activation of ET B receptors stimulates astrocytic production of these permeability factors. Increases in reactive astrocytes are observed in neurodegenerative diseases and in the chronic phase of stroke, where they facilitate the repair of damaged nerve tissues by releasing neurotrophic factors. ETs promote the induction of reactive astrocytes through ET B receptors. ETs also stimulate the production of astrocytic neurotrophic factors. Recent studies have shown high expression of ET B receptors in neural progenitors. Activation of ET B receptors in neural progenitors promotes their proliferation and migration, suggesting roles for ET B receptors in neurogenesis. Much effort has been invested in the pursuit of novel drugs to induce protection or repair of damaged nerve tissues. From these studies, the pharmacological significance of brain ET systems as a possible target of neuroprotective drugs is anticipated.
Takehashi M.,Osaka Ohtani University |
Kanatsu-Shinohara M.,Kyoto University |
Shinohara T.,Kyoto University
Development Growth and Differentiation | Year: 2010
Spermatogonial stem cells (SSCs) provide the foundation for spermatogenesis, and are unique tissue-specific stem cells because of their ability to transmit genetic information to offspring. Generation of knockout mice using mouse SSCs became feasible after the successful establishment of protocols for the transplantation and long-term culture of these cells, called germline stem (GS) cells. Furthermore, SSCs can acquire pluripotentiality similar to that of embryonic stem (ES) cells, in addition to their highly differentiated spermatogenic potential. These ES-like cells, called multipotent GS (mGS) cells, are capable of generating knockout mice in a manner similar to that of ES cells. The use of GS and mGS cells for animal transgenesis has added a new dimension to gene-targeting technology using ES cells and somatic cell nuclear transfer, which has limited application. Furthermore, for regenerative medicine purposes, the use of mGS will settle problems such as ethics issues and immunological rejection associated with ES cells, as well as risks of insertional mutagenesis associated with integrated genes into induced pluripotent stem cells. © 2010 Japanese Society of Developmental Biologists.
Koyama Y.,Osaka Ohtani University |
Michinaga S.,Osaka Ohtani University
Journal of Pharmacological Sciences | Year: 2012
The receptors for endothelins (ETs) are classified into the ETA and ETB types. ETB receptors are highly expressed in astrocytes, but pharmacological usages of this receptor are not clarified. In this article, recent studies on the pathophysiological roles of astrocytic ETB receptors in the brain are reviewed. The administration of ETB agonists and antagonists in nerve injury models showed that several astrocytic functions are regulated by ETB receptors. The activation of ETB receptors causes morphological alterations and proliferation of cultured astrocytes. Astrocytes produce various bio-active substances that can affect damage to nerve tissues. ETs stimulate the production of neurotrophic factors by astrocytes. This action improves impaired brain functions. On the other hand, the production of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which induce brain edema, also are stimulated by ETs. These findings indicate that astrocytic functions are effectively regulated by modulations of ETB receptors. In brain insults and neurodegenerative diseases, these functions of astrocytes affect the protection and repair of damaged nerve tissues. Thus, astrocytic ETB receptors could be a target for novel types of neuroprotective drugs. © The Japanese Pharmacological Society.
Koyama Y.,Osaka Ohtani University |
Tanaka K.,Osaka Ohtani University
Journal of Pharmacological Sciences | Year: 2010
Matrix metalloproteinases (MMPs), a family of zinc-endopeptidases, have a critical role in the pathophysiological responses in damaged brains. MMPs are up-regulated in brain pathologies. To clarify the extracellular signals involved in brain MMP production, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. Intracerebroventricular administration of 500 pmol/day Ala1,3,11,15-ET-1, an ETB-receptor agonist, increased the mRNAs of MMP2 and MMP9 in rat hippocampus and cerebrum. Ala1,3,11,15-ET-1 did not affect mRNA levels of MMP 1, 12, and 14. Administration of Ala1,3,11,15-ET-1 for 7 days also increased the protein content and proteolytic activities of MMP2 and MMP9 in the cerebrum. Immunohistochemical observations showed that astrocytes in the hippocampus and the cerebrum of ET-infused rats had MMP2 and MMP9 reactivities. In rat cultured astrocytes, both Ala1,3,11,15-ET-1 (100 nM) and ET-1 (100 nM) increased MMP2 and MMP9 mRNAs. ET-1 stimulated the protein releases and the proteolytic activities of MMP2 and MMP9 from cultured astrocytes. BQ788, an ETB antagonist, inhibited the effects of ET-1 on astrocytic MMP2 and MMP9. The ET-induced expression of MMP9, but not MMP2, was inhibited by pyrrolidine dithiocarbamate, proteasome inhibitor I, and MG132. These results suggest that ET stimulates astrocytic MMP2 and MMP9 production through ET B receptors. ©2010 The Japanese Pharmacological Society.
Koyama Y.,Osaka Ohtani University
Journal of neurochemistry | Year: 2014
Expressions of vascular endothelial growth factor (VEGF) receptors in astrocytes are increased in damaged brains. To clarify the regulatory mechanisms of VEGF receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Expressions of VEGF-R1 and -R2 receptor mRNA were at similar levels, whereas the mRNA expressions of VEGF-R3 and Tie-2, a receptor for angiopoietins, were lower. Placenta growth factor, a selective agonist of the VEGF-R1 receptor, induced phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Phosphorylations of FAK and ERK 1/2 were also stimulated by VEGF-E, a selective VEGF-R2 agonist. Increased phosphorylations of FAK and ERK1/2 by VEGF165 were reduced by selective antagonists for VEGF-R1 and -R2. Treatment with ET-1 increased VEGF-R1 mRNA and protein levels. The effects of ET-1 on VEGF-R1 mRNA were mimicked by Ala(1,3,11,15) -ET-1, a selective agonist for ETB receptors, and inhibited by BQ788, an ETB antagonist. ET-1 did not affect the mRNA levels of VEGF-R2, -R3, and Tie-2. Pre-treatment with ET-1 potentiated the effects of placenta growth factor on phosphorylations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes, and potentiates VEGF signals in damaged nerve tissues. To clarify the regulatory mechanisms of vascular endothelial growth factor (VEGF) receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Effects of selective VEGF-R1 and R2 agonist showed that these receptors were linked to focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Treatment with ET-1 increased expression of VEGF-R1, which was mediated by ETB receptors. Pre-treatment with ET-1 potentiated the VEGF-R1-mediated activations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes. © 2014 International Society for Neurochemistry.
Yasuda M.,Osaka Ohtani University
Rorschachiana | Year: 2015
Eye movements during the Rorschach Inkblot Method (RIM) were monitored to investigate the existence of location recognition failures that were accompanied by clients' explanations in the inquiry phase. We hypothesized that perceived locations may have differed from actual explained locations if fixations did not occur -and visual attention was diverted to other locations -just before the response in the free association phase. The eye movement data of 29 participants under a Rorschach administration were collected, and 688 responses were obtained. Of these, 195 responses that involved perception of small, specific locations were used to investigate the association between pre-response eye movements and queried locations. Six responses of three participants showed fixations within 3 s before the time of response at locations different from the locations provided in the explanation. Responses made to similar but different locations were indicative of potential failures of location recognition. © 2015 Hogrefe Publishing.
Katsuki H.,Kumamoto University |
Michinaga S.,Osaka Ohtani University
Vitamins and Hormones | Year: 2012
Non-ergot-type dopamine receptor agonists such as ropinirole are used for treatment of Parkinson disease, but they frequently produce adverse actions characterized by sleepiness and sleep attacks. Because these symptoms are similar to those observed in patients with narcolepsy, a sleep disorder caused by degeneration of hypothalamic orexin neurons, involvement of orexinergic system in the adverse drug actions is suspected. We found that ropinirole and other non-ergot dopamine D 2 receptor agonists cause selective loss of orexin-immunoreactive neurons in organotypic slice culture of rat hypothalamus. The mechanism of this action is considered to involve D 2 receptor-mediated presynaptic suppression of glutamatergic excitatory inputs to orexin neurons because continuous silencing of excitatory activity of orexin neurons can deplete orexin from cell bodies. In addition, Parkinson disease itself may accompany loss of orexin neurons. Disturbance of orexinergic system may play an important role in sleep/arousal dysfunctions under these and other clinical conditions. © 2012 Elsevier Inc..
Koyama Y.,Osaka Ohtani University
Neurochemistry International | Year: 2014
Phenotypic conversion of astrocytes from resting to reactive (i.e., astrocytic activation) occurs in numerous brain disorders. Astrocytic activation in severely damaged brain regions often leads to glial scar formation. Because astrocytic activation and glial scar largely affect the vulnerability and tissue repair of damaged brain, numerous studies have been made to clarify mechanisms regulating the astrocytic phenotype. The phenotypic conversion is accompanied by the increased expression of intermediate filament proteins and the induction of hypertrophy in reactive astrocytes. Severe brain damage results in proliferation and migration of reactive astrocytes, which lead to glial scar formations at the injured areas. Gliogenesis from neural progenitors in the adult brain is also involved in astrocytic activation and glial scar formation. Recent studies have shown that increased expression of connexin 43, aquaporin 4, matrix metalloproteinase 9, and integrins alter the function of astrocytes. The transcription factors: STAT3, OLIG2, SMAD, NF-κB, and Sp1 have been suggested to play regulatory roles in astrocytic activation and glial scar formation. In this review, I discuss the roles of these key molecules regulating the pathophysiological functions of reactive astrocytes. © 2014 Elsevier Ltd. All rights reserved.
Nagai K.,Osaka Ohtani University |
Konishi H.,Osaka Ohtani University
Fundamental and Clinical Pharmacology | Year: 2014
Nucleoside transporter (NT) and nucleic-related enzyme (NRE) play key roles in the physiology of nucleosides and the pharmacology of its analogs in mammals. In this study, we examined the effect of fluoxetine, a selective serotonin reuptake inhibitor, and pergolide, a dopamine D receptor agonist, on the expression of NTs and NREs in mouse brain. It was confirmed by the detection of corresponding mRNAs that three equilibrative nucleoside transporter (ENT1-3) isoforms, concentrative nucleoside transporter 2 (CNT2), CNT3, adenosine kinase (AK), and apyrase, but not CNT1, were expressed in brain tissue. Based on an assessment by mRNA determination, the cerebral expression of CNT2 was found to be increased by administration of fluoxetine and pergolide to mice. Furthermore, pergolide increased the expression of ENT2. However, fluoxetine and pergolide had no significant effect on the expression of mRNA for other NTs, AK, and apyrase. Therefore, we concluded that the expression of several NT isoforms, but not NREs, in mouse brain was affected by treatment with fluoxetine and pergolide. © 2012 Société Française de Pharmacologie et de Thérapeutique.
Maki S.,Osaka Ohtani University
PLoS ONE | Year: 2016
Heat transfer of magnetothermal convection with the presence or absence of the magnetic force acting on the susceptibility gradient (fsc ) was examined by three-dimensional numerical computations. Thermal convection of water enclosed in a shallow cylindrical vessel (diameter over vessel height = 6.0) with the Rayleigh-Benard model was adopted as the model, under the conditions of Prandtl number 6.0 and Ra number 7000, respectively. The momentum equations of convection were nondimensionalized, which involved the term of fsc and the term of magnetic force acting on the magnetic field gradient (fb ). All the computations resulted in axisymmetric steady rolls. The values of the averaged Nu, the averaged velocity components U, V, and W, and the isothermal distributions and flow patterns were almost completely the same, regardless of the presence or absence of the term of fsc .Asa result, we found that the effect of fsc was extremely small, although much previous research emphasized the effect with paramagnetic solutions under an unsteady state. The magnitude of fsc depends not only on magnetic conditions (magnitudes of magnetic susceptibility and magnetic flux density), but also on the thermal properties of the solution (thermal conductivity, thermal diffusivity, and viscosity). Therefore the effect of fb becomes dominant on the magnetothermal convection. Active control over the density gradient with temperature will be required to advance heat transfer with the effect of fsc. © 2016 Syou Maki. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.