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Article ; Online: Role of the Gut Microbiota in Stroke Pathogenesis and Potential Therapeutic Implications.

Yamashiro, Kazuo / Kurita, Naohide / Urabe, Takao / Hattori, Nobutaka

2021 Volume 77 Suppl 2, Page(s) 36–44

Abstract: Background: Major advances have been made in stroke treatment and prevention in the past decades. However, the burden of stroke remains high. Identification of novel targets and establishment of effective interventions to improve stroke outcomes are, ... ...

Abstract	Background: Major advances have been made in stroke treatment and prevention in the past decades. However, the burden of stroke remains high. Identification of novel targets and establishment of effective interventions to improve stroke outcomes are, therefore, needed. Recent research highlights the contribution of the gut microbiota to stroke pathogenesis. Summary: Compositional and functional alterations of the gut microbiota, termed dysbiosis, are linked to stroke risk factors, such as obesity, metabolic diseases, and atherosclerosis. In acute cerebral ischemia, the gut microbiota plays a key role in bidirectional interactions between the gut and brain, referred to as the microbiota-gut-brain axis. Gut dysbiosis prior to ischemic stroke affects outcomes. Additionally, the brain affects the gut microbiota during acute ischemic brain injury, which in turn impacts outcomes. Interactions between the gut microbiota and stroke pathogenesis are mediated by several factors including bacterial components (e.g., lipopolysaccharide), gut microbiota-related metabolites (e.g., short-chain fatty acids and trimethylamine N-oxide), and the immune and nervous systems. Clinical studies have reported that patients with acute ischemic stroke exhibit gut dysbiosis, which is associated with host metabolism and inflammation, as well as functional outcomes. Modulation of the gut microbiota or its metabolites improves conditions related to stroke pathogenesis, including inflammation, cardiometabolic disease, atherosclerosis, and thrombosis. Key Messages: Accumulating evidence indicates that the gut microbiota plays a possible role in stroke pathogenesis. Modulation of the gut microbiota may provide a novel therapeutic strategy for the treatment and prevention of stroke.
MeSH term(s)	Bacteria ; Dysbiosis ; Gastrointestinal Microbiome ; Humans ; Ischemic Stroke ; Stroke/etiology ; Stroke/therapy
Language	English
Publishing date	2021-06-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	392341-1
ISSN	1421-9697 ; 0250-6807 ; 1018-9688
ISSN (online)	1421-9697
ISSN	0250-6807 ; 1018-9688
DOI	10.1159/000516398
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Article ; Online: Novel characteristics of the temporal transition to maximum tongue pressure in Parkinson's disease: A pilot study.

Hayasaka, Sachi / Hatori, Kozo / Nojiri, Shuko / Hatano, Taku / Urabe, Takao / Hayashi, Akito / Hattori, Nobutaka / Fujiwara, Toshiyuki

Clinical parkinsonism & related disorders

2024 Volume 10, Page(s) 100244

Abstract: Introduction: The reason why maximum tongue pressure (MTP) decreases in patients with Parkinson's disease (PD) remains unclear. Repeated measurements of isometric force and MTP may be useful for analyzing muscle wasting and force generation. The purpose ...

Abstract	Introduction: The reason why maximum tongue pressure (MTP) decreases in patients with Parkinson's disease (PD) remains unclear. Repeated measurements of isometric force and MTP may be useful for analyzing muscle wasting and force generation. The purpose of this pilot study was to evaluate the clinical characteristics and temporal transition of MTP in PD and normal control (NC) groups. Methods: There were 18 participants in this study: 10 with PD and 8 NCs. The MTP was measured 20 times at regular intervals. The area under the curve of MTP temporal transitions, time to reach MTP, and total transition time of the tongue pressure (time to return to baseline) were compared between the groups. Results: MTP decreased from baseline in PD subjects. Unlike NCs, PD subjects showed diverse and inconsistent temporal transitions. The decrease in MTP and delays in time to reach MTP and time to return to baseline were significantly greater in PD subjects (p < 0.05), while there was no group difference in area under the curve values. According to repeated-measures ANOVA, MTP was not different over time between PD subjects and NCs. Conclusion: In this study, muscle fatigue did not affect the decrease in MTP seen in PD subjects, or the diversity and inconsistency of the temporal transition in MTP in that group. These findings indicate that the motor control needed for the repeated, identical movements associated with MTP generation may be impaired in PD patients.
Language	English
Publishing date	2024-02-25
Publishing country	England
Document type	Journal Article
ISSN	2590-1125
ISSN (online)	2590-1125
DOI	10.1016/j.prdoa.2024.100244
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Article ; Online: [Molecular mechanism and new protective strategy for ischemic white matter damages].

Urabe, Takao

Rinsho shinkeigaku = Clinical neurology

2012 Volume 52, Issue 11, Page(s) 908–910

Abstract: Brain white matter lesions (WMLs), which are often observed in patients with ischemic cerebrovascular diseases, contribute to cognitive decline. We analyzed the pathologic and regenerative processes in brain white matter lesions of patients diagnosed ... ...

Abstract	Brain white matter lesions (WMLs), which are often observed in patients with ischemic cerebrovascular diseases, contribute to cognitive decline. We analyzed the pathologic and regenerative processes in brain white matter lesions of patients diagnosed with vascular dementia. There was a significant increase in the number of oligodendrocyte progenitor cells (OPCs) in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. WMLs can be induced experimentally by bilateral common carotid artery ligation (BCCAL) of rats to cause chronic cerebral ischemia. After chronic cerebral hypoperfusion injury, oxygen free radicals and activated microglia acting as inflammatory elements contribute to chronic cerebral hypoperfusion-induced WMLs. The cell death of oligodendrocytes (OLGs) contributes directly to WMLs. The activation for intracellular signaling pathway of cAMP responsive element binding protein (CREB) phosphorylation in the white matter was suppressed after BCCAL. Type III phosphodiesterase inhibitor (PDE3-I) has potential therapeutic and brain-protective effects based on multitarget mechanism through cell signaling pathway of CREB phosphorylation. The OPCs subsequently underwent cell death and the number of OLGs decreased. In the rat model, PDE3-I prevented cell death, markedly increased the mature OLGs, and promoted restoration of white matter and recovery of cognitive decline.
MeSH term(s)	Animals ; Brain Ischemia/pathology ; Brain Ischemia/physiopathology ; Humans ; Oligodendroglia/physiology ; Rats
Language	Japanese
Publishing date	2012-11-08
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	604200-4
ISSN	1882-0654 ; 0009-918X
ISSN (online)	1882-0654
ISSN	0009-918X
DOI	10.5692/clinicalneurol.52.908
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Article ; Online: [New clinical concept and therapeutic strategy for TIA].

Urabe, Takao

Rinsho shinkeigaku = Clinical neurology

2011 Volume 50, Issue 11, Page(s) 910–912

Abstract: In the past, transient ischemic attack (TIA) was defined as any sudden, focal cerebral ischemic event with neurological deficit lasting <24 hours. However, in several series of patients with TIA who underwent diffusion-weighted magnetic resonance imaging, ...

Abstract	In the past, transient ischemic attack (TIA) was defined as any sudden, focal cerebral ischemic event with neurological deficit lasting <24 hours. However, in several series of patients with TIA who underwent diffusion-weighted magnetic resonance imaging, many ischemic episodes with symptoms lasting <24 hours are associated with new infarctions. Therefore, TIA working group proposed a new tissue-based, rather than a time-based, definition of TIA: "a brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms typically lasting less than 1 hour, and without evidence of infarction". The latest definition of TIA is "a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction". Recent studies have shown that stroke risk after TIA is high in the first few days. Two prognostic scores for short-term risk of stroke after TIA have been proposed: the California score and the ABCD score. The ABCD(2) score has the same components as ABCD, but with diabetes mellitus added. This score was a more accurate predictor than either of the previous scores. Antiplatelet therapy should be prescribed immediately for the secondary prevention of stroke in patients with a noncardioembolic TIA.
MeSH term(s)	Aged ; Aspirin/administration & dosage ; Cilostazol ; Clopidogrel ; Diffusion Magnetic Resonance Imaging ; Humans ; Ischemic Attack, Transient/complications ; Ischemic Attack, Transient/diagnosis ; Ischemic Attack, Transient/prevention & control ; Ischemic Attack, Transient/therapy ; Middle Aged ; Platelet Aggregation Inhibitors/administration & dosage ; Practice Guidelines as Topic ; Risk ; Secondary Prevention ; Stroke/etiology ; Stroke/prevention & control ; Tetrazoles/administration & dosage ; Ticlopidine/administration & dosage ; Ticlopidine/analogs & derivatives ; Time Factors
Chemical Substances	Platelet Aggregation Inhibitors ; Tetrazoles ; Clopidogrel (A74586SNO7) ; Cilostazol (N7Z035406B) ; Ticlopidine (OM90ZUW7M1) ; Aspirin (R16CO5Y76E)
Language	Japanese
Publishing date	2011-09-16
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	604200-4
ISSN	1882-0654 ; 0009-918X
ISSN (online)	1882-0654
ISSN	0009-918X
DOI	10.5692/clinicalneurol.50.910
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Article: [Stroke].

Urabe, Takao

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine

2011 Volume 100, Issue 5, Page(s) 1425–1433

MeSH term(s)	Humans ; Stroke/diagnosis ; Stroke/therapy
Language	Japanese
Publishing date	2011-04-19
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	952816-7
ISSN	1883-2083 ; 0021-5384
ISSN (online)	1883-2083
ISSN	0021-5384
DOI	10.2169/naika.100.1425
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Article ; Online: Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.

Shimura, Hideki / Saiko, Aiba / Hayashi, Akito / Hattori, Nobutaka / Urabe, Takao

BMC neurology

2021 Volume 21, Issue 1, Page(s) 61

Abstract: Background: Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease- ... ...

Abstract	Background: Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders. Methods: This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale. Results: After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration. Conclusion: Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function. Trial registration: UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; Cognition/drug effects ; Female ; Gait/drug effects ; Humans ; Male ; Prospective Studies ; Rivastigmine/therapeutic use ; Task Performance and Analysis
Chemical Substances	Cholinesterase Inhibitors ; Rivastigmine (PKI06M3IW0)
Language	English
Publishing date	2021-02-10
Publishing country	England
Document type	Clinical Trial ; Journal Article
ISSN	1471-2377
ISSN (online)	1471-2377
DOI	10.1186/s12883-021-02098-8
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Article ; Online: Correction to: Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery.

Kijima, Chikage / Inaba, Toshiki / Hira, Kenichiro / Miyamoto, Nobukazu / Yamashiro, Kazuo / Urabe, Takao / Hattori, Nobutaka / Ueno, Yuji

Molecular neurobiology

2023 Volume 61, Issue 2, Page(s) 1022

Language	English
Publishing date	2023-09-20
Publishing country	United States
Document type	Published Erratum
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-023-03657-5
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Article ; Online: Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery.

Kijima, Chikage / Inaba, Toshiki / Hira, Kenichiro / Miyamoto, Nobukazu / Yamashiro, Kazuo / Urabe, Takao / Hattori, Nobutaka / Ueno, Yuji

Molecular neurobiology

2023 Volume 61, Issue 2, Page(s) 1002–1021

Abstract: There are no effective treatments for post-stroke glial scar formation, which inhibits axonal outgrowth and functional recovery after stroke. We investigated whether astrocytic extracellular vesicles (AEVs) regulated by microglia modulate glial scars and ...

Abstract	There are no effective treatments for post-stroke glial scar formation, which inhibits axonal outgrowth and functional recovery after stroke. We investigated whether astrocytic extracellular vesicles (AEVs) regulated by microglia modulate glial scars and improve stroke recovery. We found that peri-infarct glial scars comprised reactive astrocytes with proliferating C3d and decreased S100A10 expression in chronic stroke. In cultured astrocytes, microglia-conditioned media and treatment with P2Y
MeSH term(s)	Rats ; Animals ; Microglia/metabolism ; NF-kappa B/metabolism ; Astrocytes/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Gliosis/pathology ; Stroke/pathology ; Extracellular Vesicles/metabolism
Chemical Substances	NF-kappa B ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-023-03629-9
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Article ; Online: Free water in gray matter linked to gut microbiota changes with decreased butyrate producers in Alzheimer's disease and mild cognitive impairment.

Yamashiro, Kazuo / Takabayashi, Kaito / Kamagata, Koji / Nishimoto, Yuichiro / Togashi, Yuka / Yamauchi, Yohsuke / Ogaki, Kotaro / Li, Yuanzhe / Hatano, Taku / Motoi, Yumiko / Suzuki, Michimasa / Miyakawa, Koichi / Ishikawa, Dai / Aoki, Shigeki / Urabe, Takao / Hattori, Nobutaka

Neurobiology of disease

2024 Volume 193, Page(s) 106464

Abstract: Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and ... ...

Abstract	Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes, Lachnospiraceae UCG-004, and [Ruminococcus] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis.
MeSH term(s)	Humans ; Gray Matter/pathology ; Alzheimer Disease/pathology ; Gastrointestinal Microbiome ; Butyrates ; Neuroinflammatory Diseases ; RNA, Ribosomal, 16S ; Cognitive Dysfunction/pathology ; Magnetic Resonance Imaging
Chemical Substances	Butyrates ; RNA, Ribosomal, 16S
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2024.106464
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Article ; Online: Randomised placebo-controlled multicentre trial to evaluate the efficacy and safety of JTR-161, allogeneic human dental pulp stem cells, in patients with Acute Ischaemic stRoke (J-REPAIR).

Suda, Satoshi / Nito, Chikako / Ihara, Masafumi / Iguchi, Yasuyuki / Urabe, Takao / Matsumaru, Yuji / Sakai, Nobuyuki / Kimura, Kazumi

BMJ open

2022 Volume 12, Issue 5, Page(s) e054269

Abstract: Introduction: JTR-161 is a novel allogeneic human cell product consisting of dental pulp stem cells isolated from the extracted teeth of healthy adults. It is currently under development as a cell-based therapy for ischaemic stroke. The aim of this ... ...

Abstract	Introduction: JTR-161 is a novel allogeneic human cell product consisting of dental pulp stem cells isolated from the extracted teeth of healthy adults. It is currently under development as a cell-based therapy for ischaemic stroke. The aim of this study is to evaluate the safety and efficacy of JTR-161 in patients with acute ischaemic stroke when given as a single intravenous administration within 48 hours of symptom onset. Methods and analysis: This is a first-in-human, randomised, double-blind, placebo-controlled, multicentre, phase 1/2 clinical trial to be conducted in Japan (from January 2019 to July 2021). Patients with a clinical diagnosis of anterior circulation ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS）score of 5-20 at baseline were enrolled. Patients previously treated with recombinant tissue-type plasminogen activator and/or endovascular thrombectomy were allowed to be enrolled. The study consists of three cohorts: cohorts 1 and 2 (each eight patients) and cohort 3 (60 patients). Subjects were randomly assigned to receive either JTR-161 or placebo in a 3:1 ratio in cohorts 1 and 2, and in a 1:1 ratio in cohort 3. The number of cells administered was increased sequentially from 1×10 Ethics and dissemination: The protocol and informed consent form were approved by the institutional review board at each participating study site. A manuscript with the results of the primary study will be published in a peer-reviewed journal. Trial registration number: NCT04608838; JapicCTI-194570 and Clinical Trials. gov.
MeSH term(s)	Adult ; Brain Ischemia/drug therapy ; Dental Pulp ; Double-Blind Method ; Hematopoietic Stem Cell Transplantation ; Humans ; Ischemic Stroke ; Stroke/drug therapy ; Treatment Outcome
Language	English
Publishing date	2022-05-24
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2021-054269
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