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Wang W, Zhang Y, Fang Y, Gao J, Thuku RC, Yang J, Na C, Lu Q, Fang M. Targeting the contact-kinin system: A cyclopeptide with anti-thromboinflammatory properties against stroke. Eur J Pharmacol 2025; 998:177497. [PMID: 40058753 DOI: 10.1016/j.ejphar.2025.177497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 02/20/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
The contact-kinin system plays a central role in the thromboinflammatory pathology of ischemic stroke. Modulating this pathway represents a promising strategy for the prevention and treatment of ischemic stroke. Based on our recent findings demonstrating that the short peptide SD6 (SLGASD), derived from a specific influenza-related immunoglobulin heavy chain junction region sequence, exhibits anti-coagulant properties, we designed a cyclized version, cycloSD6, and evaluated its anti-ischemic stroke potential. Notably, cycloSD6 showed enhanced inhibition of activated coagulation factor XII (FXIIa; with an inhibition constant (Ki) of 41.27 μM) and plasma kallikrein (PKa; Ki: 28.54 μM), two key enzymes in the contact-kinin system, surpassing the inhibitory effects of its linear form. In vitro, 4-100 μM of CycloSD6 inhibited LPS-induced inflammation. And CycloSD6 at doses of 1 and 4 mg/kg displayed significant anti-thrombotic functions in several mouse models, including carrageenan-induced tail thrombosis, FeCl3-induced arterial thrombosis, and cortical photothrombosis models, and did not affect mouse tail bleeding time. The peptide also exerted comparable anti-ischemic stroke effects to those of ecallantide (DX-88), a kallikrein inhibitor approved for the treatment of hereditary angioedema, in a mouse model of transient middle cerebral artery occlusion. Thus, this short peptide CycloSD6, which dual targets FXII and PKa, harbors anti-thromboinflammation and anti-stroke properties with low bleeding risk. And these findings suggest that cycloSD6 may serve as a potential therapeutic candidate or template for the development of agents targeting ischemic stroke.
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Affiliation(s)
- Wanting Wang
- College of Life Science, Zhengzhou University, Zhengzhou, 450001, Henan, China; Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Yan Zhang
- College of Life Science, Zhengzhou University, Zhengzhou, 450001, Henan, China; Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Yuqing Fang
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Jinai Gao
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Rebecca Caroline Thuku
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Juan Yang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Chen Na
- Yan An Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Qiumin Lu
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China
| | - Mingqian Fang
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17 Longxin Road, Kunming, 650201, Yunnan, China.
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Chu MC, Mao WC, Wu HF, Chang YC, Lu TI, Lee CW, Chung YJ, Hsieh TH, Chang HS, Chen YF, Lin CH, Tang CW, Lin HC. Transient plasticity response is regulated by histone deacetylase inhibitor in oxygen-glucose deprivation condition. Pharmacol Rep 2023; 75:1200-1210. [PMID: 37695500 DOI: 10.1007/s43440-023-00525-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/25/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND The pathological form of synaptic plasticity, ischemic long-term potentiation (iLTP), induced by oxygen and glucose deprivation (OGD), is implicated in the acute phase of stroke with the potentiation of N-methyl-D-aspartate receptor (NMDAR). While there has been widespread attention on the excitatory system, a recent study reported that γ-aminobutyric acid (GABA)ergic system is also involved in iLTP. Valproic acid (VPA), a histone deacetylase inhibitor, protects against ischemic damage. However, whether VPA regulates early phase plasticity in ischemic stroke remains unknown. The present study aims to investigate the potential role and mechanism of VPA in ischemic stroke. METHODS A brief exposure of OGD on the hippocampal slices and the induction of photothrombotic ischemia (PTI) were used as ex vivo and in vivo models of ischemic stroke, respectively. RESULTS Using extracellular recordings, iLTP was induced in the hippocampal Schaffer collateral pathway following OGD exposure. VPA treatment abolished hippocampal iLTP via GABAA receptor enhancement and extracellular signal-regulated kinase (ERK) phosphorylation. Administration of VPA reduced brain infarct volume and motor dysfunction in mice with PTI. Moreover, VPA protected against ischemic injury by upregulating the GABAergic system and ERK phosphorylation, as well as by reducing of matrix metalloproteinase in a PTI-induced ischemic stroke model. CONCLUSIONS Together, this study revealed the protection of VPA in ex vivo OGD-induced pathological form of neuroplasticity and in vivo PTI-induced brain damage and motor dysfunction through rescuing GABAergic deficiency and the pathological hallmarks of ischemia.
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Affiliation(s)
- Ming-Chia Chu
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Chang Mao
- Department of Psychiatry, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Han-Fang Wu
- Department of Optometry, MacKay Medical College, New Taipei City, Taiwan
| | - Yun-Chi Chang
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-I Lu
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi-Wei Lee
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yueh-Jung Chung
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsung-Han Hsieh
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsun-Shuo Chang
- School of Pharmacy, College of Pharmacy, Kaoshiung Medical University, Kaoshiung, Taiwan
| | - Yih-Fung Chen
- School of Pharmacy, College of Pharmacy, Kaoshiung Medical University, Kaoshiung, Taiwan
- Graduate Institute of Natural Products, College of Pharmacy, Kaoshiung Medical University, Kaoshiung, Taiwan
| | - Chia-Hsien Lin
- Department of Health Industry Management, Kainan University, Taoyuan, Taiwan
| | - Chih-Wei Tang
- Department of Neurology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Hui-Ching Lin
- Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, Taiwan.
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Wu X, Li JR, Fu Y, Chen DY, Nie H, Tang ZP. From static to dynamic: live observation of the support system after ischemic stroke by two photon-excited fluorescence laser-scanning microscopy. Neural Regen Res 2023; 18:2093-2107. [PMID: 37056116 PMCID: PMC10328295 DOI: 10.4103/1673-5374.369099] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/21/2022] [Accepted: 01/13/2023] [Indexed: 02/17/2023] Open
Abstract
Ischemic stroke is one of the most common causes of mortality and disability worldwide. However, treatment efficacy and the progress of research remain unsatisfactory. As the critical support system and essential components in neurovascular units, glial cells and blood vessels (including the blood-brain barrier) together maintain an optimal microenvironment for neuronal function. They provide nutrients, regulate neuronal excitability, and prevent harmful substances from entering brain tissue. The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis, supporting neuronal function, and reacting to injuries. However, most studies have focused on postmortem animals, which inevitably lack critical information about the dynamic changes that occur after ischemic stroke. Therefore, a high-precision technique for research in living animals is urgently needed. Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions. Two-photon fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure, information on multicellular component interactions, and provide images of structure and function in the cranial window. This technique shifts the existing research paradigm from static to dynamic, from flat to stereoscopic, and from single-cell function to multicellular intercommunication, thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain. In this review, we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy, highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain's support systems. We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.
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Affiliation(s)
- Xuan Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jia-Rui Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yu Fu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Dan-Yang Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hao Nie
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhou-Ping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Zeng L, Hu S, Zeng L, Chen R, Li H, Yu J, Yang H. Animal Models of Ischemic Stroke with Different Forms of Middle Cerebral Artery Occlusion. Brain Sci 2023; 13:1007. [PMID: 37508939 PMCID: PMC10377124 DOI: 10.3390/brainsci13071007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/24/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Ischemic stroke is a common type of stroke that significantly affects human well-being and quality of life. In order to further characterize the pathophysiology of ischemic stroke and develop new treatment strategies, ischemic stroke models with controllable and consistent response to potential clinical treatments are urgently needed. The middle cerebral artery occlusion (MCAO) model is currently the most widely used animal model of ischemic stroke. This review discusses various methods for constructing the MCAO model and compares their advantages and disadvantages in order to provide better approaches for studying ischemic stroke.
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Affiliation(s)
- Lang Zeng
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Shengqi Hu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lingcheng Zeng
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Rudong Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Hua Li
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jiasheng Yu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Hongkuan Yang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
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Kim H, Kim J, Kim J, Oh S, Choi K, Yoon J. Magnetothermal-based non-invasive focused magnetic stimulation for functional recovery in chronic stroke treatment. Sci Rep 2023; 13:4988. [PMID: 36973390 PMCID: PMC10042827 DOI: 10.1038/s41598-023-31979-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Magnetic heat-based brain stimulation of specific lesions could promote the restoration of impaired motor function caused by chronic stroke. We delivered localized stimulation by nanoparticle-mediated heat generation within the targeted brain area via focused magnetic stimulation. The middle cerebral artery occlusion model was prepared, and functional recovery in the chronic-phase stroke rat model was demonstrated by the therapeutic application of focused magnetic stimulation. We observed a transient increase in blood-brain barrier permeability at the target site of < 4 mm and metabolic brain activation at the target lesion. After focused magnetic stimulation, the rotarod score increased by 390 ± 28% (p < 0.05) compared to the control group. Standardized uptake value in the focused magnetic stimulation group increased by 2063 ± 748% (p < 0.01) compared to the control group. Moreover, an increase by 24 ± 5% (p < 0.05) was observed in the sham group as well. Our results show that non-invasive focused magnetic stimulation can safely modulate BBB permeability and enhance neural activation for chronic-phase stroke treatment in the targeted deep brain area.
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Affiliation(s)
- Hohyeon Kim
- School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea
| | - Jihye Kim
- Department of Neurology, Chonnam National University Hospital and Medical School, 8 Hak-dong, Dong-gu, Gwangju, 501-757, South Korea
| | - Jahae Kim
- Department of Nuclear Medicines, Chonnam National University Hospital and Medical School, 8 Hak-dong, Dong-gu, Gwangju, 501-757, South Korea
| | - Seungjun Oh
- School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea
| | - Kangho Choi
- Department of Neurology, Chonnam National University Hospital and Medical School, 8 Hak-dong, Dong-gu, Gwangju, 501-757, South Korea.
| | - Jungwon Yoon
- School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea.
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Seong D, Yi S, Han S, Lee J, Park S, Hwang YH, Kim J, Kim HK, Jeon M. Target ischemic stroke model creation method using photoacoustic microscopy with simultaneous vessel monitoring and dynamic photothrombosis induction. PHOTOACOUSTICS 2022; 27:100376. [PMID: 35734368 PMCID: PMC9207728 DOI: 10.1016/j.pacs.2022.100376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/02/2022] [Indexed: 06/02/2023]
Abstract
The ischemic stroke animal model evaluates the efficacy of reperfusion and neuroprotective strategies for ischemic injuries. Various conventional methods have been reported to induce the ischemic models; however, controlling specific neurological deficits, mortality rates, and the extent of the infarction is difficult as the size of the affected region is not precisely controlled. In this paper, we report a single laser-based localized target ischemic stroke model development method by simultaneous vessel monitoring and photothrombosis induction using photoacoustic microscopy (PAM), which has minimized the infarct size at precise location with high reproducibility. The proposed method has significantly reduced the infarcted region by illuminating the precise localization. The reproducibility and validity of suggested method have been demonstrated through repeated experiments and histological analyses. These results demonstrate that our method can provide the ischemic stroke model closest to the clinical pathology for brain ischemia research from inducement, occurrence mechanisms to the recovery process.
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Affiliation(s)
- Daewoon Seong
- School of Electronic and Electrical Engineering, College of IT Engineering, Kyungpook National University, Daegu 41566, the Republic of Korea
| | - Soojin Yi
- Bio-Medical Institute, Kyungpook National University Hospital, Daegu 41404, the Republic of Korea
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu 41944, the Republic of Korea
- Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu 41944, the Republic of Korea
| | - Sangyeob Han
- School of Electronic and Electrical Engineering, College of IT Engineering, Kyungpook National University, Daegu 41566, the Republic of Korea
- Institute of Biomedical Engineering, School of Medicine, Kyungpook National University, Daegu 41566, the Republic of Korea
| | - Jaeyul Lee
- School of Electronic and Electrical Engineering, College of IT Engineering, Kyungpook National University, Daegu 41566, the Republic of Korea
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
| | - Sungjo Park
- Pohang Innotown Center, Pohang University of Science and Technology, Pohang 37673, the Republic of Korea
| | - Yang-Ha Hwang
- Department of Neurology, School of Medicine, Kyungpook National University, Daegu 41944, the Republic of Korea
| | - Jeehyun Kim
- School of Electronic and Electrical Engineering, College of IT Engineering, Kyungpook National University, Daegu 41566, the Republic of Korea
| | - Hong Kyun Kim
- Bio-Medical Institute, Kyungpook National University Hospital, Daegu 41404, the Republic of Korea
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu 41944, the Republic of Korea
- Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu 41944, the Republic of Korea
| | - Mansik Jeon
- School of Electronic and Electrical Engineering, College of IT Engineering, Kyungpook National University, Daegu 41566, the Republic of Korea
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022. [DOI: 10.12998/wjcc.v10.i9.2698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022; 10:2700-2709. [PMID: 35434115 PMCID: PMC8968801 DOI: 10.12998/wjcc.v10.i9.2700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/29/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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Blood-Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke. Int J Mol Sci 2022; 23:ijms23031898. [PMID: 35163820 PMCID: PMC8836701 DOI: 10.3390/ijms23031898] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/20/2022] Open
Abstract
Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood-brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.
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Carminita E, Crescence L, Panicot-Dubois L, Dubois C. Role of Neutrophils and NETs in Animal Models of Thrombosis. Int J Mol Sci 2022; 23:ijms23031411. [PMID: 35163333 PMCID: PMC8836215 DOI: 10.3390/ijms23031411] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Thrombosis is one of the major causes of mortality worldwide. Notably, it is not only implicated in cardiovascular diseases, such as myocardial infarction (MI), stroke, and pulmonary embolism (PE), but also in cancers. Understanding the cellular and molecular mechanisms involved in platelet thrombus formation is a major challenge for scientists today. For this purpose, new imaging technologies (such as confocal intravital microscopy, electron microscopy, holotomography, etc.) coupled with animal models of thrombosis (mouse, rat, rabbit, etc.) allow a better overview of this complex physiopathological process. Each of the cellular components is known to participate, including the subendothelial matrix, the endothelium, platelets, circulating cells, and, notably, neutrophils. Initially known as immune cells, neutrophils have been considered to be part of the landscape of thrombosis for more than a decade. They participate in this biological process through their expression of tissue factor (TF) and protein disulfide isomerase (PDI). Moreover, highly activated neutrophils are described as being able to release their DNA and thus form chromatin networks known as “neutrophil extracellular traps” (NETs). Initially, described as “dead sacrifices for a good cause” that prevent the dissemination of bacteria in the body, NETs have also been studied in several human pathologies, such as cardiovascular and respiratory diseases. Many articles suggest that they are involved in platelet thrombus formation and the activation of the coagulation cascade. This review presents the models of thrombosis in which neutrophils and NETs are involved and describes their mechanisms of action. We have even highlighted the medical diagnostic advances related to this research.
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Affiliation(s)
- Estelle Carminita
- Aix Marseille Univ, INSERM 1263 (Institut National de la Santé et de la Recherche), INRAE 1260 (Institut National de la Recherche Agronomique et de l’Environnement), C2VN (Center for CardioVascular and Nutrition Research), 13885 Marseille, France; (E.C.); (L.C.); (C.D.)
- Aix Marseille University, PIVMI (Plateforme d’Imagerie Vasculaire et de Microscopie Intravitale), C2VN (Center for CardioVascular and Nutrition Research), 13385 Marseille, France
| | - Lydie Crescence
- Aix Marseille Univ, INSERM 1263 (Institut National de la Santé et de la Recherche), INRAE 1260 (Institut National de la Recherche Agronomique et de l’Environnement), C2VN (Center for CardioVascular and Nutrition Research), 13885 Marseille, France; (E.C.); (L.C.); (C.D.)
- Aix Marseille University, PIVMI (Plateforme d’Imagerie Vasculaire et de Microscopie Intravitale), C2VN (Center for CardioVascular and Nutrition Research), 13385 Marseille, France
| | - Laurence Panicot-Dubois
- Aix Marseille Univ, INSERM 1263 (Institut National de la Santé et de la Recherche), INRAE 1260 (Institut National de la Recherche Agronomique et de l’Environnement), C2VN (Center for CardioVascular and Nutrition Research), 13885 Marseille, France; (E.C.); (L.C.); (C.D.)
- Aix Marseille University, PIVMI (Plateforme d’Imagerie Vasculaire et de Microscopie Intravitale), C2VN (Center for CardioVascular and Nutrition Research), 13385 Marseille, France
- Correspondence:
| | - Christophe Dubois
- Aix Marseille Univ, INSERM 1263 (Institut National de la Santé et de la Recherche), INRAE 1260 (Institut National de la Recherche Agronomique et de l’Environnement), C2VN (Center for CardioVascular and Nutrition Research), 13885 Marseille, France; (E.C.); (L.C.); (C.D.)
- Aix Marseille University, PIVMI (Plateforme d’Imagerie Vasculaire et de Microscopie Intravitale), C2VN (Center for CardioVascular and Nutrition Research), 13385 Marseille, France
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11
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Moulson AJ, Squair JW, Franklin RJM, Tetzlaff W, Assinck P. Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity? Front Cell Neurosci 2021; 15:703810. [PMID: 34381334 PMCID: PMC8349991 DOI: 10.3389/fncel.2021.703810] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/02/2021] [Indexed: 01/02/2023] Open
Abstract
Astrocytes are essential for the development and homeostatic maintenance of the central nervous system (CNS). They are also critical players in the CNS injury response during which they undergo a process referred to as "reactive astrogliosis." Diversity in astrocyte morphology and gene expression, as revealed by transcriptional analysis, is well-recognized and has been reported in several CNS pathologies, including ischemic stroke, CNS demyelination, and traumatic injury. This diversity appears unique to the specific pathology, with significant variance across temporal, topographical, age, and sex-specific variables. Despite this, there is limited functional data corroborating this diversity. Furthermore, as reactive astrocytes display significant environmental-dependent plasticity and fate-mapping data on astrocyte subsets in the adult CNS is limited, it remains unclear whether this diversity represents heterogeneity or plasticity. As astrocytes are important for neuronal survival and CNS function post-injury, establishing to what extent this diversity reflects distinct established heterogeneous astrocyte subpopulations vs. environmentally dependent plasticity within established astrocyte subsets will be critical for guiding therapeutic development. To that end, we review the current state of knowledge on astrocyte diversity in the context of three representative CNS pathologies: ischemic stroke, demyelination, and traumatic injury, with the goal of identifying key limitations in our current knowledge and suggesting future areas of research needed to address them. We suggest that the majority of identified astrocyte diversity in CNS pathologies to date represents plasticity in response to dynamically changing post-injury environments as opposed to heterogeneity, an important consideration for the understanding of disease pathogenesis and the development of therapeutic interventions.
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Affiliation(s)
- Aaron J. Moulson
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
- International Collaboration on Repair Discoveries (ICORD), Vancouver, BC, Canada
| | - Jordan W. Squair
- Department of Clinical Neuroscience, Faculty of Life Sciences, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), NeuroRestore, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Robin J. M. Franklin
- Wellcome Trust - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries (ICORD), Vancouver, BC, Canada
- Department of Zoology, University of British Columbia, Vancouver, BC, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Peggy Assinck
- Wellcome Trust - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
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12
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Nikitin D, Choi S, Mican J, Toul M, Ryu WS, Damborsky J, Mikulik R, Kim DE. Development and Testing of Thrombolytics in Stroke. J Stroke 2021; 23:12-36. [PMID: 33600700 PMCID: PMC7900387 DOI: 10.5853/jos.2020.03349] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/28/2020] [Indexed: 12/16/2022] Open
Abstract
Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies in vitro and in vivo.
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Affiliation(s)
- Dmitri Nikitin
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Seungbum Choi
- Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, Korea
| | - Jan Mican
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.,Department of Neurology, St. Anne's Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Martin Toul
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Wi-Sun Ryu
- Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea
| | - Jiri Damborsky
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Robert Mikulik
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Department of Neurology, St. Anne's Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Dong-Eog Kim
- Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, Korea.,Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea
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13
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Protective Effects of ShcA Protein Silencing for Photothrombotic Cerebral Infarction. Transl Stroke Res 2020; 12:866-878. [PMID: 33242144 DOI: 10.1007/s12975-020-00874-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 11/03/2020] [Accepted: 11/05/2020] [Indexed: 12/26/2022]
Abstract
Reactive oxygen species (ROS) exacerbate stroke-induced cell damage. We found that ShcA, a protein that regulates ROS, is highly expressed in a Rose Bengal photothrombosis model. We investigated whether ShcA is essential for mitophagy in ROS-induced cellular damage and determined whether ROS exacerbate mitochondrial dysfunction via ShcA protein expression. Ischemic stroke was generated by Rose Bengal photothrombosis in mice. To silence ShcA protein expression in the mouse brain, ShcA-targeting siRNA-encapsulated nanoparticles were intrathecally injected into the cisterna magna. Upon staining with antibodies against ShcA counterpart caspase-3 or NeuN, we found that the ShcA protein expression was increased in apoptotic neurons. In addition, mitochondrial dysfunction and excessive mitophagy were evident in photothrombotic stroke tissue. Infarct volumes were significantly reduced, and neurological deficits were diminished in the ShcA siRNA nanoparticle-treated group, compared with the negative control siRNA nanoparticle-treated group. We confirmed that the reduction of ShcA expression by nanoparticle treatment rescued the expression of genes, associated with mitochondrial dynamics and mitophagy mediation in a stroke model. This study suggests that the regulation of ShcA protein expression can be a therapeutic target for reducing brain damage with mitochondrial dysfunction caused by thrombotic infarction.
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14
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Lv J, Li S, Zhang J, Duan F, Wu Z, Chen R, Chen M, Huang S, Ma H, Nie L. In vivo photoacoustic imaging dynamically monitors the structural and functional changes of ischemic stroke at a very early stage. Am J Cancer Res 2020; 10:816-828. [PMID: 31903152 PMCID: PMC6929999 DOI: 10.7150/thno.38554] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 09/18/2019] [Indexed: 11/24/2022] Open
Abstract
Ischemic stroke (IS) is one of the leading causes of death and accounts for 85% of stroke cases. Since the symptoms are not obvious, diagnosis of IS, particularly at an early stage, is a great challenge. Photoacoustic imaging combines high sensitivity of optical imaging and fine resolution of ultrasonography to non-invasively provide structural and functional information of IS. Methods: We adopted three rapid photoacoustic imaging systems with varying characteristics, including a portable handheld photoacoustic system, high-sensitivity bowl-shaped array photoacoustic computed tomography (PACT), and high-resolution photoacoustic microscopy (PAM) to assess the stereoscopic and comprehensive pathophysiological status of IS at an early stage. Two representative models of IS, referring to photothrombosis and middle cerebral artery occlusion (MCAO) models, were established to verify the feasibility of photoacoustic imaging detection. Results: Non-invasive, rapid PACT of the IS model in mouse provided structural information of the brain lesion, achieving early disease identification (5 min after the onset of disease). Moreover, it was able to dynamically reflect disease progression. Quantitative high-resolution PAM allowed observation of pathological changes in the microvascular system of mouse brain. In terms of functional imaging, significant differences in oxygen saturation (sO2) levels between infarcted and normal areas could be observed by PACT, permitting effective functional parameters for the diagnosis of IS. Conclusions: We used PACT to perform full-view structural imaging and functional imaging of sO2 in IS at the macroscopic level, and then observed the microvascular changes in the infarcted area at the microscopic level by using PAM. This work may provide new tools for the early diagnosis of IS and its subsequent complications as well as assessment of disease progression.
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15
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Microcirculatory Changes in Experimental Models of Stroke and CNS-Injury Induced Immunodepression. Int J Mol Sci 2019; 20:ijms20205184. [PMID: 31635068 PMCID: PMC6834192 DOI: 10.3390/ijms20205184] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/14/2019] [Accepted: 10/18/2019] [Indexed: 12/17/2022] Open
Abstract
Stroke is the second-leading cause of death globally and the leading cause of disability in adults. Medical complications after stroke, especially infections such as pneumonia, are the leading cause of death in stroke survivors. Systemic immunodepression is considered to contribute to increased susceptibility to infections after stroke. Different experimental models have contributed significantly to the current knowledge of stroke pathophysiology and its consequences. Each model causes different changes in the cerebral microcirculation and local inflammatory responses after ischemia. The vast majority of studies which focused on the peripheral immune response to stroke employed the middle cerebral artery occlusion method. We review various experimental stroke models with regard to microcirculatory changes and discuss the impact on local and peripheral immune response for studies of CNS-injury (central nervous system injury) induced immunodepression.
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16
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Barthels D, Das H. Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis 2018; 1866:165260. [PMID: 31699365 DOI: 10.1016/j.bbadis.2018.09.012] [Citation(s) in RCA: 391] [Impact Index Per Article: 55.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/24/2018] [Accepted: 09/09/2018] [Indexed: 01/09/2023]
Abstract
With more than 795,000 cases occurring every year, stroke has become a major problem in the United States across all demographics. Stroke is the leading cause of long-term disability and is the fifth leading cause of death in the US. Ischemic stroke represents 87% of total strokes in the US, and is currently the main focus of stroke research. This literature review examines the risk factors associated with ischemic stroke, changes in cell morphology and signaling in the brain after stroke, and the advantages and disadvantages of in vivo and in vitro ischemic stroke models. Classification systems for stroke etiology are also discussed briefly, as well as current ischemic stroke therapies and new therapeutic strategies that focus on the potential of stem cells to promote stroke recovery.
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Affiliation(s)
- Derek Barthels
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Hiranmoy Das
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
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17
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Korobtsov AV, Kalinichenko SG. [The experimental strategies in the study of ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 117:38-44. [PMID: 29411744 DOI: 10.17116/jnevro201711712238-44] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Literature data and own experience in the studies of experimental stroke methodology are reviewed. Advantages and disadvantages of the common models of focal ischemia used in the laboratory practice are discussed in details. The advantages of the filament occlusion of the middle cerebral artery in rats as the most adequate model of human stroke are substantiated. The authors suggest a modification of this variant using an additional coagulation of the pterygopalatine artery that allows the exclusion of the retrograde and collateral blood flow into the inner carotid artery after ligation of the common and external carotid arteries.
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Affiliation(s)
- A V Korobtsov
- Pacific State Medical University, Vladivostok, Russia
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18
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Ward SJ, Castelli F, Reichenbach ZW, Tuma RF. Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia. Life Sci 2017; 195:1-5. [PMID: 29288767 DOI: 10.1016/j.lfs.2017.12.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/19/2017] [Accepted: 12/22/2017] [Indexed: 12/24/2022]
Abstract
AIMS We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. MAIN METHODS Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. KEY FINDINGS The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. SIGNIFICANCE Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke. Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect. Surprisingly the double knockout animals had improved outcome. Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results.
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Affiliation(s)
- Sara Jane Ward
- Lewis Katz School of Medicine at Temple University, United States.
| | | | | | - Ronald F Tuma
- Lewis Katz School of Medicine at Temple University, United States
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19
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Photothrombotic Stroke as a Model of Ischemic Stroke. Transl Stroke Res 2017; 9:437-451. [DOI: 10.1007/s12975-017-0593-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 11/14/2017] [Accepted: 11/24/2017] [Indexed: 12/20/2022]
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20
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Jiun-Yi L, Ting-Chen C, Nen-Chung C, Jayakumar T, Chao-Chien C. Anti-embolic effect of Taorenchengqi Tang in rats with embolic stroke induced by occluding middle cerebral artery. J TRADIT CHIN MED 2017. [DOI: 10.1016/s0254-6272(17)30068-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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21
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Sommer CJ. Ischemic stroke: experimental models and reality. Acta Neuropathol 2017; 133:245-261. [PMID: 28064357 PMCID: PMC5250659 DOI: 10.1007/s00401-017-1667-0] [Citation(s) in RCA: 397] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/31/2016] [Accepted: 01/01/2017] [Indexed: 12/11/2022]
Abstract
The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel (“ischemic stroke”) eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models.
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Affiliation(s)
- Clemens J Sommer
- Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University Mainz; Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn2), Langenbeckstrasse 1, 55131, Mainz, Germany.
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22
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Reichenbach ZW, Li H, Ward SJ, Tuma RF. The CB1 antagonist, SR141716A, is protective in permanent photothrombotic cerebral ischemia. Neurosci Lett 2016; 630:9-15. [PMID: 27453059 DOI: 10.1016/j.neulet.2016.07.041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 07/15/2016] [Accepted: 07/20/2016] [Indexed: 01/24/2023]
Abstract
Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research.
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Affiliation(s)
- Zachary Wilmer Reichenbach
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Medical Education and Research Building, 8th floor Philadelphia, PA, 19140, United States.
| | - Hongbo Li
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Medical Education and Research Building, 8th floor Philadelphia, PA, 19140, United States.
| | - Sara Jane Ward
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Medical Education and Research Building, 8th floor Philadelphia, PA, 19140, United States.
| | - Ronald F Tuma
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Medical Education and Research Building, 8th floor Philadelphia, PA, 19140, United States.
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23
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Beard DJ, Logan CL, McLeod DD, Hood RJ, Pepperall D, Murtha LA, Spratt NJ. Ischemic penumbra as a trigger for intracranial pressure rise - A potential cause for collateral failure and infarct progression? J Cereb Blood Flow Metab 2016; 36:917-27. [PMID: 26759431 PMCID: PMC4853839 DOI: 10.1177/0271678x15625578] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/04/2015] [Indexed: 11/17/2022]
Abstract
We have recently shown that intracranial pressure (ICP) increases dramatically 24 h after minor intraluminal thread occlusion with reperfusion, independent of edema. Some of the largest ICP rises were observed in rats with the smallest final infarcts. A possible alternate mechanism for this ICP rise is an increase of cerebrospinal fluid (CSF) volume secondary to choroid plexus damage (a known complication of the intraluminal stroke model used). Alternatively, submaximal injury may be needed to induce ICP elevation. Therefore, we aimed to determine (a) if choroid plexus damage contributes to the ICP elevation, (b) if varying the patency of an important internal collateral supply to the middle cerebral artery (MCA), the anterior choroidal artery (AChA), produces different volumes of ischemic penumbra and (c) if presence of ischemic penumbra (submaximal injury) is associated with ICP elevation. We found (a) no association between choroid plexus damage and ICP elevation, (b) animals with a good internal collateral supply through the AChA during MCAo had significantly larger penumbra volumes and (c) ICP elevation at ≈24 h post-stroke only occurred in rats with submaximal injury, shown in two different stroke models. We conclude that active cellular processes within the ischemic penumbra may be required for edema-independent ICP elevation.
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Affiliation(s)
- Daniel J Beard
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Caitlin L Logan
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Damian D McLeod
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Rebecca J Hood
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Debbie Pepperall
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Lucy A Murtha
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia
| | - Neil J Spratt
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia Hunter Medical Research Institute, New Lambton, New South Wales, Australia Department of Neurology, John Hunter Hospital, Hunter New England Local Health District, New South Wales, Australia
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24
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Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. Neurosci Bull 2015; 31:717-34. [PMID: 26625873 DOI: 10.1007/s12264-015-1567-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 09/25/2015] [Indexed: 01/04/2023] Open
Abstract
Stroke, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage, is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding of the risk factors and the pathophysiology of stroke, as well as the development of therapeutic strategies for its treatment. Further development and investigation of experimental models, however, are needed to elucidate the pathogenesis of stroke and to enhance and expand novel therapeutic targets. In this article, we provide an overview of the characteristics of commonly-used animal models of stroke and focus on the inflammatory responses to cerebral stroke, which may provide insights into a framework for developing effective therapies for stroke in humans.
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Fluri F, Schuhmann MK, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:3445-54. [PMID: 26170628 PMCID: PMC4494187 DOI: 10.2147/dddt.s56071] [Citation(s) in RCA: 275] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.
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Affiliation(s)
- Felix Fluri
- Department of Neurology, University Clinic Wuerzburg, Wuerzburg, Germany
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Tregub P, Kulikov V, Motin Y, Bespalov A, Osipov I. Combined exposure to hypercapnia and hypoxia provides its maximum neuroprotective effect during focal ischemic injury in the brain. J Stroke Cerebrovasc Dis 2014; 24:381-7. [PMID: 25498739 DOI: 10.1016/j.jstrokecerebrovasdis.2014.09.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 08/22/2014] [Accepted: 09/05/2014] [Indexed: 10/24/2022] Open
Abstract
BACKGROUND In the present research, we compared the neuroprotective efficiency of combined and isolated exposure to hypoxia and hypercapnia preceding focal cerebral ischemic injury in rats. The study was conducted to verify the hypothesis of a possible increase in normobaric hypoxia (NbH; 90 mm Hg) efficiency when combined with permissive hypercapnia (PH; 50 mm Hg). METHODS The rats from the test groups were subjected to a 15-fold exposure to NbH (90 mm Hg) and/or PH (50 mm Hg). After the 15th exposure, cerebral ischemic injury was induced by photochemical thrombosis. Seventy-two hours later, neurologic deficit was determined on the Neurological Severity Score scale and by the rotarod test, and the volume of cerebral infarction was measured after focal photochemical thrombosis. RESULTS The neurologic deficit decreased most efficiently in rats that underwent PH and hypercapnic hypoxia (HH) exposure, whereas NbH had no impact on the neurologic status of the animals. On the contrary, motor coordination disturbances were minimal during exposure to hypoxia and HH. All respiratory interventions reduced the cerebral ischemic infarction volume in rats. The smallest infarction volumes were registered in the area of photochemical thrombosis in rats from the hypercapnic-hypoxic impact group, whereas exposure to NbH or PH did not show any cross difference. CONCLUSIONS The impact of PH has greater neuroprotective potential compared with NbH. Thus, we can assume that hypercapnia is a predominant factor in providing neuroprotection in combination with hypoxia.
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Affiliation(s)
- Pavel Tregub
- Department of Pathophysiology, Federal Agency for Health and Social Development, Altai State Medical University, Barnaul, Altai Region, Russia.
| | - Vladimir Kulikov
- Department of Pathophysiology, Federal Agency for Health and Social Development, Altai State Medical University, Barnaul, Altai Region, Russia
| | - Yuri Motin
- Department of Histology, Federal Agency for Health and Social Development, Altai State Medical University, Barnaul, Altai Region, Russia
| | - Andrey Bespalov
- Department of Pathophysiology, Federal Agency for Health and Social Development, Altai State Medical University, Barnaul, Altai Region, Russia
| | - Ilya Osipov
- Department of Pathophysiology, Federal Agency for Health and Social Development, Altai State Medical University, Barnaul, Altai Region, Russia
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Schunke KJ, Toung TK, Zhang J, Pathak AP, Xu J, Zhang J, Koehler RC, Faraday N. A novel atherothrombotic model of ischemic stroke induced by injection of collagen into the cerebral vasculature. J Neurosci Methods 2014; 239:65-74. [PMID: 25314906 DOI: 10.1016/j.jneumeth.2014.10.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 10/02/2014] [Accepted: 10/03/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. METHODS To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. RESULTS Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ∼80% in mice and ∼60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ∼30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. COMPARISON WITH EXISTING METHODS Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. CONCLUSION This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury.
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Affiliation(s)
- Kathryn J Schunke
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas K Toung
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jian Zhang
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Arvind P Pathak
- The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jiadi Xu
- F. M. Kirby Functional Imaging Center, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Jiangyang Zhang
- The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Raymond C Koehler
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nauder Faraday
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Labat-gest V, Tomasi S. Photothrombotic ischemia: a minimally invasive and reproducible photochemical cortical lesion model for mouse stroke studies. J Vis Exp 2013. [PMID: 23770844 DOI: 10.3791/50370] [Citation(s) in RCA: 126] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The photothrombotic stroke model aims to induce an ischemic damage within a given cortical area by means of photo-activation of a previously injected light-sensitive dye. Following illumination, the dye is activated and produces singlet oxygen that damages components of endothelial cell membranes, with subsequent platelet aggregation and thrombi formation, which eventually determines the interruption of local blood flow. This approach, initially proposed by Rosenblum and El-Sabban in 1977, was later improved by Watson in 1985 in rat brain and set the basis of the current model. Also, the increased availability of transgenic mouse lines further contributed to raise the interest on the photothrombosis model. Briefly, a photosensitive dye (Rose Bengal) is injected intraperitoneally and enters the blood stream. When illuminated by a cold light source, the dye becomes activated and induces endothelial damage with platelet activation and thrombosis, resulting in local blood flow interruption. The light source can be applied on the intact skull with no need of craniotomy, which allows targeting of any cortical area of interest in a reproducible and non-invasive way. The mouse is then sutured and allowed to wake up. The evaluation of ischemic damage can be quickly accomplished by triphenyl-tetrazolium chloride or cresyl violet staining. This technique produces infarction of small size and well-delimited boundaries, which is highly advantageous for precise cell characterization or functional studies. Furthermore, it is particularly suitable for studying cellular and molecular responses underlying brain plasticity in transgenic mice.
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The delivery of thrombi-specific nanoparticles incorporating oligonucleotides into injured cerebrovascular endothelium. Biomaterials 2013; 34:4128-4136. [PMID: 23465828 DOI: 10.1016/j.biomaterials.2013.02.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 02/06/2013] [Indexed: 01/17/2023]
Abstract
In acute vascular events, the endothelium derived tissue factor (TF) is the trigger of the coagulation cascade. In this study, EGFP-EGF1 protein-conjugated PEG-PLGA nanoparticle was employed as a TF targeting vehicle, the NF-κB decoy oligonucleotides (ODNs) was incorporated into it and the resulting EGF1-EGFP-NP-ODNs were evaluated as a vector for therapy of cortex infarction. At 2 h after transfection of TF expressed rat brain capillary endothelial cell, EGF1-EGFP-NP-ODNs was more efficiently internalized and located in the cytoplasm than NP-ODNs. At 4 h and 6 h after administration, ODNs were present in the nuclei and obviously inhibited the TF expression. At 6 h after i.v. administration in vivo, most EGF1-EGFP-NP were accumulated in the embolism vessels, distributed in the damaged endothelial cells and lowered the TF expression. At 24 h after i.v. administration, MR imaging of cortex infarcts were predominantly dwindled.
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Gauberti M, Obiang P, Guedin P, Balossier A, Gakuba C, Diependaele AS, Chazalviel L, Vivien D, Young AR, Agin V, Orset C. Thrombotic stroke in the anesthetized monkey (Macaca mulatta): characterization by MRI--a pilot study. Cerebrovasc Dis 2012; 33:329-39. [PMID: 22343114 DOI: 10.1159/000335309] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 11/17/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The lack of a relevant stroke model in large nonhuman primates hinders the development of innovative diagnostic/therapeutic approaches concerned with this cerebrovascular disease. Our objective was to develop a novel and clinically relevant model of embolic stroke in the anesthetized monkey that incorporates readily available clinical imaging techniques and that would allow the possibility of drug delivery including strategies of reperfusion. METHODS Thrombin was injected into the lumen of the middle cerebral artery (MCA) in 12 anesthetized (sevoflurane) male rhesus macaques (Macaca mulatta). Sequential MRI studies (including angiography, FLAIR, PWI, DWI, and gadolinium-enhanced T1W imaging) were performed in a 3T clinical MRI. Physiological and biochemical parameters were monitored throughout the investigations. RESULTS Once standardized, the surgical procedure induced transient occlusion of the middle cerebral artery in all operated animals. All animals studied showed spontaneous reperfusion, which occurred some time between 2 h and 7 days post-ictus. Eighty percent of the studied animals showed diffusion/perfusion mismatch. The ischemic lesions at 24 h spared both superficial and profound territories of the MCA. Some animals presented hemorrhagic transformation at 7 days post-ictus. CONCLUSION In this study, we developed a pre-clinically relevant model of embolic stroke in the anesthetized nonhuman primate.
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Affiliation(s)
- Maxime Gauberti
- INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, GIP Cyceron, Université de Caen-Basse Normandie, Caen, France
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Abstract
Receptor shedding is a mechanism for irreversible removal of transmembrane cell surface receptors by proteolysis of the receptor at a position near the extracellular surface of the plasma membrane. This process generates a soluble ectodomain fragment and a membrane-associated remnant fragment, and is distinct from loss of receptor surface expression by internalization or microparticle release or secretion of alternatively spliced soluble forms of receptors lacking a transmembrane domain. There has been an increased focus on new methods for analyzing shedding of platelet glycoprotein (GP)Ib-IX-V and GPVI because these receptors are platelet specific and are critical for the initiation of platelet adhesion and activation in thrombus formation at arterial shear rates. Platelet receptor shedding provides a mechanism for downregulating surface expression resulting in loss of ligand binding, decreasing the surface density affecting receptor cross linking and signalling and generation of proteolytic fragments that may be functional and/or provide platelet-specific biomarkers.
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Affiliation(s)
- Elizabeth E Gardiner
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
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Animal Models of Stroke for Preclinical Drug Development: A Comparative Study of Flavonols for Cytoprotection. Transl Stroke Res 2012. [DOI: 10.1007/978-1-4419-9530-8_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Abstract
Rodent models of focal cerebral ischemia have been extremely useful in elucidating pathomechanisms of human stroke. Most commonly, a monofilament is advanced through the internal carotid artery of rodents to occlude the origin of the middle cerebral artery thus leading to critical ischemia in the corresponding vascular territory. The filament can be removed after different occlusion times allowing reperfusion (transient middle cerebral artery occlusion (MCAO) model) or is left permanently within the internal carotid artery (permanent MCAO model) both mimicking clinical thromboembolic stroke in which the occluding clot may resolve spontaneously or after thrombolysis, or may persist. Overall, the occlusion time determines the extent of ischemic brain damage, but infarcts still grow during reperfusion, a process involving complex interactions between platelets, endothelial cells, immune cells, and the coagulation system.
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Karatas H, Erdener SE, Gursoy-Ozdemir Y, Gurer G, Soylemezoglu F, Dunn AK, Dalkara T. Thrombotic distal middle cerebral artery occlusion produced by topical FeCl(3) application: a novel model suitable for intravital microscopy and thrombolysis studies. J Cereb Blood Flow Metab 2011; 31:1452-60. [PMID: 21326267 PMCID: PMC3130330 DOI: 10.1038/jcbfm.2011.8] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 01/03/2011] [Accepted: 01/08/2011] [Indexed: 11/09/2022]
Abstract
Intravital or multiphoton microscopy and laser-speckle imaging have become popular because they allow live monitoring of several processes during cerebral ischemia. Available rodent models have limitations for these experiments; e.g., filament occlusion of the proximal middle cerebral artery (MCA) is difficult to perform under a microscope, whereas distal occlusion methods may damage the MCA and the peri-arterial cortex. We found that placement of a 10% FeCl(3)-soaked filter paper strip (0.3 × 1 mm(2)) on the duramater over the trunk of the distal MCA through a cranial window for 3 minutes induced intraarterial thrombus without damaging the peri-arterial cortex in the mouse. This caused a rapid regional cerebral blood flow decrease within 10 minutes and total occlusion of the MCA segment under the filter paper in 17±2 minutes, which resulted in a typical cortical infarct of 27±4 mm(3) at 24 hours and moderate sensorimotor deficits. There was no significant hemispheric swelling or hemorrhage or mortality at 24 hours. Reperfusion was obtained in half of the mice with tissue plasminogen activator, which allowed live monitoring of clot lysis along with restoration of tissue perfusion and MCA flow. In conclusion, this relatively simple and noninvasive stroke model is easy to perform under a microscope, making it suitable for live imaging and thrombolysis studies.
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Affiliation(s)
- Hulya Karatas
- Faculty of Medicine, Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Sefik Evren Erdener
- Faculty of Medicine, Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Yasemin Gursoy-Ozdemir
- Faculty of Medicine, Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Gunfer Gurer
- Faculty of Medicine, Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
| | - Figen Soylemezoglu
- Faculty of Medicine, Department of Pathology, Hacettepe University, Ankara, Turkey
| | - Andrew K Dunn
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA
| | - Turgay Dalkara
- Faculty of Medicine, Department of Neurology, Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey
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Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Kraft P, Barthel K, Schuhmann MK, Herrmann AM, Meuth SG, Stoll G, Meurer S, Schrewe A, Becker L, Gailus-Durner V, Fuchs H, Klopstock T, de Angelis MH, Jandeleit-Dahm K, Shah AM, Weissmann N, Schmidt HHHW. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 2010; 8. [PMID: 20877715 PMCID: PMC2943442 DOI: 10.1371/journal.pbio.1000479] [Citation(s) in RCA: 346] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Accepted: 07/28/2010] [Indexed: 02/07/2023] Open
Abstract
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
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Affiliation(s)
- Christoph Kleinschnitz
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
- * E-mail: (HHHWS); (CK)
| | - Henrike Grund
- Rudolf-Buchheim-Institut für Pharmakologie & Medizinische Klinik, Justus-Liebig-Universität, Gießen, Germany
| | - Kirstin Wingler
- Rudolf-Buchheim-Institut für Pharmakologie & Medizinische Klinik, Justus-Liebig-Universität, Gießen, Germany
- Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia
- Department of Pharmacology and Toxicology and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
- National Stroke Research Institute, Florey Neuroscience Institutes, Melbourne, Australia
| | - Melanie E. Armitage
- Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia
- National Stroke Research Institute, Florey Neuroscience Institutes, Melbourne, Australia
| | - Emma Jones
- Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia
| | - Manish Mittal
- Rudolf-Buchheim-Institut für Pharmakologie & Medizinische Klinik, Justus-Liebig-Universität, Gießen, Germany
| | - David Barit
- Baker IDI Heart and Diabetes Institute, Juvenile Diabetes Research Foundation (JDRF) International Center for Diabetic Complications Research, Melbourne, Australia
| | - Tobias Schwarz
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
| | - Christian Geis
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
| | - Peter Kraft
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
| | - Konstanze Barthel
- Abteilung Neurologie, Georg-August Universität Göttingen, Göttingen, Germany
| | - Michael K. Schuhmann
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
- Universitätsklinik Münster, Klinik und Poliklinik für Neurologie—Entzündliche Erkrankungen des Nervensystems und Neuroonkologie, Münster, Germany
| | - Alexander M. Herrmann
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
- Universitätsklinik Münster, Klinik und Poliklinik für Neurologie—Entzündliche Erkrankungen des Nervensystems und Neuroonkologie, Münster, Germany
| | - Sven G. Meuth
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
- Universitätsklinik Münster, Klinik und Poliklinik für Neurologie—Entzündliche Erkrankungen des Nervensystems und Neuroonkologie, Münster, Germany
| | - Guido Stoll
- Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany
| | - Sabine Meurer
- Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia
| | - Anja Schrewe
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
| | - Lore Becker
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
- Friedrich-Baur-Institut an der Neurologischen Klinik, Klinikum der Ludwig-Maximilians-Universität München, München, Germany
| | - Valérie Gailus-Durner
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
| | - Helmut Fuchs
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
| | - Thomas Klopstock
- Friedrich-Baur-Institut an der Neurologischen Klinik, Klinikum der Ludwig-Maximilians-Universität München, München, Germany
| | - Martin Hrabé de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
- Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany
| | - Karin Jandeleit-Dahm
- Baker IDI Heart and Diabetes Institute, Juvenile Diabetes Research Foundation (JDRF) International Center for Diabetic Complications Research, Melbourne, Australia
| | - Ajay M. Shah
- King's College London School of Medicine, The James Black Centre, Cardiovascular Division, London, United Kingdom
| | - Norbert Weissmann
- Rudolf-Buchheim-Institut für Pharmakologie & Medizinische Klinik, Justus-Liebig-Universität, Gießen, Germany
| | - Harald H. H. W. Schmidt
- Rudolf-Buchheim-Institut für Pharmakologie & Medizinische Klinik, Justus-Liebig-Universität, Gießen, Germany
- Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia
- Department of Pharmacology and Toxicology and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
- National Stroke Research Institute, Florey Neuroscience Institutes, Melbourne, Australia
- * E-mail: (HHHWS); (CK)
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Braeuninger S, Kleinschnitz C. Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. EXPERIMENTAL & TRANSLATIONAL STROKE MEDICINE 2009; 1:8. [PMID: 20150986 PMCID: PMC2820446 DOI: 10.1186/2040-7378-1-8] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Accepted: 11/25/2009] [Indexed: 11/10/2022]
Abstract
Rodent models of focal cerebral ischemia are essential tools in experimental stroke research. They have added tremendously to our understanding of injury mechanisms in stroke and have helped to identify potential therapeutic targets. A plethora of substances, however, in particular an overwhelming number of putative neuroprotective agents, have been shown to be effective in preclinical stroke research, but have failed in clinical trials. A lot of factors may have contributed to this failure of translation from bench to bedside. Often, deficits in the quality of experimental stroke research seem to be involved. In this article, we review the commonest rodent models of focal cerebral ischemia - middle cerebral artery occlusion, photothrombosis, and embolic stroke models - with their respective advantages and problems, and we address the issue of quality in preclinical stroke modeling as well as potential reasons for translational failure.
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Affiliation(s)
- Stefan Braeuninger
- Department of Neurology, Julius-Maximilians-Universitaet Wuerzburg, Josef-Schneider-Str. 11, 97080 Wuerzburg, Germany.
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Abstract
PURPOSE OF REVIEW Blood coagulation is a tightly regulated process, involving vascular endothelium, platelets, and plasma coagulation factors. Formation of fibrin involves a series of sequential proteolytic reactions, initiated by the 'extrinsic' and 'intrinsic' pathway of coagulation. As hereditary deficiency of factor XII, the protease that triggers the intrinsic pathway and the kallikrein-kinin system, is not associated with a bleeding disorder or other disease states, the physiological role of factor XII is unknown. RECENT FINDINGS Patient studies, genetically altered mouse models, and plasma assays analyzed functions of the factor XII-driven contact activation system for coagulation and inflammation. This review focuses on articles, which report phenotypization of animals deficient in the contact system proteins factor XII, factor XI and high-molecular-weight kininogen, as well as novel links between factor XII and edema formation, discovery of new in-vivo activators of factor XII, and functions of the factor XII downstream protease factor XI. SUMMARY Recent studies improved understanding of the factor XII-driven contact system in hemostasis, thrombosis, and inflammation. Studies in mouse models revealed that deficiency in contact system proteins protects from arterial thrombus formation, but does not affect hemostasis. Targeting contact system proteins offers new opportunities for safe anticoagulation associated with minimal bleeding risk. Furthermore, targeting factor XII activity provides an opportunity to treat edema formation.
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Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008; 112:3555-62. [DOI: 10.1182/blood-2008-04-144758] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
In ischemic stroke, treatment options are limited. Therapeutic thrombolysis is restricted to the first few hours after stroke, and the utility of current platelet aggregation inhibitors, including GPIIb/IIIa receptor antagonists, and anticoagulants is counterbalanced by the risk of intracerebral bleeding complications. Numerous attempts to establish neuroprotection in ischemic stroke have been unfruitful. Thus, there is strong demand for novel treatment strategies. Major advances have been made in understanding the molecular functions of platelet receptors such as glycoprotein Ib (GPIb) and GPVI and their downstream signaling pathways that allow interference with their function. Inhibition of these receptors in the mouse stroke model of transient middle cerebral artery occlusion prevented infarctions without increasing the risk of intracerebral bleeding. Similarly, it is now clear that the intrinsic coagulation factor XII (FXII) and FXI play a functional role in thrombus formation and stabilization during stroke: their deficiency or blockade protects from cerebral ischemia without overtly affecting hemostasis. Based on the accumulating evidence that thrombus formation and hemostasis are not inevitably linked, new concepts for prevention and treatment of ischemic stroke may eventually emerge without the hazard of severe bleeding complications. This review discusses recent advances related to antithrombotic strategies in experimental stroke research.
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Stoll G, Bendszus M. Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging. Neuroscience 2008; 158:1151-60. [PMID: 18651996 DOI: 10.1016/j.neuroscience.2008.06.045] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2008] [Revised: 06/19/2008] [Accepted: 06/20/2008] [Indexed: 11/17/2022]
Abstract
Inflammation plays a central role in the pathophysiology of numerous disorders of the nervous system, but is also pivotal for repair processes like peripheral nerve regeneration. In this review we summarize recent advances in cellular magnetic resonance imaging (MRI) while nuclear imaging methods to visualize neuroinflammation are covered by Wunder et al. [Wunder A, Klohs J, Dirnagl U (2009) Non-invasive imaging of central nervous system inflammation with nuclear and optical imaging. Neuroscience, in press]. Use of iron oxide-contrast agents allows assessment of inflammatory processes in living organisms. Upon systemic application, circulating small (SPIO) and ultrasmall particles of iron oxide (USPIO) are preferentially phagocytosed by monocytes before clearance within the reticuloendothelial system of the liver, spleen and lymph nodes. Upon acute migration into the diseased nervous system these iron oxide-laden macrophages become visible on MRI by the superparamagnetic effects of iron oxide resulting in a signal loss on T2-w and/or bright contrast on T1-w MRI. There is an ongoing controversy, however, to what extent SPIO/USPIO also diffuses passively into the brain after disruption of the blood-brain barrier pretending macrophage invasion. Other confounding factors include circulating SPIO/USPIO particles within the blood pool, local hemorrhages, and intrinsic iron oxide-loading of phagocytes. These uncertainties can be overcome by in vitro preloading of cells with iron oxide contrast agents and consecutive systemic application into animals. Iron oxide-contrast-enhanced MRI allowed in vivo visualization of cellular inflammation during wallerian degeneration, experimental autoimmune neuritis and encephalomyelitis, and stroke in rodents, but also in patients with multiple sclerosis and stroke. Importantly, cellular MRI provides additional information to gadolinium-DTPA-enhanced MRI since cellular infiltration and breakdown of the blood-brain barrier are not closely linked. Coupling of antibodies to iron oxide particles opens new avenues for molecular MRI and has been successfully used to visualize cell adhesion molecules guiding inflammation.
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Affiliation(s)
- G Stoll
- Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany.
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