Faculty Profiles - ASANUMA Masato

Papers - ASANUMA Masato

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アストロサイトとParkinson病治療 Invited

浅沼幹人, 宮崎育子

神経内科 79 ( 2 ) 257 - 261 2013

The mechanisms of electroconvulsive stimuli in BrdU-positive cells of the dentate gyrus in ACTH-treated rats Reviewed

Keiko Kuwatsuka, Hiromi Hayashi, Yuka Onoue, Ikuko Miyazaki, Toshihiro Koyama, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

Journal of Pharmacological Sciences 122 ( 1 ) 34 - 41 2013

Language：English Publishing type：Research paper (scientific journal)

In clinical studies, electroconvulsive stimuli have been associated with improvements in both depression and treatment-resistant depression. In a previous study, treatment with adrenocorticotropic hormone (ACTH) for 14 days decreased adult hippocampal cell proliferation. Furthermore, electroconvulsive stimuli significantly decreased the duration of immobility following repeated administration of ACTH for 14 days in rats. The present study was undertaken to further characterize the mechanism of treatment-resistant antidepressant effects of electroconvulsive stimuli by measuring cell proliferation, brain-derived neurotrophic factor (BDNF) levels, and phosphorylated and total cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB/CREB) levels in the hippocampus of ACTH-treated rats. Electroconvulsive stimuli increased cell proliferation in both saline-treated and ACTH-treated rats. Mature-BDNF protein levels showed a tendency to decrease in ACTH-treated rats. Electroconvulsive stimuli treatment increased mature-BDNF protein levels in the hippocampus of both saline-treated and ACTH-treated rats. Furthermore, electroconvulsive stimuli increased phospho-Ser133-CREB (pCREB) levels and the ratio of pCREB/CREB in both saline-treated and ACTH-treated rats. These findings suggest that the treatment-resistant antidepressant effects of electroconvulsive stimuli may be attributed, at least in part, to an enhancement of hippocampal cell proliferation. © The Japanese Pharmacological Society.

DOI： 10.1254/jphs.13015FP

Bibliographic review on the central actions of theanine

9 ( 9 ) 45 - 58 2012.12

Centrosomal aggregates and Golgi fragmentation disrupt vesicular trafficking of DAT Reviewed

Francisco J. Diaz-Corrales, Ikuko Miyazaki, Masato Asanuma, Diego Ruano, Rosa M. Rios

Neurobiology og Aging 33 ( 10 ) 2462 - 2477 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Lewy bodies containing the centrosomal protein gamma-tubulin and fragmentation of Golgi apparatus (GA) have been described in nigral neurons of Parkinson's disease (PD) patients. However, the relevance of these features in PD pathophysiology remains unknown. We analyzed the impact of proteasome inhibition in the formation of gamma-tubulin-containing aggregates as well as on GA structure. SH-SY5Y cells were treated with the proteasome inhibitor Z-Leu-Leu-Leu-al (MG132) to induce centrosomal-protein aggregates. Then, microtubules (MTs) and Golgi dynamics, as well as the vesicular transport of dopamine transporter (DAT) were evaluated both in vitro and in living cells. MG132 treatment induced gamma-tubulin aggregates which altered microtubule nucleation. MG132-treated cells containing gamma-tubulin aggregates showed fragmentation of GA and perturbation of the trans-Golgi network. Under these conditions, the DAT accumulated at the centrosomal-Golgi region indicating that the vesicular transport of DAT was disrupted. Thus, centrosomal aggregates and fragmentation of GA are 2 closely related processes that could result in the disruption of the vesicular transport of DAT toward the plasma membrane in a model of dopaminergic neuronal degeneration. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neurobiolaging.2011.11.014

Cyclooxygenase-Independent Neuroprotective Effects of Aspirin Against Dopamine Quinone-Induced Neurotoxicity Reviewed

Masato Asanuma, Ikuko Miyazaki, Yuri Kikkawa, Naotaka Kimoto, Mika Takeshima, Shinki Murakami, Ko Miyoshi

Neurochemical Research 37 ( 9 ) 1944 - 1951 2012.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER/PLENUM PUBLISHERS

Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

DOI： 10.1007/s11064-012-0813-2

Effluent free radicals are associated with residual renal function and predict technique failure in peritoneal dialysis patients. Reviewed

Hiroshi Morinaga, Hitoshi Sugiyama, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Masashi Kitagawa, Shigeru Akagi, Kazushi Nakao, Yohei Maeshima, Ikuko Miyazaki, Masato Asanuma, Makoto Hiramatsu, Hirofumi Makino

Peritoneal Dialysis International 32 ( 4 ) 453 - 461 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MULTIMED INC

Objective: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD.
Methods: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months.
Results: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma beta(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005).
Conclusions: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients. Perit Dial Int 2012; 32(4): 453-461

DOI： 10.3747/pdi.2011.00032

Dipeptidyl compounds ameliorate the serum-deprivation-induced reduction in cell viability via the neurotrophin-activating effect in SH-SY5Y cells Reviewed

Ken-ichi Tanaka, Hiroya Ogo, Hiroaki Kaji, Kaori Miyatake, Erika Tokudome, Kanako Sonoda, Norio Ogawa, Masato Asanuma

Neurological Research 34 ( 6 ) 619 - 622 2012.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MANEY PUBLISHING

Objectives and methods: We have searched for low-molecular-weight compounds as potent new non-immunosuppressive immunophilin ligands (NI-IPLs) that are stronger than existent NI-IPLs such as GPI1046 and/or V10367 from the perspective of neuroprotective efficacy. We selected six dipeptidyl compounds as new NI-IPL candidates, and first examined the effects of each of these compounds on the serum-deprivation-induced reduction in the viability of SH-SY5Y cells. In addition, we clarified the effects of these compounds on neurotrophin release into medium in SH-SY5Y cells.
Results: Pre-treatment with Leu-Ile and Ile-Ile prevented the serum deprivation-induced reduction in cell viability in SH-SY5Y cells. In naive SH-SY5Y cells, treatment with Leu-Ile and Ile-Ile for 24 hours significantly increased both brain-derived neurotrophic factor and glial cell-line-derived neurotrophic factor releases in comparison with relative vehicle treatments. Moreover, none of the dipeptidyl compounds could prevent the concanavalin A-induced enhancement in interleukin-2 and interleukin-4 release in mouse spleen cells.
Discussion: The immunosuppressive effect is not essential to the neuroprotective properties of dipeptidyl compounds, and Leu-Ile and Ile-Ile have neurotrophin-activating effects, like FK506 and its existing non-immunosuppressive derivatives.

DOI： 10.1179/1743132812Y.0000000001

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats

Hayashi Hiromi, Doi Maho, Onoue Yuka, Kuwatsuka Keiko, Miyake Ayaka, Koyama Toshihiro, Shinomiya Kazuaki, Miyazaki Ikuko, Aasanuma Masato, Kitamura Yoshihisa

YAKUGAKU ZASSHI 132 ( 2 ) 173 - 178 2012

Language：Japanese Publishing type：Research paper (conference, symposium, etc.) Publisher：The Pharmaceutical Society of Japan

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.<br>

DOI： 10.1248/yakushi.132.173

Other Link： https://jlc.jst.go.jp/DN/JALC/00387666301?from=CiNii

A study on L-theanine-mediated cytoprotection in glial cells : L-theanine up-regulates antioxidant defenses in astrocytes

8 ( 8 ) 43 - 53 2011.12

Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity Reviewed

Mika Takeshima, Maiko Murata, Natsuho Urasoe, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma, Taizo Kita

Neurological Research 33 ( 10 ) 1050 - 1056 2011.12

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

Objectives: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses antioxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH. a cells.
Methods and results: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH. a cells.
Discussion: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage.

DOI： 10.1179/1743132811Y.0000000032

Factors That Influence Primary Cilium Length Reviewed

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 65 ( 5 ) 279 - 285 2011.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Almost all mammalian cells carry one primary cilium that functions as a biosensor for chemical and mechanical stimuli. Genetic damages that compromise cilia formation or function cause a spectrum of disorders referred to as ciliapathies. Recent studies have demonstrated that some pharmacological agents and extracellular environmental changes can alter primary cilium length. Renal injury is a well-known example of an environmental insult that triggers cilia length modification. Lithium treatment causes primary cilia to extend in several cell types including neuronal cells; this phenomenon is likely independent of glycogen synthase kinase-3 beta inhibition. In renal epithelial cell lines, deflection of the primary cilia by fluid shear shortens them by reducing the intracellular cyclic AMP level, leading to a subsequent decrease in mechanosensitivity to fluid shear. Primary cilium length is also influenced by the dynamics of actin filaments and microtubules through the levels of soluble tubulin in the cytosol available for primary cilia extension. Thus, mammalian cells can adapt to the extracellular environment by modulating the primary cilium length, and this feedback system utilizing primary cilia might exist throughout the mammalian body. Further investigation is required concerning the precise molecular mechanisms underlying the control of primary cilium length in response to environmental factors.

DOI： 10.18926/AMO/47009

alpha 7 Nicotinic acetylcholine receptors in the central amygdaloid nucleus alter naloxone-induced withdrawal following a single exposure to morphine Reviewed

Shigeru Ishida, Yoichi Kawasaki, Hiroaki Araki, Masato Asanuma, Hisashi Matsunaga, Toshiaki Sendo, Hiromu Kawasaki, Yutaka Gomita, Yoshihisa Kitamura

Psychopharmacology 214 ( 4 ) 923 - 931 2011.4

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

Negative motivational withdrawal from acute opiate dependence was induced by an opioid antagonist, and the withdrawal signs prevented by pretreatment with nicotine.
The present study was undertaken to examine the mechanism of nicotine-induced attenuation of withdrawal precipitated by naloxone in rats administered a single dose of morphine.
Conditioned place aversion (CPA) was precipitated by naloxone in rats exposed once to morphine. Nicotinic acetylcholine receptor (nAChR) agonists were microinjected into the central amygdaloid nucleus (CeA) before naloxone was administered. Additionally, c-Fos expression in the amygdala was measured in rats exposed to alpha 7 nAChR ligands.
The microinjection of nicotine (0.3 and 1.0 mu g/mu l) into the CeA dose-dependently inhibited naloxone-induced CPA. This inhibition of CPA was reversed by methyllycaconitine (MLA), an alpha 7 nAChR antagonist. CPA was also significantly attenuated by the microinjection of tropisetron (3.0 mu g/mu l), an alpha 7 nAChR agonist and 5-hydroxytriptamine 3 (5-HT3) receptor antagonist, but not by ondansetron (1.0 and 3.0 mu g/mu l), a 5-HT3 receptor antagonist. The microinjection of PNU-282987 (3.0 mu g/mu l), a selective alpha 7 nAChR agonist, into the CeA also inhibited CPA. Furthermore, nicotine increased c-Fos expression in the CeA, but not the medial or basolateral amygdaloid nucleus. The increase of c-Fos in the CeA was significantly inhibited by MLA.
Nicotine-induced attenuation of CPA precipitated by naloxone is mediated by the alpha 7 nAChR subtype, and the CeA is one of the regions of the brain involved in the effect of nicotine on acutely opiate-dependent subjects.

DOI： 10.1007/s00213-010-2101-7

Astrocyte-Derived Metallothionein Protects Dopaminergic Neurons from Dopamine Quinone Toxicity Reviewed

Ikuko Miyazaki, Masato Asanuma, Yuri Kikkawa, Mika Takeshima, Shinki Murakami, Ko Miyoshi, Norio Sogawa, Taizo Kita

Glia 59 ( 3 ) 435 - 451 2011.3

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

Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L-DOPA-treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine-rich metal-binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone-quenching property. The aim of this study was to examine MT induction in astrocytes in response to excess DA and the potential neuroprotective effects of astrocyte-derived MTs against DA quinone toxicity. DA exposure significantly upregulated MT-1/-2 in cultured striatal astrocytes, but not in mesencephalic neurons. This DA-induced MT upregulation in astrocytes was blocked by treatment with a DA-transporter (DAT) inhibitor, but not by DA-receptor antagonists. Expression of nuclear factor erythroid 2-related factor (Nrf2) and its binding activity to antioxidant response element of MT-1 gene were significantly increased in the astrocytes after DA exposure. Nuclear translocation of Nrf2 was suppressed by the DAT inhibitor. Quinone formation and reduction of mesencephalic DA neurons after DA exposure were ameliorated by preincubation with conditioned media from DA-treated astrocytes. These protective effects were abrogated by MT-1/-2-specific antibody. Adding exogenous MT-1 to glial conditioned media also showed similar neuroprotective effects. Furthermore, MT-1/-2 expression was markedly elevated specifically in reactive astrocytes in the striatum of L-DOPA-treated hemi-parkinsonian mice or METH-injected mice. These results suggested that excess DA taken up by astrocytes via DAT upregulates MT-1/-2 expression specifically in astrocytes, and that MTs or related molecules secreted specifically by astrocytes protect dopaminergic neurons from damage through quinone quenching and/or scavenging of free radicals. (C)2010 Wiley-Liss, Inc.

DOI： 10.1002/glia.21112

Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats Reviewed

Yoshihisa Kitamura, Maho Doi, Keiko Kuwatsuka, Yuka Onoue, Ikuko Miyazaki, Kazuaki Shinomiya, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

Biological & Pharmaceutical Bulletin 34 ( 1 ) 77 - 81 2011.1

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

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

DOI： 10.1248/bpb.34.77

High glucose increases metallothionein expression in renal proximal tubular epithelial cells． Reviewed

Daisuke Ogawa, Masato Asanuma, Ikuko Miyazaki, Hiromi Tachibana, Jun Wada, Norio Sogawa, Takeshi Sugaya, Shinji Kitamura, Yohei Maeshima, Kenichi Shikata, Hirofumi Makino

Experimental Diabetes Research 2011 534872 - 534872 2011

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

Metallothionein(MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

DOI： 10.1155/2011/534872

パーキンソン病とアストロサイト─新たな神経保護療法の標的. Invited

浅沼幹人, 宮崎育子

Clinical Neuroscience 29 ( 11 ) 1295 - 1297 2011

Effects of Imipramine and Lithium on the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in Adrenocorticotropic Hormone-treated Rats Reviewed

Maho Doi, Ikuko Miyazaki, Tomoko Nagamachi, Kazuaki Shinomiya, Hisashi Matsunaga, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita, Yoshihisa Kitamura

Acta Medica Okayama 64 ( 4 ) 219 - 223 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We examined the influence of chronic adrenocorticotropic hormone (ACTH) treatment on the number of Ki-67-positive cells in the dentate gyrus of the hippocampus in rats. ACTH treatment for 14 days decreased the number of such cells. The administration of imipramine or lithium alone for 14 days had no effect in saline-treated rats. The effect of ACTH was blocked by the administration of imipramine. Furthermore, the coadministration of imipramine and lithium for 14 days significantly increased the number of Ki-67-positive cells in both the saline and ACTH-treated rats. The coadministration of imipramine and lithium normalized the cell proliferation in the dentate gyrus of the hippocampus in rats treated with ACTH.

Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats Reviewed

Yoshihisa Kitamura, Takahiko Yagi, Kouhei Kitagawa, Kazuaki Shinomiya, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

Naunyn-Schmiedebergs Archives of Pharmacology 382 ( 2 ) 151 - 158 2010.8

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

The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

DOI： 10.1007/s00210-010-0521-x

Induction of Parkinsonism-Related Proteins in the Spinal Motor Neurons of Transgenic Mouse Carrying a Mutant SOD1 Gene Reviewed

Nobutoshi Morimoto, Makiko Nagai, Kazunori Miyazaki, Yasuyuki Ohta, Tomoko Kurata, Yasushi Takehisa, Yoshio Ikeda, Tohru Matsuura, Masato Asanuma, Koji Abe

Journal of Neuroscience Research 88 ( 8 ) 1804 - 1811 2010.6

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

Amyotrophic lateral sclerosis is a progressive and fatal disease caused by selective death of motor neurons, and a number of these patients carry mutations in the superoxide dismutase 1 (SOD1) gene involved in ameliorating oxidative stress. Recent studies indicate that oxidative stress and disruption of mitochondrial homeostasis is a common mechanism for motor neuron degeneration in amyotrophic lateral sclerosis and the loss of midbrain dopamine neurons in Parkinson's disease. Therefore, the present study investigated the presence and alterations of familial Parkinson's disease-related proteins, PINK1 and DJ-1, in spinal motor neurons of G93ASOD1 transgenic mouse model of amyotrophic lateral sclerosis. Following onset of disease, PINK1 and DJ-1 protein expression increased in the spinal motor neurons. The activated form of p53 also increased and translocated to the nuclei of spinal motor neurons, followed by increased expression of p53-activated gene 608 (PAG608). This is the first report demonstrating that increased expression of PAG608 correlates with activation of phosphorylated p53 in spinal motor neurons of an amyotrophic lateral sclerosis model. These results provide further evidence of the profound correlations between spinal motor neurons of amyotrophic lateral sclerosis and parkinsonism-related proteins. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/jnr.22341

Neuroprotective Effects of Zonisamide Target Astrocyte Reviewed

Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Naotaka Kimoto, Yuri Kikkawa, Mika Takeshima, Ko Miyoshi, Miho Murata

Annals of Neurology 67 ( 2 ) 239 - 249 2010.2

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Objective: Recent double-blind, controlled trials in Japan showed that the antiepileptic agent zonisamide (ZNS)improves the cardinal symptoms of Parkinson's disease. Glutathione (GSH) exerts antioxidative activity through quenching reactive oxygen species and dopamine quinone. GSH depletion within dopaminergic neurons impairs mitochondrial complex I activity, followed by age-dependent nigrostriatal neurodegeneration. This study examined changes in GSH and GSH synthesis-related molecules, and the neuroprotective effects of ZNS on dopaminergic neurodegeneration using 6-hydroxydopamine-injected hemiparkinsonian mice brain and cultured neurons or astrocytes.
Methods and Results: ZNS increased both the cell number and GSH levels in astroglial C6 cells, but not in dopaminergic neuronal CATH.a cells. Repeated injections of ZNS (30mg/kg intraperitoneally) for 14 days also significantly increased GSH levels and S100 beta-positive astrocytes in mouse basal ganglia. Repeated ZNS injections (30mg/kg) for 7 days in the hemiparkinsonian mice increased the expression of cystine/glutamate exchange transporter xCT in activated astrocytes, which supply cysteine to neurons for GSH synthesis. Treatment of these mice with ZNS also increased GSH levels and completely suppressed striatal levodopa-induced quinone formation. Reduction of nigrostriatal dopamine neurons in the lesioned side of hemiparkinsonian mice was significantly abrogated by repeated injections of ZNS with or without adjunctive levodopa starting 3 weeks after 6-hydroxydopamine lesioning.
Interpretation: These results provide new pharmacological evidence for the effects of ZNS. ZNS markedly increased GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation via S100 beta production or secretion. ZNS acts as a neuroprotectant against oxidative stress and progressive dopaminergic neurodegeneration. ANN NEUROL 2010;67:239-249

DOI： 10.1002/ana.21885

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