Faculty Profiles - SAKAMOTO Hirotaka

Papers - SAKAMOTO Hirotaka

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In Vivo Effects of Ovarian Steroid Hormones on the Expressions of Estrogen Receptors and the Composition of Extracellular Matrix in the Anterior Cruciate Ligament in Rats Reviewed

Atsuhiko Yoshida, Toru Morihara, Yoshiteru Kajikawa, Yuji Arai, Yasushi Oshima, Toshikazu Kubo, Ken-ichi Matsuda, Hirotaka Sakamoto, Mitsuhiro Kawata

CONNECTIVE TISSUE RESEARCH 50 ( 2 ) 121 - 131 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Female athletes have a significantly higher rate of anterior cruciate ligament (ACL) injury than their male counterparts. Sex steroid hormones are considered to have an influence as risk factors for female ACL injuries. We hypothesized that estrogen and progesterone have specific and synergistic influences on the composition of extracellular matrix in ACL. By ovariectomy (OVX) followed by subcutaneous estradiol (E2) and/or progesterone (P4) replacement, 40 female rats were divided into 5 groups: E2, P4, combined E2 and P4 (EP), OVX control, and sham group. After 30 days, using undecalcified sections of knee joints in conjunction with immunofluorescence staining of estrogen receptor and (ER and ER), collagen types 1 and 3, and cartilage oligomeric matrix protein (COMP), the immunoreactivities of these proteins in two distinct parts of ACL, proximal and middle portions, were compared semiquantitatively among experimental groups. By E2 replacement, the expressions of ER in ACL fibroblasts were elevated compared to the OVX group. At the proximal portion, the immunoreactivities of type 1 collagen by E2 replacement, type 3 collagen by P4 replacement, and COMP by E2 or P4 replacement were significantly reduced. At the middle portion, the immunoreactivity of type 3 collagen was significantly elevated by E2 replacement. However, no differences were observed between the sham and OVX groups. These findings suggest that ACL is ER-dependent and that ovarian hormones alter ligament tissue composition, especially at the proximal portion. Female hormonal influences are partly involved in the biological properties of ACL.

DOI： 10.1080/03008200802531287

Androgen action in the brain and spinal cord for the regulation of male sexual behaviors Reviewed

Ken-ichi Matsuda, Hirotaka Sakamoto, Mitsuhiro Kawata

CURRENT OPINION IN PHARMACOLOGY 8 ( 6 ) 747 - 751 2008.12

Language：English Publisher：ELSEVIER SCI LTD

Circulating levels of androgens determine the sexual differentiation of the brain and spinal cord at a critical period, Although estradiol, which is converted from testosterone by aromatase action, can explain the cytological basis for the sexual dimorphism, androgen has its own regulatory mechanism to promote male-specific behavior through receptors. The central nervous system (CNS) employs a sex-specific neuronal network involving peptides and steroids for the expression of the sexual phenotype. Elucidation of the molecular mechanism along with the neuroanatomical background should guide the development of novel pharmacotherapeutics for sexual behavior dysfunction.

DOI： 10.1016/j.coph.2008.08.010

Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation Reviewed

KenIchi Matsuda, Hirotaka Sakamoto, Hiroko Mori, Koji Hosokawa, Akeo Kawamura, Minoru Itose, Mayumi Nishi, Eric R. Prossnitz, Mitsuhiro Kawata

NEUROSCIENCE LETTERS 441 ( 1 ) 94 - 99 2008.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Although the expression and distribution of nuclear estrogen receptors in the hippocampus has been described, it has been proposed that the nuclear receptors may not explain all aspects of estrogen function in the hippocampus. Recently, a G protein-coupled receptor for estrogen, GPR30, was identified as a membrane-localized estrogen receptor in several cancer cell lines. In this study, we examined the expression and intracellular distribution of GPR30 in the rat hippocampal formation. We found expression of GPR30 in pyramidal cells of CA1-3 and granule cells of the dentate gyrus at both mRNA and protein levels. Specific markers for intracellular organelles and immunoelectron microscopy revealed that GPR30 was mainly localized to the Golgi apparatus and partially in the endoplasmic reticulum of the neuron but could not detect the protein at the cell surface. Expression levels were not different among male, female in proestrus and female in estrus at the adult stage, but were higher in newborn male than newborn female. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.05.108

Platelet-rich plasma enhances the initial mobilization of circulation-derived cells for tendon healing Reviewed

Yoshiteru Kajikawa, Toru Morihara, Hirotaka Sakamoto, Ken-Ichi Matsuda, Yasushi Oshima, Atsuhiko Yoshida, Masateru Nagae, Yuji Arai, Mitsuhiro Kawata, Toshikazu Kubo

JOURNAL OF CELLULAR PHYSIOLOGY 215 ( 3 ) 837 - 845 2008.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Circulation-derived cells play a crucial role in the healing processes of tissue. In early phases of tendon healing processes, circulation-derived cells temporarily exist in the wounded area to initiate the healing process and decrease in number with time. We assumed that a delay of time-dependent decrease in circulation-derived cells could improve the healing of tendons. In this study, we injected platelet-rich plasma (PRP) containing various kinds of growth factors into the wounded area of the patellar tendon, and compared the effects on activation of circulation-derived cells and enhancement of tendon healing with a control group (no PRP injection). To follow the circulation-derived cells, we used a green fluorescent protein (GFP) chimeric rat expressing GFP in the circulating cells and bone marrow cells. In the PRP group, the numbers of GFP-positive cells and heat-shock protein (HSP47; collagen-specific molecular chaperone)-positive cells were significantly higher than in the control group at 3 and 7 days after injury. At the same time, the immunoreactivity for types I and III collagen was higher in the PRP group than in the control group at early phase of tendon healing. These findings suggest that locally injected PRP is useful as an activator of circulation-derived cells for enhancement of the initial tendon healing process.

DOI： 10.1002/jcp.21368

Expression, localization and possible actions of 25-Dx, a membrane-associated putative progesterone-binding protein, in the developing Purkinje cell of the cerebellum: A new insight into the biosynthesis, metabolism and multiple actions of progesterone as a neurosteroid Reviewed

Hirotaka Sakamoto, Kazuyoshi Ukena, Mitsuhiro Kawata, Kazuyoshi Tsutsui

CEREBELLUM 7 ( 1 ) 18 - 25 2008.3

Authorship：Lead author,　Corresponding author Language：English Publisher：SPRINGER

Neurosteroids are now known to be steroids that are synthesized de novo from cholesterol in the central and peripheral nervous systems of vertebrates through mechanisms at least partly independent of peripheral steroidogenic glands, such as the adrenal and gonads. A series of our studies have demonstrated that the rat Purkinje cell, a cerebellar neuron, actively produces progesterone de novo from cholesterol only during neonatal life and progesterone promotes dendritic growth, spinogenesis and synaptogenesis via its nuclear receptor in this neuron. Thus the Purkinje cell serves as an excellent cellular model for understanding the formation of cerebellar neuronal circuit in relation to genomic neurosteroid actions. Recently, we have further found that Purkinje cells express the putative membrane progesterone receptor, 25-Dx in rats. By immunocytochemistry, the expression of 25-Dx was localized in the Purkinje cell and external granule cell layer. RT-PCR and Western immunoblot analyses revealed the expressions of 25-Dx and its mRNA in the rat cerebellum, which increased during neonatal life. Therefore, progesterone would promote dendritic growth, spinogenesis and synaptogenesis via 25-Dx as well as its nuclear receptor in the Purkinje cell in the neonate. Because the subcellular localization of 25-Dx was associated with membrane structures of the endoplasmic reticulum and Golgi, 25-Dx may also play a role in the regulation of neurosteroidogenesis in the developing Purkinje cell. Here we summarize the advances made in our understanding of the expression, localization and its possible actions of 25-Dx in the developing Purkinje cell.

DOI： 10.1007/s12311-008-0007-2

Behavior of host and graft cells in the early remodeling process of rotator cuff defects in a transgenic animal model Reviewed

Yoshio Iwata, Toru Morihara, Hisakazu Tachiiri, Yoshiteru Kajikawa, Atsuhiko Yoshida, Yuji Arai, Daisaku Tokunaga, Hirotaka Sakamoto, Ken-ichi Matsuda, Masao Kurokawa, Mitsuhiro Kawata, Toshikazu Kubo

JOURNAL OF SHOULDER AND ELBOW SURGERY 17 ( 1 ) 101S - 107S 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Autologous tissue graft is one of the treatment options for a large rotator cuff defect. To develop appropriate strategies for enhanced solid graft integration at the bone-tendon interface and tendon-tendon interface, clarifying the fate of the graft and host cells that contribute to repair and remodeling is necessary. We have developed a new grafting model using green fluorescent protein-transgenic rats and wild-type rats to simulate autologous transplantation for examining the behavior of the host and graft cells in the remodeling process after tendon grafting. We found that the host cells commenced proliferation in the graft at 1 day after grafting. The host cells infiltrated into the graft from the subacromial synovium, proximal tendon, and bone-tendon insertion. The number of graft-derived cells decreased with time. Our result clearly demonstrated that host cells, rather than graft cells, were essential for rotator cuff remodeling after tendon grafting for rotator cuff defect.

DOI： 10.1016/j.jse.2007.07.008

Mode of action and functional significance of estrogen-inducing dendritic growth, spinogenesis, and synaptogenesis in the developing purkinje cell Reviewed

Katsunori Sasahara, Hanako Shikimi, Shogo Haraguchi, Hirotaka Sakamoto, Shin-ichiro Honda, Nobuhiro Harada, Kazuyoshi Tsutsui

JOURNAL OF NEUROSCIENCE 27 ( 28 ) 7408 - 7417 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC NEUROSCIENCE

Neurosteroids are synthesized de novo from cholesterol in the brain. To understand neurosteroid action in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. Recently, we identified the Purkinje cell as an active neurosteroidogenic cell. In rodents, this neuron actively produces several neurosteroids including estradiol during neonatal life, when cerebellar neuronal circuit formation occurs. Estradiol may be involved in cerebellar neuronal circuit formation through promoting neuronal growth and neuronal synaptic contact, because the Purkinje cell expresses estrogen receptor-beta (ER beta). To test this hypothesis, in this study we examined the effects of estradiol on dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell using neonatal wild-type (WT) mice or cytochrome P450 aromatase knock-out (ArKO) mice. Administration of estradiol to neonatal WT or ArKO mice increased dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell. In contrast, WT mice treated with tamoxifen, an ER antagonist, or ArKO mice exhibited decreased Purkinje dendritic growth, spinogenesis, and synaptogenesis at the same neonatal period. To elucidate the mode of action of estradiol, we further examined the expression of brain-derived neurotrophic factor ( BDNF) in response to estrogen actions in the neonate. Estrogen administration to neonatal WT or ArKO mice increased the BDNF level in the cerebellum, whereas tamoxifen decreased the BDNF level in WT mice similar to ArKO mice. BDNF administration to tamoxifen-treated WT mice increased Purkinje dendritic growth. These results indicate that estradiol induces dendritic growth, spinogenesis, and synaptogenesis in the developing Purkinje cell via BDNF action during neonatal life.

DOI： 10.1523/JNEUROSCI.0710-07.2007

GFP chimeric models exhibited a biphasic pattern of mesenchymal cell invasion in tendon healing Reviewed

Yoshiteru Kajikawa, Toru Morihara, Nobuyoshi Watanabe, Hirotaka Sakamoto, Ken-Ichi Matsuda, Masashi Kobayash, Yasushi Oshima, Atsuhiko Yoshida, Mitsuhiro Kawata, Toshikazu Kubo

JOURNAL OF CELLULAR PHYSIOLOGY 210 ( 3 ) 684 - 691 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

The healing of an injured musculoskeletal system requires an influx of mesenchymal cells that can differentiate into osteoblasts, fibroblasts, chondroblasts, and skeletal myoblasts. However, whether these mesenchymal cells arise from the circulation (bone marrow) or the injured tissues themselves has been controversial. To reveal the spatiotemporal characteristics of the reparative mesenchymal cells, we investigated the healing process after patellar tendon injury using two types of green fluorescent protein (GFP) chimeric rats; one expressing GFP in the circulating cells, and the other expressing it in the patellar tendon. We analyzed the behavior of GFP-positive cells after experimental tendon injury in both chimeric rats to clarify the origin of reparative cells. At 24 h after the injury, the wound contained circulation-derived cells but not tendon-derived cells. Tendon-derived cells first appeared in the wounded area at 3 days after the injury, and had significantly increased in number with time and had maintained a high level of proliferative activity until 7 days after the injury, whereas the circulation-derived cells had decreased in number and had been replaced by the tendon-derived cells. These findings suggest that circulation-derived and tendon-derived cells contribute to the healing of tendons in different periods as part of a biphasic process.

DOI： 10.1002/jcp.20876

Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres Reviewed

Masateru Nagae, Takumi Ikeda, Yasuo Mikami, Hitoshi Hase, Hitoshi Ozawa, Ken-Ichi Matsuda, Hirotaka Sakamot, Yasuhiko Tabata, Mitsuhiro Kawata, Toshikazu Kubo

TISSUE ENGINEERING 13 ( 1 ) 147 - 158 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：MARY ANN LIEBERT INC

This study evaluated the regenerative effects of platelet-rich plasma (PRP) for the degenerated intervertebral disc (IVD) in vivo. After induction of IVD degeneration in rabbits, we prepared PRP by centrifuging blood obtained from these rabbits. These PRP were injected into the nucleus pulposus (NP) of the degenerated IVDs after impregnation into gelatin hydrogel microspheres that can immobilize PRP growth factors physiochemically and release them in a sustained manner with the degradation of the microspheres. As controls, microspheres impregnated with phosphate-buffered saline (PBS) and PRP without microspheres were similarly injected. Histologically, notable progress in IVD degeneration with time courses was observed in the PBS control, PRP-only, and sham groups. In contrast, progress was remarkably suppressed over the 8-week period in the PRP group. Moreover, in immunohistochemistry, intense immunostaining for proteoglycan in the NP and inner layer of the annulus fibrosus was observed 8 weeks after administration of PRP-impregnated microspheres. Almost all microspheres were indistinct 8 weeks after the injection, and there were no apparent side effects in this study. Our results suggest that the combined administration of PRP and gelatin hydrogel microspheres into the IVD may be a promising therapeutic modality for IVD degeneration.

DOI： 10.1089/ten.2006.0042

Intrauterine proximity to male fetuses affects the morphology of the sexually dimorphic nucleus of the preoptic area in the adult rat brain Reviewed

M Pei, K Matsuda, H Sakamoto, M Kawata

EUROPEAN JOURNAL OF NEUROSCIENCE 23 ( 5 ) 1234 - 1240 2006.3

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Previous studies on polytocous rodents have revealed that the fetal intrauterine position influences its later anatomy, physiology, reproductive performance and behavior. To investigate whether the position of a fetus in the uterus modifies the development of the brain, we examined whether the structure of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of rat brains accorded to their intrauterine positions. Brain sections of adult rats gestated between two male fetuses (2M) and between two female fetuses (2F) in the uterus were analysed for their immunoreactivity to calbindin-D28k, which is a marker of the SDN-POA. The SDN-POA volume of the 2M adult males was greater than that of the 2F adult males, whereas the SDN-POA volume of the 2M and 2F adult females showed no significant difference. This result indicated that contiguous male fetuses have a masculinizing effect on the SDN-POA volume of the male. To further examine whether the increment of SDN-POA volume in adulthood was due to exposure to elevated steroid hormones during fetal life, concentrations of testosterone and 17 beta-estradiol in the brain were measured with 2M and 2F fetuses during gestation, respectively. On gestation day 21, the concentrations of testosterone and 17 beta-estradiol in the brain were significantly higher in the 2M male rats as compared with the 2F male rats. The results suggested that there was a relationship between the fetal intrauterine position, hormone transfer from adjacent fetuses and the SDN-POA volume in adult rat brains.

DOI： 10.1111/j.1460-9568.2006.04661.x

Stress and corticosteroid receptors Reviewed

Mitsuhiro Kawata, Mayumi Nishi, Ken-Ichi Matsuda, Hirotaka Sakamoto, Cui Honghai, Takanori Yoshii

PTSD: Brain Mechanisms and Clinical Implications 29 - 36 2006

Language：English Publishing type：Part of collection (book) Publisher：Springer Japan

The hypothalamo-pituitary-adrenal (HPA) axis is the main hormonal system involvedin stress response. Neurons in the hypothalamic paraventricular nucleus secreteadrenocorticotrophic hormone-releasing hormone (CRF) and vasopressin,which then synergistically induce the secretion of adrenocorticotrophic hormone(ACTH) from corticotrophs in the anterior pituitary, activating the secretion of theglucocorticoids from the adrenal cortex. Glucocorticoids (Cortisol in human andcorticosterone in rodents) readily enter the brain from the circulating blood andbind to their receptors to induce the secretion of CRF and ACTH for feedback regulationto keep homeostasis through the HPA axis. Over the past decades there hasbeen increasing evidence supporting a critical role for the hippocampus in stressresponse (McEwen 1999). Neurons in the hippocampus express receptors for circulatingglucocorticoids, and animal models of repeated stress caused dendritic atrophyin CAS pyramidal neurons (Woolley et al. 1990
Watanabe et al. 1992
Magarinosand McEwen 1995
Sousa et al. 2000). In the primate prominent pyramidalneuron examples of damage such as dendritic atrophy and pyknotic changes wereobserved in the CAS area of animals subjected to repeated social stress and longtermtreatment of Cortisol (Uno et al. 1989, Sapolsky et al. 1990). These results suggestthat dendritic atrophy of the pyramidal neurons may be one of the factors contributingto the clinically observed decrease of hippocampal volume in humans sufferingfrom stress-related disorders including the posttraumatic stress disorder(PTSD) (Bremner et al. 1995). Transsynaptic inhibitory projection of the hippocampusto hypothalamic paraventricular nucleus has been demonstrated. Therefore, thehippocampus has been the focus of the stress response not only due to its susceptibilityto stress-related damages but also to its negative feedback regulation of thestress response via the HPA axis (Herman and Cullinan 1997). In contrast to thehippocampus, little has been known about how stress affects the amygdala and thenature of its role in the stress response. Recent evidence has demonstrated that theamygdala also plays a critical role in stress response and activation of the HPA axis(Le Doux 1994). It has been suggested that hippocampal plasticity mediates cogni-tive aspects of behavioral impairments caused by stress, whereas changes in theamygdala are more likely to contribute to the affective aspects of stress disorderswith memory consolidation.

DOI： 10.1007/4-431-29567-4_3

Dendritic growth in response to environmental estrogens in the developing Purkinje cell in rats Reviewed

H Shikimi, H Sakamoto, Y Mezaki, K Ukena, K Tsutsui

NEUROSCIENCE LETTERS 364 ( 2 ) 114 - 118 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

The cerebellar Purkinje cell is a major site for neurosteroid formation. We have demonstrated recently that the Purkinje cell actively produces sex steroids, such as estradiol and progesterone, de novo from cholesterol only during rat neonatal life, when cerebellar cortical formation occurs. We have further demonstrated that both estradiol and progesterone promote the growth of Purkinje cells through intranuclear receptor-mediated mechanisms during cerebellar development. On the other hand, environmental estrogens, such as octylphenol (OP), bisphenol A (BPA), and nonylphenol (NP) are thought to mimic the action of estrogen in the developing central nervous system. Therefore, in this study, the effect of these environmental estrogens on the growth of Purkinje cells was examined in vivo using newborn rats. OP and BPA promoted a dose-dependent dendritic outgrowth of the Purkinje cell but did not affect its soma and cell number. The stimulatory effect of OP and BPA on Purkinje dendritic growth was induced by an injection of 500 mug/day into the cerebrospinal fluid for 4 days and blocked by the estrogen receptor antagonist tamoxifen. However, there was no significant effect of NP on any Purkinje cell morphology. These results suggest that the environmental estrogens, OP and BPA, promote Purkinje dendritic growth during neonatal life. This effect may be mediated by estrogen receptor in the Purkinje cell. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2004.04.023

Organizing actions of neurosteroids in the Purkinje neuron Reviewed

K Tsutsui, H Sakamoto, H Shikimi, K Ukena

NEUROSCIENCE RESEARCH 49 ( 3 ) 273 - 279 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

It is becoming clear that steroids can be synthesized de novo by the brain of vertebrates. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To understand neurosteroid actions in the brain, we need data on the specific biosynthesis in particular sites of the brain at particular times. Therefore our studies for this exciting area of neuroscience research have focused on the biosynthesis and action of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This neuron actively synthesizes progesterone and estradiol de novo from cholesterol only during neonatal life, when cerebellar cortical formation occurs dramatically. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently the actions of progesterone and estradiol during cerebellar development have become clear by a series of our studies using an excellent Purkinje cellular model. These neurosteroids promote dendritic growth, spinogenesis and synaptogenesis via each receptor in the Purkinje cell. Here we summarize the advances made in our understanding of organizing actions of neurosteroids in the Purkinje cell, an important brain neuron. (C) 2004 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2004.03.006

Synapse formation in response to estrogen synthesized de novo in the developing Purkinje cell.

H. Shikimi, H. Sakamoto, K. Ukena, K. Tsutsui

In: Trends in Comparative Endocrinology, 319 - 321 2004

Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell Reviewed

H Sakamoto, Y Mezaki, H Shikimi, K Ukena, K Tsutsui

ENDOCRINOLOGY 144 ( 10 ) 4466 - 4477 2003.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Neurosteroids are synthesized de novo in the brain, and the cerebellar Purkinje cell is a major site for neurosteroid formation. We have demonstrated that the Purkinje cell possesses intranuclear receptor for progesterone and actively produces progesterone de novo from cholesterol only during rat neonatal life, when cerebellar cortical formation occurs dramatically. We have further demonstrated that progesterone promotes dendritic growth, spinogenesis, and synaptogenesis via its receptor in this neuron in the neonate. On the other hand, estrogen may also play an important role in the process of cerebellar cortical formation, because the neonatal rat Purkinje cell possesses estrogen receptor (ER) beta. However, estrogen formation in the neonatal cerebellum is still unclear. In this study, we therefore analyzed the biosynthesis and action of estrogen in Purkinje cells during neonatal life. RT-PCR-Southern and in situ hybridization analyses showed that Purkinje cells expressed the key enzyme of estrogen formation, cytochrome P450 aromatase, in neonatal rats. A specific enzyme immunoassay for estradiol further indicated that cerebellar estradiol concentrations in the neonate were significantly higher than those in the prepuberty and adult. Both in vitro and in vivo studies with newborn rats showed that estradiol promoted dose-dependent dendritic growth of Purkinje cells. Estradiol also increased the density of Purkinje dendritic spines. These effects were inhibited by the ER antagonist tamoxifen. These results suggest that estradiol in the developing Purkinje cell promotes dendritic growth and spinogenesis via ERbeta in this neuron. Estradiol as well as progesterone may contribute to the growth of Purkinje cells during the cerebellar cortical formation.

DOI： 10.1210/en.2003-0307

Biosynthesis and action of neurosteroids in the cerebellar Purkinje neuron Reviewed

K Tsutsui, H Sakamoto, K Ukena

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 85 ( 2-5 ) 311 - 321 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The brain is considered to be a target site of peripheral steroid hormones. In contrast to this classical concept, new findings over the past decade have established that the brain itself also synthesizes steroids de novo from cholesterol through mechanisms at least partly independent of peripheral steroidogenic glands. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To understand neurosteroid actions in the brain, we need data on the specific synthesis in particular sites of the brain at particular times. Therefore, our studies for this exciting area of brain research have focused on the biosynthesis and action of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently, genomic and nongenomic actions of neurosteroids have become clear by a series of our studies using an excellent Purkinje cellular model. On the basis of these findings, we summarize the advances made in our understanding of biosynthesis and action of neurosteroids in the cerebellar Purkinje cell. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/S0960-0760(03)00229-2

Neonatal expression of progesterone receptor isoforms in the cerebellar Purkinje cell in rats Reviewed

H Sakamoto, H Shikimi, K Ukena, K Tsutsui

NEUROSCIENCE LETTERS 343 ( 3 ) 163 - 166 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

The cerebellar Purkinje cell (PC) is a typical site for neurosteroid formation. Progesterone synthesized de novo in developing PCs participates in the promotion of dendritic growth, spinogenesis and synaptogenesis in this neuron and such organizing actions may contribute to the formation of the cerebellar neuronal circuit during rat neonatal life. Progesterone receptors (PR) occur as two isoforms (PR-A and PR-B) derived from a single gene. To clarify the mode of organizing actions of progesterone, therefore, we examined the expression of these PR isoforms in the rat cerebellum during development. Western immunoblot analysis revealed that both PR isoforms were expressed highly in the cerebellum during neonatal life and the expression decreased thereafter. PR-like immunoreactivity was localized primarily in PCs in the neonatal cerebellum. Thus, progesterone may act directly on PCs via PR isoforms to promote its dendritic growth, spinogenesis and synaptogenesis. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-9340(03)000362-8

A novel aspect of the cerebellum: biosynthesis of neurosteroids in the Purkinje cell Reviewed

K Tsutsui, H Sakamoto, K Ukena

CEREBELLUM 2 ( 3 ) 215 - 222 2003

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Peripheral steroid hormones act on brain tissues through intracellular receptor-mediated mechanisms to regulate several important brain neuronal functions. The brain is therefore considered to be a target site of steroid hormones. In contrast to this classical concept, new findings over the past decade have established that the brain itself also synthesizes steroids de novo from cholesterol through mechanisms at least partly independent of peripheral steroidogenic glands. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To analyze neurosteroid actions in the brain, we need data on the specific synthesis in particular sites of the brain at particular times. Such information is crucial to developing hypotheses predicting the potential roles of particular neurosteroids in the developing and adult brains. Thus our studies for this exciting area of brain research have focused on the biosynthesis of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently genomic and nongenomic actions of neurosteroids have been suggested by a series of our studies using an excellent Purkinje cellular model. Here we summarize the advances made in our understanding of biosynthesis of neurosteroids in the cerebellar Purkinje cell.

DOI： 10.1080/14734220310016169

総説:ニューロンが合成するニューロステロイドのノンゲノミック作用とゲノミック作用

筒井和義, 坂本浩隆, 食見花子, 浮穴和義

生殖内分泌学会雑誌 8 19 - 26 2003

総説:ニューロステロイドのシナプス形成誘導作用

筒井和義, 坂本浩隆, 浮穴和義, 古川康雄

生体の科学 54 ( 2 ) 101 - 108 2003

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