研究者詳細 - 山下　徹

論文 - 山下　徹

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Macrophage infiltration, lectin-like oxidized-LDL receptor-1, and monocyte chemoattractant protein-1 are reduced by chronic HMG-CoA reductase inhibition. 査読国際誌

Atsushi Tsuchiya, Shoko Nagotani, Takeshi Hayashi, Kentaro Deguchi, Yoshihide Sehara, Toru Yamashita, HanZhe Zhang, Violeta Lukic, Tatsushi Kamiya, Koji Abe

Current neurovascular research 4 ( 4 ) 268 - 73 2007年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Statin reduces cerebrovascular events independent of its cholesterol lowering effect. We hypothesized that statin inhibits early atherosclerotic change in common carotid artery (CCA), and investigated its effect on lectin-like oxidized-LDL receptor-1 (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) expression, both of which are early atherosclerotic markers. Stroke-prone spontaneous hypertensive rats (SHR-SP) of 8 weeks old were orally treated with vehicle or simvastatin (20mg/kg) daily. After 4 weeks of simvastatin or vehicle treatment, or 2 weeks of vehicle and 2 weeks of simvastatin treatment, CCA was removed. LOX-1 and MCP-1 expression as well as macrophage infiltration were histologically investigated. Lipid deposition was also investigated by Sudan III staining. Simvastatin groups showed significantly smaller amount of lipid deposition and LOX-1 and MCP-1 expression, independent of serum lipid levels. Macrophage infiltration was also decreased. Reduction of cerebrovascular events by statins may be brought by the direct inhibition of atherosclerotic change.

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beta-Catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone 査読国際誌

Kazuhide Adachi, Zaman Mirzadeh, Masanori Sakaguchi, Toru Yamashita, Tania Nikolcheva, Yukiko Gotoh, Gary Peltz, Leyi Gong, Takeshi Kawase, Arturo Alvarez-Buylla, Hideyuki Okano, Kazunobu Sawamoto

STEM CELLS 25 ( 11 ) 2827 - 2836 2007年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ALPHAMED PRESS

The subventricular zone (SVZ) is the largest germinal zone in the mature rodent brain, and it continuously produces young neurons that migrate to the olfactory bulb. Neural stem cells in this region generate migratory neuroblasts via highly proliferative transit-amplifying cells. The Wnt/beta-catenin signaling pathway partially regulates the proliferation and neuronal differentiation of neural progenitor cells in the embryonic brain. Here, we studied the role of beta-catenin signaling in the adult mouse SVZ. beta-Catenin-dependent expression of a destabilized form of green fluorescent protein was detected in progenitor cells in the adult SVZ of Axin2-d2EGFP reporter mice. Retrovirus-mediated expression of a stabilized beta-catenin promoted the proliferation of Mash1+ cells and inhibited their differentiation into neuroblasts. Conversely, the expression of Dkk1, an inhibitor of Wnt signaling, reduced the proliferation of Mash1+ cells. In addition, an inhibitor of GSK3 beta promoted the proliferation of Mash1+ cells and increased the number of new neurons in the olfactory bulb 14 days later. These results suggest that beta-catenin signaling plays a role in the proliferation of progenitor cells in the SVZ of the adult mouse brain.

DOI： 10.1634/stemcells.2007-0177

Web of Science

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Prevention of neuronal damage by calcium channel blockers with antioxidative effects after transient focal ischemia in rats. 査読国際誌

Violeta Lukic-Panin, Tatsushi Kamiya, Hanzhe Zhang, Takeshi Hayashi, Atsushi Tsuchiya, Yoshihide Sehara, Kentaro Deguchi, Toru Yamashita, Koji Abe

Brain research 1176 143 - 50 2007年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Cerebral ischemia is a major leading cause of death and at the first place cause of disability all over the world. There are a lot of drugs that are in experimental stage for treatment of stroke. Among them are calcium channel blockers (CCBs) that have, in animal models, different effectiveness in healing of ischemic damage in brain. Mechanism of CCBs' action in cerebral ischemia is still unclear, but antioxidative property is supposed to be implicated. In the present study, we investigated antioxidative and neuroprotective properties of two CCBs, azelnidipine and amlodipine. METHODS: Male Wistar Kyoto rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) by a nylon thread. Animals were divided into 3 groups, vehicle, azelnidipine and amlodipine group. In the azelnidipine and amlodipine groups, rats were treated with azelnidipine (1 mg/kg) and amlodipine (1 mg/kg) by gastric gavage for 2 weeks before MCAO. Vehicle group was treated by solution of methyl cellulose for 2 weeks. Rats were killed 24 h after MCAO. Physiological parameters (mean arterial pressure, heart rate, body weight), infarct volume, brain edema index, cerebral blood flow (CBF), oxidative stress markers which are HEL, 4-HNE, AGE and 8-OHdG, and evidence of apoptosis by TUNEL, were investigated. RESULTS: There were no significant differences among groups in mean arterial pressure, heart rate and body weight. Treatment with azelnidipine and amlodipine reduced infarct volume and brain edema. Azelnidipine treated group showed more marked reduction of infarct volume and cerebral edema than amlodipine group. There was no attenuation of CBF in CCBs groups. The number of HEL, 4-HNE, AGE and 8-OHdG positive cells were significantly decreased in the CCBs treated groups. These molecules were again fewer in the azelnidipine group than in the amlodipine group. In TUNEL staining, the numbers of positive cells was smaller in the CCBs treated groups, especially in the azelnidipine group. CONCLUSIONS: Pretreatment of azelnidipine and amlodipine had a neuroprotective effect in ischemic brain. Antioxidative property is one of the important profiles of CCBs that is implicated in brain protection.

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Decreased focal inflammatory response by G-CSF may improve stroke outcome after transient middle cerebral artery occlusion in rats. 査読国際誌

Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

Journal of neuroscience research 85 ( 10 ) 2167 - 74 2007年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent studies have shown that administration of granulocyte colony-stimulating factor (G-CSF) is neuroprotective. However, the precise mechanisms of the neuroprotective effect of G-CSF are not entirely known. We carried out 90-min transient middle cerebral occlusion (tMCAO) of rats. The rats were injected with vehicle or G-CSF (50 mug/kg) immediately after reperfusion and sacrificed 8, 24, or 72 hr later. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was carried out using brain sections of 72 hr, and immunohistochemistry was carried out with those of 8, 24, and 72 hr. TTC-staining showed a significant reduction of infarct volume in the G-CSF-treated group (**P < 0.01). Immunohistochemistry showed a significant decrease of the number of cells expressing tumor necrosis factor-alpha (TNF-alpha) at 8-72 hr, transforming growth factor-beta (TGF-beta) and inducible nitric oxide synthase (iNOS) at 24 and 72 hr after tMCAO in the peri-ischemic area (*P < 0.05 each). Our data suggest that the suppression of inflammatory cytokines and iNOS expression may be one mechanism of neuroprotection by G-CSF.

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Expression of netrin-1 and its receptors DCC and neogenin in rat brain after ischemia. 査読国際誌

Atsushi Tsuchiya, Takeshi Hayashi, Kentaro Deguchi, Yoshihide Sehara, Toru Yamashita, HanZhe Zhang, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

Brain research 1159 1 - 7 2007年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

It is very important to investigate the mechanism of axonal growth in the ischemic brain in order to consider a novel mean of therapy for stroke. Netrins are chemotropic factors for axon with chemoattractant or chemorepellant guidance activities, and deleted in colorectal cancer (DCC) and neogenin are receptors for netrins. In this study, we examined expressions of netrin-1, DCC, and neogenin in the brain after 90 min of transient middle cerebral artery occlusion (tMCAO). Netrin-1 was expressed in neurons at the peri-ischemic area with a peak at 14 days. DCC was expressed both in neurons and astrocytic feet with a peak at 14 days, though neogenin was expressed in endothelial cells at MCA territory with a peak at the same time point. These results suggest that netrin-1 is involved in the promotion of axonal growth. The expression of netrin-1 and DCC was overlapped both in the spatial and temporal patterns, indicating that DCC plays a role in netrin-1's axonal growth promoting effects. The location of neogenin positive cells differed from that of netrin-1 positive cells, thus its angiogenic activity may not have relevance with netrin-1.

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Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats. 査読国際誌

Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

Brain research 1151 142 - 9 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recently, granulocyte colony-stimulating factor (G-CSF) is expected to demonstrate beneficial effects on cerebral ischemia. Here, we showed the potential benefit of G-CSF administration after transient middle cerebral artery occlusion (tMCAO). Adult male Wistar rats received vehicle or G-CSF (50 microg/kg) subcutaneously after reperfusion, and were treated with 5-bromodeoxyuridine (BrdU, 50 mg/kg) once daily by the intraperitoneal route for 3 days after tMCAO. Nissl-stained sections at 7 days after tMCAO showed significant reduction of the infarction area (31%, P<0.01). At 7 days after tMCAO, BrdU plus NeuN double-positive cells increased by 43.3% in the G-CSF-treated group (P<0.05), and BrdU-positive endothelial cells were increased 2.29 times in the G-CSF-treated group, to a level as high as that in the vehicle-treated group (P<0.01), in the periischemic area. Our results indicate that G-CSF caused potentiation of neuroprotection and neurogenesis and is expected to have practical therapeutic potential in treating individuals after ischemic brain injury.

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G-CSF enhances stem cell proliferation in rat hippocampus after transient middle cerebral artery occlusion. 査読国際誌

Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

Neuroscience letters 418 ( 3 ) 248 - 52 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Granulocyte colony-stimulating factor (G-CSF) enhances the survival and stimulates the proliferation of neutrophil progenitors. Recently, the neurogenerative effect of G-CSF has been intensely investigated. In this study, we explored the possibility that G-CSF enhanced the cell proliferation in the rat dentate gyrus (DG) after focal cerebral ischemia, using a rat transient middle cerebral artery occlusion (tMCAO) model. At 7 days after tMCAO, the number of 5-bromodeoxyuridine (BrdU)-positive cells in the G-CSF-treated group was significantly increased compared with that in the vehicle-treated group in the ipsilateral SGZ (16.6+/-5.5/mm(2) in the vehicle-treated group versus 33.0+/-7.2/mm(2) in the G-CSF-treated group, **p<0.01) and in the ipsilateral GCL (14.2+/-2.8/mm(2) in the vehicle-treated group versus 21.0+/-3.8/mm(2) in the G-CSF-treated group, *p<0.05). This result showed the possibility of a neurogenerative role of G-CSF after tMCAO in rats.

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Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. 査読国際誌

Mikiko Ninomiya, Toru Yamashita, Nobuo Araki, Hideyuki Okano, Kazunobu Sawamoto

Neuroscience letters 403 ( 1-2 ) 63 - 7 2006年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

In the subventricular zone (SVZ) of the adult mammalian brain, neural stem cells continually produce transit-amplifying precursors, which generate neuroblasts migrating into the olfactory bulb. Previous studies have suggested that SVZ cells also have the capacity to generate some striatal neurons after cerebral ischemia. The infusion of epidermal growth factor (EGF) has been demonstrated to increase the number of these regenerated neurons. However, which cell types in the SVZ are stimulated to proliferate or differentiate after EGF infusion remains unknown. In this paper, we demonstrated that cerebral ischemia results in an increase in the number of EGF receptor (EGFR)-positive transit-amplifying cells in the SVZ. EGF infusion into the ischemic brain caused the number of transit-amplifying cells to increase and the number of neuroblasts to decrease. On the other hand, after an interval of 6 days after the discontinuation of EGF infusion, a significant increase in the number of neuroblasts was found, both in the striatum and the SVZ. These results suggest that the replacement of neurons in injured striatum can be enhanced by an EGF-induced expansion of transit-amplifying cells in the SVZ.

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Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. 査読国際誌

Toru Yamashita, Mikiko Ninomiya, Pilar Hernández Acosta, Jose Manuel García-Verdugo, Takehiko Sunabori, Masanori Sakaguchi, Kazuhide Adachi, Takuro Kojima, Yuki Hirota, Takeshi Kawase, Nobuo Araki, Koji Abe, Hideyuki Okano, Kazunobu Sawamoto

The Journal of neuroscience : the official journal of the Society for Neuroscience 26 ( 24 ) 6627 - 36 2006年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.

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Neuroprotection and neurosupplementation in ischaemic brain 査読

T. Yamashita, K. Deguchi, K. Sawamoto, H. Okano, T. Kamiya, K. Abe

Biochemical Society Transactions 34 ( 6 ) 1310 - 1312 2006年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）

Possible strategies for treating ischaemic stroke include: (i) neuroprotection (preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischaemia), and (ii) neurosupplementation (the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischaemia). In this paper, we review our recent progress in development of these distinct new strategies for treatment of damaged brain following a stroke. Firstly, we investigated the role of endogenous IL-6 (interleukin-6), which is one of the cytokines drastically induced by ischaemic stimuli, by administering IL-6RA (anti-IL-6 receptor monoclonal antibody) to mice.We found that endogenous IL-6 plays a critical role in neuroprotection and that its role may be mediated by STAT3 (signal transducer and activator of transcription-3) activation. Secondly, we studied the endogenous sources of the newly born neurons in the ischaemic striatum by region- and cell-type-specific cell labelling techniques. The results revealed that the SVZ (subventricular zone) is the principal source of the neuronal progenitors that migrate laterally towards the infarcted regions, and differentiate into newly born neurons. Finally, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is an appropriate poly-porous structure releasing bioactive substances such as neurotrophic factor. This bio-affinitive scaffold is able to give an appropriate environment for newly born neurons. In future, we will combine these strategies to develop more effective therapies for treatment of strokes. ©2006 Biochemical Society.

DOI： 10.1042/BST0341310

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Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. 査読国際誌

Toru Yamashita, Kazunobu Sawamoto, Shigeaki Suzuki, Norihiro Suzuki, Kazuhide Adachi, Takeshi Kawase, Masahiko Mihara, Yoshiyuki Ohsugi, Koji Abe, Hideyuki Okano

Journal of neurochemistry 94 ( 2 ) 459 - 68 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Interleukin (IL)-6 expression transiently increases in the acute phase of cerebral ischemia. To investigate the physiological significance of endogenous IL-6 expression and to identify the main signal pathway for the action of IL-6, we administered anti-mouse IL-6 receptor monoclonal antibody (IL-6RA), which blocks IL-6 signaling, to mice immediately after a 45-min period of middle cerebral artery occlusion (MCAO). At 6 h after MCAO, IL-6RA administration had resulted in a significant reduction in the amount of phosphorylated signal transducer and activator of transcription-3 (Stat3) protein in the peri-infarct area of the cortex. At 24 h after MCAO, blockade of IL-6 signaling had led to an increase in number of apoptotic cells in the peri-infarct area and enlargement of the size of the infarct, and it had adversely affected neurological function. These results suggest that endogenous IL-6 plays a critical role in preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia and that its role may be mediated by Stat3 activation.

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Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats. 査読国際誌

Shigeaki Suzuki, Toru Yamashita, Kortaro Tanaka, Hidenori Hattori, Kazunobu Sawamoto, Hideyuki Okano, Norihiro Suzuki

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 25 ( 6 ) 685 - 93 2005年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 is known to exert a neurotrophic action in the central nervous system, although the role of this signaling in cerebral ischemia remains unknown. We examined the effect of intracerebral injection of LIF after focal cerebral ischemia in rats. The animals underwent a sham operation (sham group) or middle cerebral artery occlusion (MCAO) followed by direct injection of either vehicle (phosphate-buffered saline, the PBS group) or recombinant LIF (10 ng in the low-LIF group and 100 ng in the high-LIF group) into the cerebral cortex adjacent to the inner boundary zone of the infarct area, and neurologic and histologic evaluations were conducted 24 h later. Expression of LIFR, gp130, and phosphorylated Stat3, Akt, and ERK1/2 was investigated by Western blot analysis and immunohistochemistry. The neurologic deficits and ischemic damage were significantly less severe in the high-LIF group than in the PBS group and the low-LIF group. Leukemia inhibitory factor receptor and gp130 were expressed in neurons, and the ischemic damage of these proteins was rescued in the high-LIF group. Early induction of phosphorylated Stat3 was significantly detected on the ischemic side in the high-LIF group after LIF injection. Exogenous LIF attenuates ischemic brain injury by activating cytokine signaling through LIFR/gp130.

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