研究者総覧

瀬原 吉英 (セハラ ヨシヒデ)

  • 遺伝子治療研究部 講師
Last Updated :2021/11/23

研究者情報

学位

  • 医学博士(岡山大学大学院)

ホームページURL

J-Global ID

研究分野

  • ライフサイエンス / 神経内科学

経歴

  • 2016年 - 現在  自治医科大学分子病態治療研究センター遺伝子治療研究部講師
  • 2014年 - 2015年  自治医科大学分子病態治療研究センター遺伝子治療研究部客員研究員
  • 2013年 - 2014年  埼玉医科大学 医学部 国際医療センター 神経内科・脳卒中内科 専任講師
  • 2010年 - 2013年  Albert Einstein College of MedicineDepartment of NeuroscienceResearch Fellow

学歴

  •         - 2008年   岡山大学大学院   医歯学総合研究科   神経病態内科学
  •         - 2001年   自治医科大学   医学部

研究活動情報

論文

  • Yoshihide Sehara, Yuka Hayashi, Kenji Ohba, Ryosuke Uchibori, Masashi Urabe, Ayumu Inutsuka, Kuniko Shimazaki, Kensuke Kawai, Hiroaki Mizukami
    Human gene therapy 2021年09月 [査読有り]
     
    The safety and high efficiency of adeno-associated virus (AAV) vectors has facilitated their wide-scale use to deliver therapeutic genes for experimental and clinical purposes in diseases affecting the central nervous system (CNS). AAV1, 2, 5, 8, 9, and rh10 are the most commonly used serotypes for CNS applications. Most AAVs are known to transduce genes predominantly into neurons. However, the precise tropism of AAVs in the dentate gyrus (DG), the region where persistent neurogenesis occurs in the adult brain, is not fully understood. We stereotaxically injected 1.5 × 1010 viral genomes of AAV2, 5, or rh10 carrying green fluorescent protein (GFP) into the right side of gerbil hippocampus, and performed immunofluorescent analysis using differentiation stage-specific markers 1 week after injection. We found that AAV5 showed a significantly larger number of double-positive cells for GFP and Sox2 in the DG, compared with the AAV2 and rh10 groups. On the contrary, AAVrh10 presented a substantially larger number of double-positive cells for GFP and NeuN in the DG, compared with AAV2 and AAV5. Our findings indicated that AAV5 showed high transduction efficiency to neural stem cells and precursor cells, whereas AAVrh10 showed much higher efficiency to mature neurons in the DG.
  • Yoshihide Sehara, Yoshihito Ando, Takumi Minezumi, Nozomi Funayama, Kensuke Kawai, Mikio Sawada
    Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology 34 1 70 - 75 2021年03月 [査読有り]
     
    Global autobiographical amnesia is a rare disorder that is characterized by a sudden loss of autobiographical memories covering many years of an individual's life. Generally, routine neuroimaging studies such as CT and MRI yield negative findings in individuals with global autobiographical amnesia. However, in recent case reports, functional analyses such as SPECT and fMRI have revealed changes in activity in various areas of the brain when compared with controls. Studies using iomazenil (IMZ) SPECT with individuals with global autobiographical amnesia have not been reported. We report the case of a 62-year-old Japanese woman with global autobiographical amnesia who had disappeared for ∼4 weeks. [123I]-IMZ SPECT showed reduced IMZ uptake in her left medial temporal lobe and no significant reduction on N-isopropyl-[123I] p-iodoamphetamine (IMP) SPECT in the identical region. Because IMZ binds to the central benzodiazepine receptor, this dissociation between IMZ and IMP SPECT was thought to reflect the breakdown of inhibitory neurotransmission in the left medial temporal lobe. Moreover, when the woman recovered most of her memory 32 months after fugue onset, the IMZ SPECT-positive lesion had decreased in size. Because the woman had long suffered verbal abuse from her former husband's sister and brother, which can also cause global autobiographical amnesia, it is difficult to conclude whether the IMZ SPECT-positive lesion in the left medial temporal lobe was the cause or the result of her global autobiographical amnesia. Although only one case, these observations suggest that IMZ SPECT may be useful in uncovering the mechanisms underlying global autobiographical amnesia.
  • Yoshihide Sehara, Haruna Yabe, Akio Iwanami, Nobuyuki Nakamura
    Internal medicine (Tokyo, Japan) 59 22 2965 - 2965 2020年11月 [査読有り]
  • Naoki Kaneko, Henrik Ullman, Fadil Ali, Philipp Berg, Yinn Cher Ooi, Satoshi Tateshima, Geoffrey P Colby, Yutaro Komuro, Peng Hu, Kasra Khatibi, Lucido L Ponce Mejia, Viktor Szeder, May Nour, Lea Guo, Aichi Chien, Fernando Vinuela, Shigeru Nemoto, Toshihiro Mashiko, Yoshihide Sehara, Jason D Hinman, Gary Duckwiler, Reza Jahan
    World neurosurgery 141 e873-e879  2020年09月 [査読有り]
     
    BACKGROUND: Current in vitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed in vitro AVM model for embolic material testing, preclinical training, and flow analysis. METHODS: Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI. RESULTS: The manufacture of 3D in vitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the in vitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis. CONCLUSIONS: An in vitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials.
  • Yoshihide Sehara, Hideaki Otsuka, Naoki Kaneko, Yoshihito Ando, Mikio Sawada
    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 70 260 - 263 2019年12月 [査読有り][通常論文]
     
    Hemichorea is relatively an uncommon clinical presentation while its known etiology are vascular, metabolic, neoplastic, infectious, autoimmune, and inherited disorders. In the acquired case of hemichorea, the most common cause is the cerebrovascular insult, which is often diagnosed by the magnetic resonance (MR) imaging. An 84-year-old woman reported a one-week history of involuntary movements in the left side of her face and left limbs. Blood tests were normal and brain MR imaging showed no responsible hyperintense lesion on T1-, FLAIR, and diffusion-weighted imaging. N-isopropyl-[123I] p-iodoamphetamine single-photon emission computed tomography (SPECT) detected hypoperfusion in the right thalamus. Further three-dimensional tomography clearly detected the hypoperfusion in the right subthalamic nucleus. The hypoperfused lesion was MR-negative and remained unchanged in SPECT one year after the onset. After the treatment with 0.35 mg of oral haloperidol was initiated, the hemichorea was gradually decreased and completely disappeared in 9 months. Because the three-dimensional analysis performs voxel-by-voxel analysis, it possibly detects the precise hypoperfusion in a specific region. In conclusion, evaluation of cerebral blood flow using SPECT on patients presenting with acute hemichorea can lead to the detection of responsible lesion when the routine examinations are negative.
  • Neurosarcoidosis Occurring 6 Years after Onset of Vogt-Koyanagi-Harada Disease.
    Yoshihide Sehara, Hideaki Otsuka, Shinichi Sakamoto, Yoshihito Ando, Mikio Sawada.
    Case Rep Ophthalmol. 10 1 32 - 40 2019年05月 [査読有り][通常論文]
  • Ryosuke Uchibori, Takeshi Teruya, Hiroyuki Ido, Ken Ohmine, Yoshihide Sehara, Masashi Urabe, Hiroaki Mizukami, Junichi Mineno, Keiya Ozawa
    Molecular therapy oncolytics 12 16 - 25 2019年03月 [査読有り][通常論文]
     
    Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor locality. Here, we aimed to develop an inducible promoter driven by activation signals from a CAR. Transgene expression in T cells transduced with the CD19-targeted CAR and an inducible promoter, including inducible reporter genes (CAR-T/iReporter), was only induced strongly by co-culture with CD19-positive target cells. CAR-T/iReporter cells also showed redirected cytolysis toward CD19-positive, but not CD19-negative, tumor cells. Overall, our study indicated that the inducible promoter was selectively driven by activation signals from the CAR, and transduction with the inducible promoter did not affect original effector activities including interleukin-2 and interferon-γ production and the antitumor activity of CAR-redirected cytotoxic T lymphocytes. Moreover, this inducible promoter permits visualization and quantification of the activation status in CAR-T cells.
  • Yoshihide Sehara, Toshiki Inaba, Takao Urabe, Fumio Kurosaki, Masashi Urabe, Naoki Kaneko, Kuniko Shimazaki, Kensuke Kawai, Hiroaki Mizukami
    The European journal of neuroscience 48 12 3466 - 3476 2018年12月 [査読有り][通常論文]
     
    Survivin, a member of the inhibitors of apoptosis protein gene family, inhibits the activity of caspase, leading to a halt of the apoptotic process. Our study focused on the neuroprotective effect of survivin after transient middle cerebral artery occlusion (MCAO) with intraparenchymal administration of an adeno-associated virus (AAV) vector. His-tagged survivin was cloned and packaged into the AAV-rh10 vector. Four-week-old Sprague-Dawley rats were injected with 4 × 109  vg of AAV-GFP or AAV-His-survivin into the right striatum and were treated 3 weeks later with transient MCAO for 90 min. Twenty-four hours after MCAO, functional and histological analyses of the rats were performed. The result showed that rats that had been treated with AAV-green fluorescent protein (GFP) and those that had been treated with AAV-His-survivin did not show a significant difference in neurological scores 24 hr after MCAO, however, infarction volume was significantly reduced in the AAV-His-survivin group compared to that in the AAV-GFP group. Although the neutrophil marker myeloperoxidase did not show a significant difference in the ischemic boundary zone, cells positive for active caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were significantly decreased in the AAV-His-survivin group. In conclusion, survivin overexpression in the ischemic boundary zone induced by using an AAV vector has the potential for amelioration of ischemic damage via an antiapoptotic mechanism.
  • Fumio Kurosaki, Ryosuke Uchibori, Yoshihide Sehara, Yasushi Saga, Masashi Urabe, Hiroaki Mizukami, Koichi Hagiwara, Akihiro Kume
    Human gene therapy 29 11 1242 - 1251 2018年11月 [査読有り][通常論文]
     
    Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder with limited therapeutic options. An aberrant wound healing process in response to repetitive lung injury has been suggested for its pathogenesis, and a number of cytokines including transforming growth factor β1 play pivotal roles in the induction and progression of fibrosis. Thus, the regulation of these pro-inflammatory conditions may reduce the progression of IPF and ameliorate its symptoms in patients. Interleukin-10 (IL-10), a pleiotropic cytokine, exerts anti-inflammatory and anti-fibrotic effects in numerous biological settings. In the present study, we investigated the preventive effects of IL-10 on bleomycin-induced pulmonary fibrosis in mice with the continuous expression of this cytokine via an adeno-associated virus serotype 6 vector. Mice were administered the adeno-associated virus serotype 6 vector encoding mouse IL-10 by intratracheal injection, and osmotic minipumps containing bleomycin were subcutaneously implanted seven days later. Lung histology and the expression levels of pro-inflammatory cytokines and fibrogenic cytokines were then analyzed. In mice exhibiting persistent IL-10 expression on day 35, the number of infiltrated inflammatory cells and the development of fibrosis in lung tissues were significantly reduced. Increases in transforming growth factor β1 and decreases in IFN-γ were also suppressed in treated animals, with changes in these cytokines playing important roles in the pathogenesis of pulmonary fibrosis. Furthermore, IL-10 significantly improved survival in bleomycin-induced mice. Our results provide insights into the potential benefit of the anti-fibrotic effects of IL-10 as a novel therapeutic approach for IPF.
  • Yoshihide Sehara, Kuniko Shimazaki, Fumio Kurosaki, Naoki Kaneko, Ryosuke Uchibori, Masashi Urabe, Kensuke Kawai, Hiroaki Mizukami
    Neuroscience letters 682 27 - 31 2018年08月 [査読有り][通常論文]
     
    Adeno-associated virus (AAV) is an ideal vector for gene transduction into the central nervous system because of its safety and efficiency. While it is currently widely used for clinical trials and is expected to become more widespread, the appropriate combination of viral serotypes and promoters have not been fully investigated. In this study, we compared the transduced gene expression of AAVrh10 to AAV5 in gerbil hippocampus using three different promoters, including cytomegalovirus (CMV), chicken β-actin promoter with the CMV immediate-early enhancer (CAG), and the Synapsin 1 (Syn1) promoter. Four-week-old male gerbils underwent stereotaxic injection with 1 × 1010 viral genome of AAV carrying green fluorescent protein (GFP). Quantification of the GFP-positive areas 3 weeks after injection showed that AAVrh10-CMV and AAVrh10-CAG were the most efficient (p < 0.001, compared with the control) and AAVrh10-Syn1 and AAV5-CMV were the next most efficient (p < 0.05, compared with the control). On the other hand, AAV5-Syn1 showed little expression, which was only observed at the injected site. In conclusion, we should note that some combinations of viral capsids and promoters can result in failure of gene delivery, while most of them will work appropriately in the transgene expression in the brain.
  • Naoki Kaneko, Mayumi Tsunoda, Masatsugu Mitsuhashi, Keisuke Okubo, Taro Takeshima, Yoshihide Sehara, Mutsumi Nagai, Kensuke Kawai
    Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine 36 10 2071 - 2077 2017年10月 [査読有り][通常論文]
     
    OBJECTIVES: The purpose of this study was to examine the feasibility of an optical see-through head-mounted display (OST-HMD) to improve ergonomics during ultrasound-guided fine-needle aspiration (FNA) in the neck region. METHODS: This randomized controlled study compared an OST-HMD with a normal ultrasound monitor during an ultrasound-guided FNA in the neck region. Patients with a neck tumor were recruited and randomized into one of two groups. Two practitioners performed ultrasound-guided FNA with or without the HMD, as indicated. An independent researcher measured the procedure time, the number and time of head movements, as well as the number of needle redirections. In addition, practitioners completed questionnaires after performing the FNA on each patient. RESULTS: In 93% of the sessions with the OST-HMD, practitioners performed ultrasound-guided FNA without turning the patients' heads. There was no difference in procedural time and number of needle redirections between the two groups. Results from the questionnaire revealed not only good wearability and low fatigue, but also the practitioners' preference for the HMD. CONCLUSIONS: The OST-HMD improved the practitioners' ergonomics and can be adopted for performing ultrasound-guided interventional procedures in clinical settings.
  • Yoshihide Sehara, Ken-Ichi Fujimoto, Kunihiko Ikeguchi, Yuko Katakai, Fumiko Ono, Naomi Takino, Mika Ito, Keiya Ozawa, Shin-Ichi Muramatsu
    Human gene therapy. Clinical development 28 2 74 - 79 2017年06月 [査読有り][通常論文]
     
    Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.
  • F. Kurosaki, R. Uchibori, N. Mato, Y. Sehara, Y. Saga, M. Urabe, H. Mizukami, Y. Sugiyama, A. Kume
    Gene Therapy 24 5 290 - 297 2017年05月 [査読有り][通常論文]
     
    An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.
  • Yoshihide Sehara, Yuka Hayashi, Kenichi Ohya, Naoki Kaneko, Mikio Sawada
    Case reports in medicine 2017 6030561 - 6030561 2017年 [査読有り][通常論文]
     
    Ischemic stroke following acute myocardial infarction is a rare but a serious complication. Because the pathophysiology of stroke is dynamic, it is often hard to identify the cause of stroke. Here, we present the case of a 75-year-old man with ischemic stroke following angina pectoris caused by severe anemia and localized peritonitis due to gastrointestinal stromal tumor of small intestine. On admission, he showed consciousness disturbance, fever, and left hemiplegia. The electrocardiogram on admission showed ST-segment depression in V2 to V6 which was normalized 4 hours later. The ultrasound cardiogram showed the mild hypokinesis in the apical portion of left ventricle which was also normalized later. The magnetic resonance imaging and angiography showed ischemic stroke in watershed area between right anterior and middle cerebral arteries area and stenosis of distal portion of right middle cerebral artery. The computed tomography of abdomen showed a mass of small intestine. We decided to perform curative surgery after transfusion and successfully resected the mass of the small intestine, which was revealed to be a gastrointestinal stromal tumor (GIST). This is a successfully treated case of GIST in which the complicated pathophysiology of watershed cerebral infarction following angina pectoris might be clearly revealed.
  • Naoki Kaneko, Makoto Sato, Taro Takeshima, Yoshihide Sehara, Eiju Watanabe
    Journal of clinical ultrasound : JCU 44 8 487 - 91 2016年10月 [査読有り][通常論文]
     
    PURPOSE: We examined the feasibility of using a head-mounted display (HMD) to improve the ergonomics of sonographic-guided interventional procedures. METHODS: Five physicians with experience of more than 20 central venous catheterizations participated in this study. Each participant performed five pairs of simulated jugular vein catheterization under sonographic guidance with and without the HMD. The procedure time was determined as well as the number of head movements, needle redirections, posterior wall punctures, and guidewire malpositionings. RESULTS: All participants could perform simulated sonographic-guided catheterization using this HMD without turning their heads. There were no differences in the procedural time, the number of needle redirections, posterior wall punctures, and guidewire malpositionings. CONCLUSIONS: The binocular optical see-through HMD could be adopted for sonographic-guided interventional procedures © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:487-491, 2016.
  • Yuji Kato, Takeshi Hayashi, Yoshihide Sehara, Ichiro Deguchi, Takuya Fukuoka, Hajime Maruyama, Yohsuke Horiuchi, Yuito Nagamine, Hiroyasu Sano, Norio Tanahashi
    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 24 4 890 - 3 2015年04月 [査読有り][通常論文]
     
    BACKGROUND: Essential thrombocythemia (ET) is considered a rare cause of stroke partly because it is not detected if the platelet count is not elevated. However, early detection of ET is important because thrombosis can recur frequently, unless adequately treated. METHODS: We retrospectively collected data from 10 stroke cases with ET. Clinical characteristics, location of stroke, laboratory data (platelet and leukocyte count, hemoglobin, and JAK2 V617F mutation), and treatment were reviewed. RESULTS: The population consisted of 7 women and 3 men aged 18-83 years. Most patients had atherosclerotic risk factors. Half of the patients had a history of ischemic stroke. In 8 patients, ischemic stroke was the first manifestation of ET. Of 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. Three patients presented with watershed-type infarcts without large artery stenosis. Two patients had atherosclerotic stenosis of the large artery and experienced atherothrombotic infarction. The mean platelet count was 966 ± 383 × 10(9)/L. JAK2 V617F mutation was found in 5 of 7 patients. Despite treatment with combined antiplatelet and cytoreductive therapy in all patients, 3 experienced recurrent ischemic stroke. CONCLUSIONS: These findings suggest that ET is an adjunctive risk factor for stroke and the patients with ET are subject to watershed-type infarcts even in the absence of large artery stenosis. Early diagnosis of ET and strict management of vascular risk factors may help prevent additional cerebrovascular events.
  • Yoshihide Sehara, Yuka Hayashi, Jun Mimuro
    Case reports in neurological medicine 2015 543927 - 543927 2015年 [査読有り][通常論文]
     
    An 80-year-old man was admitted for acute subdural hematoma caused by a mild brain injury. His coagulation test showed an isolated prolongation of activated partial thromboplastin time (aPTT). Though the subdural hematoma did not progress, oozing bleed from the wound of tracheostomy continued. Failure of correction on aPTT mixing test supported the presence of an inhibitor to a coagulation factor. Once the diagnosis of acquired hemophilia A (AHA) was made, steroid therapy was performed, which leads him to complete remission of AHA. Isolated prolongation of aPTT can be the key to diagnose a rare coagulopathy, such as AHA.
  • Ichiro Deguchi, Takuya Fukuoka, Takeshi Hayashi, Hajime Maruyama, Yoshihide Sehara, Yuji Kato, Yohsuke Horiuchi, Yuito Nagamine, Hiroyasu Sano, Norio Tanahashi
    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES 23 10 2840 - 2844 2014年11月 [査読有り][通常論文]
     
    Background: We compared the clinical outcomes of persistent atrial fibrillation (PeAF) and paroxysmal atrial fibrillation (PAF) in patients with cardioembolic stroke caused by nonvalvular atrial fibrillation (NVAF) because the nature of the fibrillation can cause persistent cerebral infarction. Methods: We classified 619 of 964 patients hospitalized with cardioembolic stroke between April 2007 and December 2013 within 24 hours of onset as having PeAF (n = 447) and PAF (n = 172) according to a retrospective analysis of their clinical records, including National Institutes of Health Stroke Scale (NIHSS) scores on admission, clinical outcomes (modified Rankin Scale [mRS] scores) at 90 days after admission, and major cerebral artery occlusion. Results: The PeAF group was significantly older (P,. 001) and had a higher prevalence of hypertension (P = .007), diabetes (P = .039), heart failure (P = .004), previous coronary artery disease (P = .002) and cerebral infarction (P < .001), medication with anticoagulants (P < .001), and elevated blood glucose on admission (P = .002). Neurologic severity assessed by NIHSS scores on admission was significantly worse in the PeAF than in the PAF group (P < .001). Significantly more patients in the PAF group had favorable outcomes (mRS, 0-2) after 90 days (P < .001). The incidence of major cerebral artery occlusion was significantly higher in the PeAF group (P < .001). Conclusions: Patients with PeAF and cardioembolic stroke due to NVAF had more severe neurologic deficits on admission, more frequent major arterial occlusion, and poorer outcomes than those with PAF.
  • Ichiro Deguchi, Yohsuke Horiuchi, Takeshi Hayashi, Yoshihide Sehara, Yuji Kato, Yasuko Ohe, Takuya Fukuoka, Hajime Maruyama, Hiroyasu Sano, Yuito Nagamine, Norio Tanahashi
    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 8 2007 - 2011 2014年09月 [査読有り][通常論文]
     
    BACKGROUND: We investigated the effect of rosuvastatin, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on serum lipids and arteriosclerosis in dyslipidemic patients with cerebral infarction. METHODS: The subjects were 24 patients with noncardiogenic cerebral infarction complicated by dyslipidemia (low-density lipoprotein cholesterol [LDL-C] ≥ 140 mg/dL). Serum lipids and highly sensitive C-reactive protein (hs-CRP) were measured at the start of the study and at 3 and 12 months after the initiation of oral rosuvastatin (5 mg/day). Cardio-ankle vascular index (CAVI), intima-media thickness (IMT), and plaque score (PS) were also determined at the start of the study and at 12 months. RESULTS: Of the 24 patients admitted, 17 were eligible for statistical analysis. Total cholesterol (TC), LDL-C, and non-high-density lipoprotein cholesterol (non-HDL-C) (mean [standard deviation {SD}], mg/dL) were significantly decreased at 3 months (TC, 149.4 [20.4]; LDL-C, 78.7 [18.6]; non-HDL-C, 94.6 [21.7]) and at 12 months (TC, 154.9 [27.2]; LDL-C, 82.5 [23.3]; non-HDL-C, 100.2 [28.8]) compared with the baseline data (TC, 232.8 [29.7]; LDL-C, 162.2 [21.2]; non-HDL-C, 183.0 [27.7]). The serum hs-CRP level (mean [SD], ng/mL) was 1053.1 [818.8] at baseline, 575.2 [481.8] at 3 months, and 488.1 [357.7] at 12 months. The decrease in this parameter at 12 months was statistically significant. There was a decrease, although not statistically significant, in CAVI (mean [SD]) at 12 months (right [Rt.] 8.7 [.9]; left [Lt.] 8.6 [1.0]), compared with baseline (Rt. 9.1 [1.1]; Lt. 9.0 [1.1]). The max-IMT (mean [SD], mm) was (Rt. 2.11 [.97]; Lt. 2.01 [.75]) at baseline and (Rt. 2.18 [.82]; Lt. 2.06 [.79]) at 12 months of study treatment. The PS (mean [SD], mm) was 8.93 [4.33] at baseline and 9.61 [4.79] at 12 months; neither parameter showed a significant change. CONCLUSIONS: Rosuvastatin at 5 mg/day significantly reduced serum levels of TC, LDL-C, non-HDL-C, and hs-CRP in dyslipidemic patients with cerebral infarction. No significant change in CAVI, max-IMT, or PS was noted after the study treatment.
  • Takeshi Hayashi, Yoshihide Sehara, Yuji Kato, Takuya Fukuoka, Ichiro Deguchi, Yasuko Ohe, Hajime Maruyama, Yohsuke Horiuchi, Hiroyasu Sano, Yuito Nagamine, Norio Tanahashi
    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 8 2169 - 2173 2014年09月 [査読有り][通常論文]
     
    BACKGROUND: Previous studies show that 6%-31% of transient ischemic attacks (TIA) were caused by cardiogenic cerebral embolism (cardioembolic TIA). As prompt initiation of therapy is essential in TIA to prevent subsequent strokes, determining their cause is important. In this study, we aim to determine the features of cardioembolic TIA and to compare them with those of noncardioembolic etiology. METHODS: We retrospectively reviewed patients with a tissue-defined TIA who were admitted to our hospital from April 2007 to August 2013. The etiology was categorized according to Trial of Org 10172 in Acute Stroke Treatment, and TIA of cardioembolic origin and cervicocerebrovascular etiology (noncardioembolic TIA) were included in this study. Those with 2 or more possible causes or undetermined etiologies were excluded. Age, sex, comorbidities, ABCD2 score, and CHADS2 score were assessed and compared between the 2 groups. RESULTS: There were no significant differences in the neurologic symptoms and their duration, morbidities of hypertension, diabetes, and dyslipidemia between the 2 groups. Coronary and peripheral artery diseases were more common in the cardioembolic TIA group (18.4% vs. 6.9%). Incidences of prior stroke and cerebral infarction determined by MRI were similar between the 2 groups. The ABCD2 score showed a similar distribution, but the CHADS2 score was significantly different; the cardioembolic TIA group showed a higher score (P = .005). CONCLUSIONS: Clinical features are similar in tissue-defined TIA of cardioembolic and noncardioembolic etiologies. The CHADS2 score can be useful in assessing the probability of cardioembolic TIA.
  • Hajime Maruyama, Takuya Fukuoka, Ichiro Deguchi, Yasuko Ohe, Yohsuke Horiuchi, Yuji Kato, Yoshihide Sehara, Yuito Nagamine, Hiroyasu Sano, Takeshi Hayashi, Norio Tanahashi
    Internal medicine (Tokyo, Japan) 53 22 2575 - 9 2014年 [査読有り][通常論文]
     
    OBJECTIVE: Clopidogrel is used to prevent the recurrence of non-cardiogenic ischemic stroke, but individual responsiveness to the drug varies. Moreover, it is known that smoking, which is a risk factor for ischemic stroke, affects the drug's pharmacokinetics. The objective of the present study was to investigate a possible relationship between smoking and responsiveness to clopidogrel in non-cardiogenic ischemic stroke patients. METHODS: The study involved 209 non-cardiogenic ischemic stroke patients who were administered oral clopidogrel at a dosage of 75 mg/day for at least 1 week. Platelet aggregation in response to adenosine diphosphate (20 μM) was measured in each patient using the VerifyNow P2Y12 Assay. Platelet aggregation and the incidence of resistance to clopidogrel were compared between a smokers group (70 patients) and a non-smokers group (139 patients). Clopidogrel resistance was defined as a P2Y12 Reaction Units (PRU) value >230 and/or % inhibition <20%. RESULTS: The mean PRU was 128.3±85.5 in the smokers group and 167.7±86.6 in the non-smokers group (p=0.002). The incidence of PRU >230 was 12.9% (9 patients) in the smokers group and 25.9% (36 patients) in the non-smokers group (p=0.033). The mean % inhibition was 48.6±30.7% in the smokers group and 36.9±27.6% in the non-smokers group (p=0.009). The incidence of patients with % inhibition <20% was 24.3% (17 patients) in the smokers group and 34.5% (48 patients) in the non-smokers group (p=0.155). CONCLUSION: The incidence of clopidogrel resistance was lower in the non-cardiogenic ischemic stroke patients who were smokers, thus indicating that these patients' responsiveness to this drug may be enhanced.
  • Yoshihide Sehara, Kirsty Sawicka, Jee-Yeon Hwang, Adrianna Latuszek-Barrantes, Anne M Etgen, R Suzanne Zukin
    The Journal of neuroscience : the official journal of the Society for Neuroscience 33 30 12364 - 74 2013年07月 [査読有り][通常論文]
     
    Transient global ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons in humans and animals. It is well established that estrogens ameliorate neuronal death in animal models of focal and global ischemia. However, the role of signal transducer and activator of transcription-3 (STAT3) and its target genes in estradiol neuroprotection in global ischemia remains unclear. Here we show that a single intracerebral injection of 17β-estradiol to ovariectomized female rats immediately after ischemia rescues CA1 neurons destined to die. Ischemia promotes activation of STAT3 signaling, association of STAT3 with the promoters of target genes, and STAT3-dependent mRNA and protein expression of prosurvival proteins in the selectively vulnerable CA1. In animals subjected to ischemia, acute postischemic estradiol further enhances activation and nuclear translocation of STAT3 and STAT3-dependent transcription of target genes. Importantly, we show that STAT3 is critical to estradiol neuroprotection, as evidenced by the ability of STAT3 inhibitor peptide and STAT3 shRNA delivered directly into the CA1 of living animals to abolish neuroprotection. In addition, we identify survivin, a member of the inhibitor-of-apoptosis family of proteins and known gene target of STAT3, as essential to estradiol neuroprotection, as evidenced by the ability of shRNA to survivin to reverse neuroprotection. These findings indicate that ischemia and estradiol act synergistically to promote activation of STAT3 and STAT3-dependent transcription of survivin in insulted CA1 neurons and identify STAT3 and survivin as potentially important therapeutic targets in an in vivo model of global ischemia.
  • Toru Yamashita, Kentaro Deguchi, Yoshihide Sehara, Violeta Lukic-Panin, Hanzhe Zhang, Tatsushi Kamiya, Koji Abe
    Neurochemical research 34 4 707 - 10 2009年04月 [査読有り][通常論文]
     
    Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.
  • Yoshihide Sehara
    Internal medicine (Tokyo, Japan) 48 8 615 - 8 2009年 [査読有り][通常論文]
     
    Autonomic dysfunction in patients with Parkinson's disease has been recognized since the original description by James Parkinson in 1817. In the present case, an 80-year-old woman who had been diagnosed with Parkinson's disease 3 years earlier (Hoehn and Yahr stage III) was admitted with a few days history of lethargy and bradykinesia. She lived in a heated house and used an electric blanket at night. On examination, her core temperature was 29.7 degrees C. Her initial ECG showed sinus bradycardia, QT prolongation, and Osborn waves, which disappeared after rewarming. Successful rewarming was achieved with an external rewarming blanket over 12 hours. Follow-up ECG showed resolution of the Osborn waves. In Parkinson's disease, rapidly progressive hypothermia can occur in a well-heated house. Determining a rewarming strategy is a complex but not insurmountable task. In the elderly, the use of careful active external rewarming and a low stress strategy may be recommended.
  • Kentaro Deguchi, Takeshi Hayashi, Shoko Nagotani, Yoshihide Sehara, Hanzhe Zhang, Atsushi Tsuchiya, Yasuyuki Ohta, Koji Tomiyama, Nobutoshi Morimoto, Masahiro Miyazaki, Nam-Ho Huh, Atsunori Nakao, Tatsushi Kamiya, Koji Abe
    Brain research 1188 1 - 8 2008年01月 [査読有り][通常論文]
     
    Biliverdin (BV), one of the byproducts of heme catalysis through heme oxygenase (HO) system, is a scavenger of reactive oxygen species (ROS). We hypothesized that BV treatment could protect rat brain cells from oxidative injuries via its anti-oxidant efficacies. Cerebral infarction was induced by transient middle cerebral artery occlusion (tMCAO) for 90 min, followed by reperfusion. BV or vehicle was administered intraperitoneally immediately after reperfusion. The size of the cerebral infarction 2 days after tMCAO was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) stain. Superoxide generation 4 h after tMCAO was determined by detection of oxidized hydroethidine. In addition, the oxidative impairment of neurons were immunohistochemically assessed by stain for lipid peroxidation with 4-hydroxy-2-nonenal (4-HNE) and damaged DNA with 8-hydroxy-2'-deoxyguanosine (8-OHdG). BV treatment significantly reduced infarct volume of the cerebral cortices associated with less superoxide production and decreased oxidative injuries of brain cells. The present study demonstrated that treatment with BV ameliorated the oxidative injuries on neurons and decreased brain infarct size in rat tMCAO model.
  • 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 [査読有り][通常論文]
     
    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.
  • 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 [査読有り][通常論文]
     
    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.
  • Masanori Fujii, Katsuyuki Kiura, Nagio Takigawa, Tetsuya Yumoto, Yoshihide Sehara, Masahiro Tabata, Mitsune Tanimoto
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 9 877 - 8 2007年09月 [査読有り][通常論文]
     
    Garcin syndrome consists of unilateral palsies of almost all cranial nerves without either sensory or motor long-tract disturbances and without intracranial hypertension, and it is caused by a malignant osteoclastic lesion at the skull base. A 60-year-old woman presented with dizziness and left facial palsy. Progressive left cranial nerve palsies developed over 2 months until gadolinium-enhanced magnetic resonance imaging of the brain revealed an intracranial extension of a tumor from the left skull base. A systemic survey revealed adenocarcinoma of the lung, which had metastasized along the skull base. We experienced a rare case of Garcin syndrome due to skull base metastases from lung cancer.
  • 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08月 [査読有り][通常論文]
     
    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.
  • 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07月 [査読有り][通常論文]
     
    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.
  • T. Hayashi, X. Q. Wang, H. Z. Zhang, K. Deguchi, S. Nagotani, Y. Sehara, A. Tsuchiya, M. Nagai, M. Shoji, K. Abe
    Neurological Research 29 5 463 - 468 2007年07月 [査読有り][通常論文]
     
    Objectives: Platelet derived-endothelial cell growth factor (PD-ECCF) is a highly potent angiogenic factor. Although angiogenesis plays an active role in pathophysiology of stroke, the expression pattern of this molecule in ischemic brain has not been investigated. In the present study, therefore, we investigated the change of PD-ECCF expression in the brain after ischemia. Methods: Using male Wistar rats, the right middle cerebral artery was occluded by a nylon thread for 90 minutes. The animals were decapitated 3 hours, 1, 4 and 10 days after the reperfusion, and frozen sections were prepared. We then performed immunohistochemistry for PD-ECGF and identified the cell phenotype which strongly expressed it by fluorescent double staining. Results: In the sham-operated brain, only small numbers of cells slightly expressed PD-ECGF. The number of positively stained cells increased at the peri-ischemic area from hour 3 of reperfusion. Not only small-sized cells but also large-sized cells became stained. The number of stained cells further increased, and peaked at day 4 for large-sized cells and at day 10 as to small-sized cells. Fluorescent double staining revealed that both large-sized and small-sized cells were neurons, indicating that neurons are the main source of PD-ECGF production in the ischemic brain. Discussion: PD-ECGF has a strong angiogenic property without vascular permeability increasing effect. This molecule may have a therapeutic potential for ischemic stroke treatment. © 2007 W. S. Maney & Son Ltd.
  • 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06月 [査読有り][通常論文]
     
    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.
  • 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05月 [査読有り][通常論文]
     
    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.
  • Takeshi Hayashi, Hiroshi Kamada, Guang Jin, Kentaro Deguchi, Shoko Nagotani, Yoshihide Sehara, Hanzhe Zhang, Isao Nagano, Mikio Shoji, Koji Abe
    Neurological research 28 8 822 - 5 2006年12月 [査読有り][通常論文]
     
    OBJECTIVES: Reduction of brain plasticity underlies the poor outcome of aged stroke patients. The molecular mechanism of plasticity reduction by aging is uncertain, but disturbed lipid metabolism may be implicated. METHODS: We investigated the expression of low density lipoprotein receptors (LDL-R) and apolipoprotein E (ApoE), both of which play active roles in lipid metabolism in young adult and old rat brains after ischemia. RESULTS: LDL-R, trivially expressed in the sham-operated brain neurons, was increased from day 1 and became prominent at days 7 and 21 at the peri-ischemic cortex. The magnitude was smaller in the old than in the young adult rats. ApoE was increased in the astrocytes and neurons of the peri-ischemic cortex at day 1, which became further pronounced in the neurons but not in the astrocytes at days 7 and 21. ApoE expression was again less prominent in the old animals at days 7 and 21. DISCUSSION: As ApoE-containing lipoprotein is recruited via LDL-R, the present results suggest that old brains had less capability to induce LDL-R, which resulted in impaired recruitment of lipoprotein after the ischemic injury. Impaired lipid recruitment causes disturbance of synaptogenesis and thus brain plasticity reduction. This molecular mechanism may result in poor functional recovery of aged stroke patients.
  • Kentaro Deguchi, Kanji Tsuru, Takeshi Hayashi, Mikiro Takaishi, Mitsuyuki Nagahara, Shoko Nagotani, Yoshihide Sehara, Guang Jin, HanZhe Zhang, Satoshi Hayakawa, Mikio Shoji, Masahiro Miyazaki, Akiyoshi Osaka, Nam-Ho Huh, Koji Abe
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 26 10 1263 - 73 2006年10月 [査読有り][通常論文]
     
    For brain tissue regeneration, any scaffold for migrated or transplanted stem cells with supportive angiogenesis is important once necrotic brain tissue has formed a cavity after injury such as cerebral ischemia. In this study, a new porous gelatin-siloxane hybrid derived from the integration of gelatin and 3-(glycidoxypropyl) trimethoxysilane was implanted as a three-dimensional scaffold into a defect of the cerebral cortex. The porous hybrid implanted into the lesion remained at the same site for 60 days, kept integrity of the brain shape, and attached well to the surrounding brain tissues. Marginal cavities of the scaffolds were occupied by newly formed tissue in the brain, where newly produced vascular endothelial, astroglial, and microglial cells were found with bromodeoxyuridine double positivity, and the numbers of those cells were dose-dependently increased with the addition of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Extension of dendrites was also found from the surrounding cerebral cortex to the newly formed tissue, especially with the addition of bFGF and EGF. The present study showed that a new porous gelatin-siloxane hybrid had biocompatibility after implantation into a lesion of the central nervous system, and thus provided a potential scaffold for cell migration, angiogenesis and dendrite elongation with dose-dependent effects of additive bFGF and EGF.
  • Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Shoko Nagotani, Hanzhe Zhang, Mikio Shoji, Koji Abe
    Brain research 1093 1 190 - 7 2006年06月 [査読有り][通常論文]
     
    Nitric oxide (NO) can be neuroprotective or neurotoxic during cerebral ischemia, depending on the NO synthase (NOS) isoform involved. In addition to neurotoxic effect in ischemic brain, inducible NOS (iNOS) also adversely affect ischemic outcome by blocking neurogenesis. In the present study, therefore, we studied the chronological and spatial change of the distribution of iNOS and cell proliferation in subventricular zone (SVZ) after transient focal cerebral ischemia. After 90 min of transient middle cerebral artery occlusion (tMCAO), iNOS-positive cells decreased in the ischemic core at 1 to 21 days, and increased in the ipsilateral periischemic area at 1 and 3 days. 5-Bromodeoxyuridine (BrdU)-positive cells appeared in the ischemic core at 3 to 21 days, appeared in the periischemic area at 3 and 7 days, and increased in the ipsilateral SVZ at 7 days. ED-1-positive cells appeared in the ischemic core at 3 to 21 days, and some of them were double positive with BrdU or iNOS, but the majority were BrdU-negative. The present study suggests that astrocytes are born within the periischemic area at early stage after tMCAO and migrate from SVZ into periischemic area at later stage, and that time-dependent and spatial changes of iNOS expression may be involved in the proliferation and differentiation of adult neurogenesis after focal cerebral ischemia.
  • Takeshi Hayashi, Kentaro Deguchi, Shoko Nagotani, Hanzhe Zhang, Yoshihide Sehara, Atsushi Tsuchiya, Koji Abe
    Current neurovascular research 3 2 119 - 29 2006年05月 [査読有り][通常論文]
     
    Angiogenesis occurs in a wide range of conditions. As ischemic tissue usually depends on collateral blood flow from newly produced vessels, acceleration of angiogenesis should be of therapeutic value to ischemic disorders. Indeed, therapeutic angiogenesis reduced tissue injury in myocardial or limb ischemia. In ischemic stroke, on the other hand, angiogenic factors often increase vascular permeability and thus may deteriorate tissue damage. In order to apply safely the therapeutic angiogenesis for ischemic stroke treatment, elucidating precise mechanism of brain angiogenesis is mandatory. In the present article, we review previous reports which investigated molecular mechanisms of angiogenesis. Endothelial cell mitogens, enzymes that degrade surrounding extracellular matrix, and molecules implicated in endothelial cells migration are induced rapidly in the ischemic brain. Their possible neuroprotective or injury exacerbating effects are discussed. Because therapeutic potential of angiogenic factors application had gained much attention, we here extensively reviewed relevant previous reports. In the future however, there is a need to consider angiogenesis in relation with regenerative medicine, as angiogenic factors sometimes possess neuron producing property.
  • Takeshi Hayashi, Masanori Iwai, Tomoaki Ikeda, Guang Jin, Kentaro Deguchi, Shoko Nagotani, Hanzhe Zhang, Yoshihide Sehara, Isao Nagano, Mikio Shoji, Tsuyomu Ikenoue, Koji Abe
    Brain research 1038 1 41 - 9 2005年03月 [査読有り][通常論文]
     
    Ischemia/hypoxia (I/H) causes severe perinatal brain disorders such as cerebral palsy. The neonatal brain possesses much plasticity, and to enhance new cell production would be an innovative means of therapy for such disorders. In order to elucidate the dynamic changes of neural progenitor cells in the neonatal brain after ischemia, we investigated new cells production in the subventricular zone and subsequent migration of these cells to the injured area. Newly produced cells were confirmed by incorporation of bromodeoxyuridine (BrdU), and attempt for differentiation was investigated by immunohistochemistry for molecular markers of each cellular lineage. In the sham-control brain, there were many BrdU-labeled cells which gradually decreased as the animal becomes older. Many of these cells were oligodendroglial progenitor or microglial cells. Although there were only few neuronal cells labeled for BrdU in the sham-control, they dramatically increased after I/H. They were located at just beneath the subventricular zone where the progenitor cells reside and to the injured area, indicating that newly produced cells migrated to the infarct region and differentiated into neuronal precursor cells in order to compensate the lost neural cells. We found that BrdU-labeled astroglial, oligodendroglial progenitor, and microglial cells were also increased after I/H, suggesting that they also play active roles in recovery. Progenitor cells may have potential for treating perinatal brain disorders.
  • Takeshi Hayashi, Keiko Hamakawa, Shoko Nagotani, Guang Jin, Feng Li, Kentaro Deguchi, Yoshihide Sehara, Hanzhe Zhang, Isao Nagano, Mikio Shoji, Koji Abe
    Brain research 1037 1-2 52 - 8 2005年03月 [査読有り][通常論文]
     
    Statins possess neuroprotective effect against ischemic damage, but how they protect neurons is not exactly made clear. We speculated that anti-oxidative property of statins is implicated, and investigated statins' influences on the oxidative neuronal damage in the brain after ischemia. After 14 days of atorvastatin, pitavastatin, simvastatin, or vehicle administration, 90 min of middle cerebral artery occlusion was imposed on Wistar rats. The production of 4-hydroxynonenal (HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), both of which are oxidative stress markers, as well as infarction formation were investigated at 1 day after the reperfusion. In the vehicle group, massive infarction was confirmed and HNE and 8-OHdG are robustly produced. In the statins-treated group, the infarction was smaller and the HNE and 8-OHdG production was less prominent than the vehicle group. Among the statins investigated, simvastatin was most effective for reducing oxidative stress and infarction volume, which may be brought by its highly lipophilic property. Reduction of oxidative stress by statins may be one main reason in ameliorating ischemic brain damage in rats.

受賞

  • 2017年 日本遺伝子細胞治療学会 学会賞
     
    受賞者: 瀬原 吉英

共同研究・競争的資金等の研究課題

  • 新しい臓器指向性を持ったアデノ随伴ウイルスベクターの研究開発
    AMED:革新的医療技術創出拠点プロジェクト(東大拠点)シーズA
    研究期間 : 2021年04月 -2022年03月
  • 脳虚血後における海馬ニューロン新生の調節機構とてんかん原性との関連
    日本脳神経財団:学術助成
    研究期間 : 2019年04月 -2020年03月 
    代表者 : 瀬原 吉英
  • 一過性全脳虚血後における異常シナプス形成の発生機序
    大樹生命厚生財団:医学研究助成
    研究期間 : 2019年04月 -2020年03月 
    代表者 : 瀬原 吉英
  • 一過性全脳虚血後に促進される海馬ニューロン新生の調節機構とその意義
    日本学術振興会:基盤研究C
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 瀬原 吉英
  • ミトコンドリア異常症の遺伝子治療
    ノバルティスファーマ研究助成:
    研究期間 : 2018年04月 -2019年03月 
    代表者 : 瀬原 吉英
  • ミトコンドリア異常症の遺伝子治療を目指した基礎的検討
    金原一郎記念医学医療振興財団:第32回基礎医学医療研究助成金
    研究期間 : 2017年04月 -2018年03月 
    代表者 : 瀬原 吉英
  • アデノ随伴ウイルスベクターを用いた多系統萎縮症モデルマウスの作出
    ノバルティスファーマ研究助成
    研究期間 : 2017年04月 -2018年03月 
    代表者 : 瀬原 吉英
  • 成体虚血脳における内因性幹細胞の制御を用いた新規脳梗塞治療の開発
    成人血管病研究振興財団:学術研究支援助成
    研究期間 : 2015年04月 -2017年03月 
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