研究者詳細 - 山下　徹

論文 - 山下　徹

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Early and selective reduction of NOP56 (Asidan) and RNA processing proteins in the motor neuron of ALS model mice. 査読国際誌

Kazunori Miyazaki, Toru Yamashita, Nobutoshi Morimoto, Kota Sato, Takafumi Mimoto, Tomoko Kurata, Yoshio Ikeda, Koji Abe

Neurological research 35 ( 7 ) 744 - 54 2013年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: There is increasing evidence to support that altered RNA processing is implicated in the pathogenesis of motor neuron degeneration of amyotrophic lateral sclerosis (ALS). We evaluate the expression of three RNA processing-related proteins in ALS model mice in this study. METHODS: We analyzed expression and distribution patterns of three RNA processing-related proteins, nucleolar protein (NOP) 56 (identified as causative gene for spinocerebellar ataxia (SCA) 36, nicknamed Asidan), TDP-43, and fused in sarcoma/translocated in liposarcoma (FUS) in lumbar and cervical cords, hypoglossal nucleus, cerebral motor cortex, and cerebellum of transgenic (Tg) SOD1 G93A ALS model mice throughout the course of motor neuron degeneration. RESULTS: Compared to age-matched wild type (WT) mice, Tg mice showed progressive reduction of NOP56 levels in the large motor neurons of lumbar and cervical cords from the early-symptomatic stage (14 weeks of age) to the end stage of the disease (18 weeks). TDP-43 and FUS protein levels showed a later decrease in the nucleus of large motor neuron at 18 weeks (end stage of the disease). These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum. DISCUSSION: The present study suggests a progressive loss of these three nuclear proteins and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration.

DOI： 10.1179/1743132813Y.0000000196

Mitochondrial fusion and fission proteins expression dynamically change in a murine model of amyotrophic lateral sclerosis. 査読国際誌

Wentao Liu, Toru Yamashita, Fengfeng Tian, Nobutoshi Morimoto, Yoshio Ikeda, Kentaro Deguchi, Koji Abe

Current neurovascular research 10 ( 3 ) 222 - 30 2013年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mitochondria dynamically change their shape through frequent fusion and fission to continuously perform their function in the cell. Although a change in mitochondrial morphology was reported in amyotrophic lateral sclerosis (ALS), detailed changes of mitochondrial fusion and fission proteins have not been reported in ALS model mice. In transgenic (Tg) mice with the G93A human SOD1 mutation (G93ASOD1), both mitochondrial fusion proteins (Mfn1 and Opal) and fission proteins (Drp1 and Fis1) showed a significant increase in the anterior half of the lumbar spinal cord. Such changes in Tg mice were already noticeable at presymptomatic 10 week (W) compared with wildtype (WT) mice, detected through immunohistochemical as well as Western blot analyses. Furthermore, fusion protein levels of Mfn1 and Opa1 showed a progressive decrease from 10 to 18 W in Tg mice while fission protein levels of P-Drp1 and Fis1 maintained a high level of expression in Tg mice from 10 to 18 W. These data suggest that abnormal changes in mitochondrial morphology began before the onset of ALS and that the balanced mitochondrial morphology becomes altered by fissions in motor neurons (MNs) in this ALS model.

Combination benefit of amlodipine plus atorvastatin treatment on carotid atherosclerosis in Zucker metabolic rats. 査読国際誌

Hiromi Kawai, Tomoko Kurata, Kentaro Deguchi, Shoko Deguchi, Toru Yamashita, Yasuyuki Ohta, Yoshio Omote, Syoichiro Kono, Koji Abe

Neurological research 35 ( 2 ) 181 - 6 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases. METHODS: We studied effects of amlodipine, atorvastatin, and their combination on carotid arteriosclerotic processes in a metabolic syndrome model of Zucker fatty rats. Zucker fatty rats were treated with vehicle, amlodipine, atorvastatin, or combination amlodipine plus atorvastatin for 28 days. RESULTS: Compared with the single treatment with amlodipine or atorvastatin, the combination of amlodipine plus atorvastatin treatment prevented arteriosclerotic processes, and induced a strong recovery of Sirtuin1 (Sirt1) expression and a marked reduction in p53, p21, and monocyte chemoattractant protein-1 (MCP-1). DISCUSSION: As Sirt1 is a longevity gene that prevents endothelial atherosclerotic processes, and p53, p21, and MCP-1 play pivotal roles in the initiation and development of atherosclerosis, these data suggest a strong synergistic benefit of combination therapy with amlodipine and atorvastatin for preventing atherosclerotic processes, and potentially reducing the clinical risk of cerebrovascular events in metabolic obesity patients.

DOI： 10.1179/1743132812Y.0000000131

Neuroleptic malignant syndrome associated with risperidone long-acting injection: a case report. 査読国際誌

Toru Yamashita, Yasuo Fujii, Fuminari Misawa

Journal of clinical psychopharmacology 33 ( 1 ) 127 - 9 2013年2月

Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods. 査読国際誌

Nobutoshi Morimoto, Toru Yamashita, Kota Sato, Tomoko Kurata, Yoshio Ikeda, Toshimasa Kusuhara, Naomichi Murata, Koji Abe

Journal of the neurological sciences 324 ( 1-2 ) 149 - 55 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: We report on a unique complication of cerebellar ataxia and motor neuron disease named Asidan/SCA36 with a high frequency of tongue atrophy. We aimed to elucidate dysphagia in amyotrophic lateral sclerosis (ALS) and spinal, bulbar muscular atrophy (SBMA), and Asidan/SCA36 patients with new methods. METHODS: Patients diagnosed with ALS (n=20), SBMA (n=6), and Asidan (n=12) were included. A videofluoroscopic swallow study (VFS), an assessment of maximal tongue pressure (MTP), and impedance pharyngography (IPG) were applied. RESULTS: The frequencies of VFS abnormalities were 70%, 50%, and 33% in ALS, SBMA, and Asidan/SCA36, respectively. Compared with control subjects (31.6 ± 6.3 kPa, mean ± SD), MTP was significantly decreased in ALS patients and SBMA patients, but was relatively preserved in Asidan patients. ALS patients performed more swallowing actions (Ns) detected by IPG than did control subjects, but SBMA and Asidan/SCA36 patients performed similar Ns to control subjects. CONCLUSIONS: VFS showed a higher frequency of swallowing abnormalities in ALS patients. MTP and IPG measurements showed the most severe involvement in ALS patients and a relatively preserved swallowing function in SBMA and Asidan/SCA36 patients.

DOI： 10.1016/j.jns.2012.10.025

Synchronized Babinski and Chaddock signs preceded the MRI findings in a case of repetitive transient ischemic attack. 査読

Kosuke Matsuzono, Takao Yoshiki, Yosuke Wakutani, Yasuhiro Manabe, Toru Yamashita, Kentaro Deguchi, Yoshio Ikeda, Koji Abe

Internal medicine (Tokyo, Japan) 52 ( 18 ) 2127 - 9 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）

We herein report a 53-year-old female with repeated transient ischemic attack (TIA) symptoms including 13 instances of right hemiparesis that decreased in duration over 4 days. Two separate examinations using diffusion weighted image (DWI) in magnetic resonance imaging (MRI) revealed normal findings, but we observed that both Babinski and Chaddock signs were completely synchronized with her right hemiparesis. We were only able to diagnose this case of early stage TIA using clinical signs. This diagnosis was confirmed 4 days after the onset by the presence of abnormalities on the MRI. DWI-MRI is generally useful when diagnosing TIA, but a neurological examination may be more sensitive, especially in the early stages.

Two Unique Cases with Anti-GluR Antibody-Positive Encephalitis. 査読国際誌

Kosuke Matsuzono, Tomoko Kurata, Shoko Deguchi, Toru Yamashita, Kentaro Deguchi, Yoshio Ikeda, Koji Abe

Clinical medicine insights. Case reports 6 113 - 7 2013年

記述言語：英語

We report two cases of anti-glutamic acid receptor (anti-GluR) antibody-positive encephalitis in males with symptoms such as Parkinsonism, urinary retention, and paralytic ileus. Although non-herpetic encephalitis typically shows magnetic resonance imaging (MRI) lesions in the limbic system during early stages, the present cases showed MRI lesions during later stages in the bilateral claustrum and pons. In both cases, anti-GluRɛ2 and δ2 antibodies were later shown to be positive in the cerebrospinal fluid but negative in the serum. Although early detection of anti-GluR antibodies is essential, early treatment may be significantly more important.

DOI： 10.4137/CCRep.S11890

Dynamic Changes of Mitochondrial Fusion and Fission Proteins in a Murine Model of Amyotrophic Lateral Sclerosis

Wentao Liu, Yamashita Toru, Deguchi Kentaro, Ning Liu, Miao Sun, Koji Abe

CEREBROVASCULAR DISEASES 36 49 - 50 2013年

Prevention of hyperglycemic signal pathways in metabolic syndrome carotid artery of rats. 査読国際誌

Hiromi Kawai, Fengfeng Tian, Tomoko Kurata, Kentaro Deguchi, Toru Yamashita, Yoshio Omote, Syoichiro Kono, Koji Abe

Translational stroke research 3 ( 4 ) 466 - 72 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor /insulin receptor substrate 1(IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Zucker fatty rats (8 weeks) were treated with vehicle (0.5 % methyl cellulose in physiological saline, p.o.), amlodipine (3 mg/kg/day, p.o.), atorvastatin (10 mg/kg/day, p.o.), or the combination of amlodipine plus atorvastatin (3 + 10 mg/kg/day, p.o.) for 28 days, and anti-insulin-like growth factor 1 (IGF-1)/IRS-1/PI3K/Akt pathways were evaluated. Our present immunohistochemical study first demonstrated that a combination of amlodipine plus atorvastatin treatment prevented an arteriosclerotic process compared to the single treatment with amlodipine or atorvastatin with strong recoveries of pTyr IRS-1, pPI3K, and pAkt expressions and with remarkable restraints of IGF-1 and pSer IRS-1. As a result, combination therapy with amlodipine plus atorvastatin showed a strong synergistic effect to prevent atherosclerotic processes. The present study newly suggests a synergistic benefit of combination therapy with amlodipine plus atorvastatin for strong prevention of atherosclerotic processes, which could reduce the clinical risk of cerebrovascular events for obesity patients.

DOI： 10.1007/s12975-012-0205-6

Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging. 査読国際誌

Ning Liu, Kentaro Deguchi, Toru Yamashita, Wentao Liu, Yoshio Ikeda, Koji Abe

Journal of neuroscience research 90 ( 11 ) 2086 - 93 2012年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Detection and protection of the neurovascular unit (NVU) are essential for treatment of acute stroke patients, especially the use of tissue plasminogen activator (tPA). In the present study, we conducted in vivo and ex vivo optical imaging for detecting activation of matrix metalloproteinases (MMPs) and evaluated the protective effect of intracerebral transplantation of bone marrow stromal cells (BMSCs) obtained from green fluorescent protein (GFP) transgenic (Tg) mice on the NVU in tPA-mediated brain damage after transient middle cerebral artery occlusion (tMCAO) in mice. Compared with the tMCAO group, the tMCAO plus BMSC group showed significant reductions of in vivo and ex vivo fluorescent signals for MMPs at 48 hr after tMCAO, with a partial colocalization of BMSC-GFP signals. Intracerebrally transplanted BMSCs ameliorated MMP-9 activation by immunohistochemistry and Western blot with differentiation into microglial and astroglial cells. Double-immunofluorescence study revealed improved NVU disruption in the tMCAO plus BMSC group. The present study suggests that intracerebral BMSC transplantation reduced MMP activation and subsequent NVU disruption caused by tPA after tMCAO and that this MMP activation and BMSC effect were detectable with in vivo and ex vivo optical imaging.

DOI： 10.1002/jnr.23104

Strong neuroprotection with a novel platinum nanoparticle against ischemic stroke- and tissue plasminogen activator-related brain damages in mice 査読

M. Takamiya, Y. Miyamoto, T. Yamashita, K. Deguchi, Y. Ohta, K. Abe

Neuroscience 221 47 - 55 2012年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Reactive oxygen species (ROS) are major exacerbation factor in acute ischemic stroke, and thrombolytic agent tissue plasminogen activator (tPA) may worsen motor function and cerebral infarcts. The platinum nanoparticle (nPt) is a novel ROS scavenger, and thus we examined the clinical and neuroprotective effects of nPt in ischemic mouse brains. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60. min and divided into the following four groups by intravenous administration upon reperfusion, vehicle, tPA, tPA. +. nPt, and nPt. At 48. h after tMCAO, motor function, infarct volume, immunohistochemical analyses of neurovascular unit (NVU), in vivo imaging of matrix metalloproteinase (MMP), and zymography for MMP-9 activity were examined. Superoxide anion generation at 2. h after tMCAO was also examined with hydroethidine (HEt). As a result, administration of tPA deteriorated the motor function and infarct volume as compared to vehicle. In vivo optical imaging of MMP showed strong fluorescent signals in affected regions of tMCAO groups. Immunohistochemical analyses revealed that tMCAO resulted in a minimal decrease of NAGO and occludin, but a great decrease of collagen IV and a remarkable increase of MMP-9. HEt stain showed increased ROS generation by tMCAO. All these results became pronounced with tPA administration, and were greatly reduced by nPt. The present study demonstrates that nPt treatment ameliorates neurological function and brain damage in acute cerebral infarction with neuroprotective effect on NVU and inactivation of MMP-9. The strong reduction of ROS production by nPt could account for these remarkable neurological and neuroprotective effects against ischemic stroke. © 2012 IBRO.

DOI： 10.1016/j.neuroscience.2012.06.060

Alternative alpha-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology 査読国際誌

Herve Rhinn, Liang Qiang, Toru Yamashita, David Rhee, Ari Zolin, William Vanti, Asa Abeliovich

NATURE COMMUNICATIONS 3 1084 - 1084 2012年9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：NATURE PUBLISHING GROUP

α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.

DOI： 10.1038/ncomms2032

Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. 査読国際誌

Claudia A Doege, Keiichi Inoue, Toru Yamashita, David B Rhee, Skylar Travis, Ryousuke Fujita, Paolo Guarnieri, Govind Bhagat, William B Vanti, Alan Shih, Ross L Levine, Sara Nik, Emily I Chen, Asa Abeliovich

Nature 488 ( 7413 ) 652 - 5 2012年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.

DOI： 10.1038/nature11333

Stem cell therapy for cerebral ischemia: from basic science to clinical applications. 査読国際誌

Koji Abe, Toru Yamashita, Shunya Takizawa, Satoshi Kuroda, Hiroyuki Kinouchi, Nobutaka Kawahara

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 32 ( 7 ) 1317 - 31 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.

DOI： 10.1038/jcbfm.2011.187

Clinical and pathological improvement in stroke-prone spontaneous hypertensive rats related to the pleiotropic effect of cilostazol. 査読国際誌

Yoshio Omote, Kentaro Deguchi, FengFeng Tian, Hiromi Kawai, Tomoko Kurata, Toru Yamashita, Yasuyuki Ohta, Koji Abe

Stroke 43 ( 6 ) 1639 - 46 2012年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND PURPOSE: Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). METHODS: Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1Rβ expression in the hippocampus was assessed by Western blotting. RESULTS: The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin. Only cilostazol improved motor and cognitive functions with a significant increase (P<0.05) in the memory-related IGF-1R-positive ratio and IGF-1Rβ expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. CONCLUSIONS: The present results suggest that a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. The increase of IGF-1R-positive cells in the hippocampal CA1 region could partly explain the preservation of spatial cognitive function in stroke-prone spontaneously hypertensive rats.

DOI： 10.1161/STROKEAHA.111.643098

Potential treatment strategies for enhancing neuroplasticity and regeneration after ischemic stroke

Toru Yamashita, Koji Abe

Future Neurology 7 ( 3 ) 279 - 285 2012年5月

記述言語：英語

Strokes are a major cause of death and result in a drastic reduction in quality of life. Novel therapeutic strategies for patients suffering from stroke are thus required. Two possible strategies can be proposed for treating ischemic stroke: enhancing neuroplasticity, allowing the surviving neuronal cells to compensate for stroke-related impairment through brain reorganization, sprouting and rewiring of neuronal cells, or regeneration of neuronal cells, including enhancement of intrinsic neurogenesis and stem cell transplantation therapy with neural stem cells, embryonic stem cells or induced pluripotent stem cells. Endogenous neurogenesis or transplanted neural stem cells, embryonic stem cells or induced pluripotent stem cell-derived cells are able to not only supply newborn neurons integrated into a damaged neuronal network, but also produce growth factors into the recovering brains. These secretory factors enhance sprouting and angiogenesis and may be important in neuroplasticity and recovery in the poststroke brain. © 2012 Future Medicine Ltd.

DOI： 10.2217/fnl.12.12

Asymmetric Pattern of Cerebrovascular Lesions in Patients After Left Ventricular Assist Device Implantation 査読国際誌

Tomoko S. Kato, Takeyoshi Ota, P. Christian Schulze, Maryjane Farr, Ulrich Jorde, Hiroo Takayama, Yoshifumi Naka, Toru Yamashita, Donna M. Mancini

STROKE 43 ( 3 ) 872 - 874 2012年3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：LIPPINCOTT WILLIAMS & WILKINS

BACKGROUND AND PURPOSE: Stroke is a major adverse event after left ventricular assist device (LVAD) surgery. The purpose of this study was to describe differences in hemispheric distribution of stroke in LVAD patients. METHODS: We reviewed 317 consecutive patients who underwent LVAD surgery between November 2000 and July 2011. Stroke during LVAD support was analyzed. RESULTS: In total, 46 strokes occurred at 76.0±96.8 days postoperatively. Among the 46 strokes, 27 events (58.7%) occurred in right hemisphere, 13 events (28.2%) in the left hemisphere, 3 events (8.7%) occurred bilaterally, and 2 events (4.3%) were vertebrobasilar lesions. The right hemispheric stroke was significantly more common in patients with postoperative infection compared with left hemispheric events. CONCLUSIONS: Stroke after LVAD implantation has a right hemispheric predominance. This finding suggests LVAD-related thrombus in the setting of infection and/or the anatomic configuration of LVAD outflow cannula-ascending aorta anastomosis to be highly associated with stroke after LVAD surgery.

DOI： 10.1161/STROKEAHA.111.639682

Mechanisms of endogenous endothelial repair in stroke. 査読国際誌

Toru Yamashita, Koji Abe

Current pharmaceutical design 18 ( 25 ) 3649 - 52 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent evidence indicates that circulating endothelial progenitor cells can play an important role, not only in endothelium homeostasis of the pre-stroke brain, but also in angiogenesis of the post-stroke brain. Circulating endothelial progenitor cells are considered to repair endothelial cells by incorporating them into newly formed vessels, or by releasing pro-angiogenic factors. The number or function of circulating endothelial progenitor cells can be modulated by various kinds of factors. For example, elevated serum cholesterol, hypertension, diabetes and smoking decreased the number whereas vascular endothelial growth factor (VEGF), exercise, and statins can increase it. In this review, we discuss the present knowledge of endogenous mechanisms for the repair of endothelial cells, and how to enhance their possible capacity to remodel vascular units as neuronal self-repair strategies.

[iPS cell transplantation for ischemic brain]. 査読

Koji Abe, Toru Yamashita, Hiromi Kawai

Rinsho shinkeigaku = Clinical neurology 52 ( 11 ) 1143 - 6 2012年

記述言語：日本語掲載種別：研究論文（学術雑誌）

Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5×10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

Amlodipine and atorvastatin exert protective and additive effects via antiapoptotic and antiautophagic mechanisms after transient middle cerebral artery occlusion in Zucker metabolic syndrome rats. 査読国際誌

Xuemei Zhang, Shoko Deguchi, Kentaro Deguchi, Yasuyuki Ohta, Toru Yamashita, Jingwei Shang, Fengfeng Tian, Ning Liu, Wentao Liu, Yoshio Ikeda, Tohru Matsuura, Koji Abe

Journal of neuroscience research 89 ( 8 ) 1228 - 34 2011年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

We examined the neuroprotective effects amlodipine and/or atorvastatin in metabolic syndrome (MetS) Zucker fatty rats against transient (90 min) middle cerebral artery occlusion (MCAO). The rats were pretreated with vehicle, amlodipine, atorvastatin, or amlodipine plus atorvastatin for 28 days, and 24 hr after transient MCAO the infarct size was assessed via hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and microtubule-associated protein 1 light chain 3 (LC3) expression were examined by immunohistochemistry to evaluate apoptosis and autophagy, respectively. Compared with the vehicle group, rats treated with amlodipine or atorvastatin alone showed a significant decrease in infarct volume (P < 0.01), which was further decreased in the amlodipine plus atorvastatin group (P < 0.001). Compared with the vehicle group, the numbers of TUNEL- and LC3-positive cells were markedly reduced by amlodipine or atorvastatin alone (P < 0.01) and further decreased by amlodipine plus atorvastatin (P < 0.001). The number of apoptotic TUNEL/autophagic LC3 double-positive cells was also significantly decreased with amlodipine or atorvastatin alone compared with vehicle (P < 0.01) and was further decreased by amlodipine plus atorvastatin (P < 0.001). These data suggest additive neuroprotective effects of combination amlodipine and atorvastatin treatment after acute ischemic stroke in MetS model Zucker rats. These effects are mediated, at least in part, via antiapoptotic and antiautophagic mechanisms. Further studies are now needed to expand these preliminary results to understand fully the mechanisms involved in the protective effects of amlodipine and atorvastatin against ischemic stroke.

DOI： 10.1002/jnr.22633

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