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Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

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Neural Regeneration Research 2019年第7期14卷 1138-1143页

作者： Hideki Kanamaru hidenori suzuki Department of Neurosurgery Mie University Graduate School of Medicine

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities.Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure,followed by global cerebral ischemia.Post-subarachnoid hemorrhage ischemia,tissue injuries as well as extravasated blood components and the breakdown products activate microglia,astrocytes and Toll-like receptor 4,and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades.Once blood-brain barrier is disrupted,brain tissues are directly exposed to harmful blood contents and immune cells,which aggravate brain injuries furthermore.Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins.Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage,but the exact mechanisms remain unclear.Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage.This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

关键词： blood-brain barrier early brain injury endothelial cell subarachnoid hemorrhage tight junction inflammation matricellular protein Toll-like receptor 4 TLR4

Lessons from tenascin-C knockout mice and potential clinical application to subarachnoid hemorrhage

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Neural Regeneration Research 2019年第2期14卷 262-264页

作者： Masato Shiba hidenori suzuki Department of Neurosurgery Mie University Graduate School of Medicine

Subarachnoid hemorrhage by a ruptured cerebral aneurysmremains the most devastating cerebrovascular disorderswith high morbidity and mortality (suzuki et al.,2017), which are mainly caused by early brain injury anddelayed cerebral ischemia. Despite many experimentaland clinical research efforts, the mechanisms of earlybrain injury as well as delayed cerebral ischemia remainunclarified. However, recent works have suggested thattenascin-C, which is a special type of secreted extracellularmatrix proteins, is promising as a novel therapeutictarget against post-subarachnoid hemorrhage early braininjury and delayed cerebral ischemia.

关键词： cerebral clinical ischemia hemorrhage

Implications of periostin in the development of subarachnoid hemorrhage-induced brain injuries

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Neural Regeneration Research 2017年第12期12卷 1982-1984页

作者： Hirofumi Nishikawa hidenori suzuki Department of Neurosurgery Mie University Graduate School of Medicine Tsu Japan

Target of research in subarachnoid hemorrhage（SAH）：The outcome of aneurysmal SAH remains poor despite advances in the diagnosis and treatment.Although many factors related to patients,aneurysms,and institutions,as ... 详细信息

关键词： Implications of periostin the development subarachnoid hemorrhage-induced brain injuries

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

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Neural Regeneration Research 2017年第2期12卷 193-196页

作者： Takeshi Okada hidenori suzuki Department of Neurosurgery Mie University Graduate School of Medicine Tsu Japan

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

关键词： cerebral aneurysm cerebral vasospasm early brain injury delayed brain injury delayed cerebral ischemia inflammation subarachnoid hemorrhage Toll-like receptor 4

Periostin in cerebrovascular disease

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Neural Regeneration Research 2020年第1期15卷 63-64页

作者： Fumihiro Kawakita hidenori suzuki Department of Neurosurgery Mie University Graduate School of Medicine

Cerebrovascular diseases,which include ischemic and hemorrhagic strokes,remain serious conditions with high mortality and disability worldwide(He et al.,2018).Ischemic stroke accounts for around 80%of all strokes(He et al.,2018).Hemorrhagic stroke consisting of intracerebral hemorrhage and subarachnoid hemorrhage(SAH)occurs less frequently but may cause poorer outcomes than ischemic stroke(Ji et al.,2017;Luo et al.,2018).It is also well known that aneurysmal SAH may have delayed cerebral ischemia(DCI):thus aneurysmal SAH has both characteristics of hemorrhagic and ischemic strokes(Kanamaru et al.,2019).In spite of enormous efforts to improve outcomes,no conclusive treatment exists thus far,once stroke is completed.

关键词： al. hemorrhagic mortality

Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage

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Neural Regeneration Research 2018年第7期13卷 1175-1178页

作者： hidenori suzuki Hirofumi Nishikawa Fumihiro Kawakita Department of Neurosurgery Mie University Graduate School of Medicine

Aneurysmal subarachnoid hemorrhage remains devastating,and the most important determinant of poor outcome is early brain injury（EBI）.In clinical settings,as a surrogate marker of EBI,loss of consciousness at ictus,poor initial clinical grades,and some radiographic findings are used,but these markers are somewhat subjective.Thus,it is imperative to find biomarkers of EBI that have beneficial prognostic and therapeutic implications.In our opinion,an ideal biomarker is a molecule that is implicated in the pathogenesis of both EBI and subsequently developing delayed cerebral ischemia（DCI）,being a therapeutic target,and can be measured easily in the peripheral blood in an acute stage.A good candidate of such a biomarker is a matricellular protein,which is a secreted,inducible and multifunctional extracellular matrix protein.There are many kinds of matricellular proteins reported,but only tenascin-C,osteopontin,galectin-3 and periostin are reported relevant to EBI and DCI.Reliable biomarkers of EBI may stratify aneurysmal subarachnoid hemorrhage patients into categories of risk to develop DCI,and allow objective monitoring of the response to treatment for EBI and earlier diagnosis of DCI.This review emphasizes that further investigation of matricellular proteins as an avenue for biomarker discovery is warranted.

关键词： biomarker early brain injury galectin-3 matricellular protein osteopontin periostin subarachnoid hemorrhage tenascin-C

Tenascin-C in aneurysmal subarachnoid hemorrhage: deleterious or protective?

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Neural Regeneration Research 2016年第2期11卷 230-231页

作者： hidenori suzuki Fumihiro Kawakita Department of Neurosurgery Mie University Graduate School of Medicine

Subarachnoid hemorrhage（SAH）caused by the rupture of a cerebral aneurysm is a well-known devastating cerebrovascular disease.Post-SAH brain is vulnerable,associated with early brain injury（EBI;suzuki,2015）.

关键词： SAH Tenascin-C in aneurysmal subarachnoid hemorrhage

Compression analysis of the gray and white matter of the spinal cord

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Neural Regeneration Research 2020年第7期15卷 1344-1349页

作者： Norihiro Nishida Fei Jiang Junji Ohgi Akihiro Tanaka Yasuaki Imajo hidenori suzuki Masahiro Funaba Takashi Sakai Itsuo Sakuramoto Xian Chen Department of Orthopedic Surgery Yamaguchi University Graduate School of MedicineYamaguchiJapan Faculty of Engineering Yamaguchi UniversityYamaguchiJapan Department of Mechanical and Electrical Engineering National Institute of Technology Tokuyama CollegeYamaguchiJapan

The spinal cord is composed of gray matter and white matter.It is well known that the properties of these two tissues differ considerably.Spinal diseases often present with symptoms that are caused by spinal cord compression.Understanding the mechanical properties of gray and white matter would allow us to gain a deep understanding of the injuries caused to the spinal cord and provide information on the pathological changes to these distinct tissues in several disorders.Previous studies have reported on the physical properties of gray and white matter,however,these were focused on longitudinal tension tests.Little is known about the differences between gray and white matter in terms of their response to compression.We therefore performed mechanical compression test of the gray and white matter of spinal cords harvested from cows and analyzed the differences between them in response to compression.We conducted compression testing of gray matter and white matter to detect possible differences in the collapse rate.We found that increased compression(especially more than 50%compression)resulted in more severe injuries to both the gray and white matter.The present results on the mechanical differences between gray and white matter in response to compression will be useful when interpreting findings from medical imaging in patients with spinal conditions.

关键词： biomechanical study cervical spondylotic myelopathy collapse rate compression gray matter mechanical properties spinal cord injury white matter

Tensile mechanical analysis of anisotropy and velocity dependence of the spinal cord white matter:a biomechanical study

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Neural Regeneration Research 2021年第12期16卷 2557-2562页

作者： Norihiro Nishida Itsuo Sakuramoto Yoshihiro Fujii Rudolf Yoga Hutama Fei Jiang Junji Ohgi Yasuaki Imajo hidenori suzuki Masahiro Funaba Xian Chen Takashi Sakai Department of Orthopedic Surgery Yamaguchi University Graduate School of MedicineMinami-KogushiUbeYamaguchiJapan Department of Mechanical and Electrical Engineering National Institute of Technology Tokuyama CollegeGakuendaiShunanYamaguchiJapan Faculty of Engineering Yamaguchi UniversityTokiwadai UbeYamaguchiJapan

In spinal cord injuries,external forces from various directions occur at various velocities.Therefore,it is important to physically evaluate whether the spinal cord is susceptible to damage and an increase in internal stress for external forces.We hypothesized that the spinal cord has mechanical features that vary under stress depending on the direction and velocity of injury.However,it is difficult to perform experiment because the spinal cord is very soft.There are no reports on the effects of multiple external forces.In this study,we used bovine spinal cord white matter to test and analyze the anisotropy and velocity dependence of the spinal cord.Tensile-vertical,tensile-parallel,shear-vertical,and shear-parallel tests were performed on the white matter in the fibrous direction(cranial to caudal).Strain rate in the experiment was 0.1,1,10,and 100/s.We calculated the Young’s modulus of the spinal cord.Results of the tensile and shear tests revealed that stress tended to increase when external forces were applied parallel to the direction of axon fibers,such as in tensile-vertical and shear-vertical tests.However,external forces those tear against the fibrous direction and vertically,such as in tensile-parallel and shear-parallel tests,were less likely to increase stress even with increased velocity.We found that the spinal cord was prone to external forces,especially in the direction of the fibers,and to be under increased stress levels when the velocity of external forces increased.From these results,we confirmed that the spinal cord has velocity dependence and anisotropy.The Institutional Animal Care and Use Committee of Yamaguchi University waived the requirement for ethical approval.

关键词： anisotropy dependence external force mechanistic analysis spinal cord injury straining rate stress velocity dependence white matter