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Justić H, Barić A, Ratko M, Šimunić I, Radmilović M, Pongrac M, Škokić S, Dobrivojević Radmilović M. The temporal dynamic of bradykinin type 2 receptor effects reveals its neuroprotective role in the chronic phase of cerebral and retinal ischemic injury. J Cereb Blood Flow Metab 2025; 45:153-170. [PMID: 39113417 PMCID: PMC11572167 DOI: 10.1177/0271678x241270241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/31/2024] [Accepted: 06/17/2024] [Indexed: 11/20/2024]
Abstract
The activation of the bradykinin type 2 receptor is intricately involved in acute post-ischemic inflammatory responses. However, its precise role in different stages of ischemic injury, especially in the chronic phase, remains unclear. Following simultaneous cerebral and retinal ischemia, bradykinin type 2 receptor knockout mice and their controls were longitudinally monitored for 35 days via magnetic resonance imaging, fundus photography, fluorescein angiography, behavioral assessments, vascular permeability measurements, and immunohistochemistry, as well as glycemic status assessments. Without impacting the lesion size, bradykinin type 2 receptor deficiency reduced acute cerebral vascular permeability preventing the loss of pericytes and tight junctions. In the chronic phase of ischemia, however, it resulted in increased astrogliosis and cortical neuronal loss, as well as higher functional deficits. The retinal findings demonstrated a similar pattern. Bradykinin type 2 receptor deficiency delayed, but exacerbated the development of retinal necrosis, increased subacute vascular permeability, and promoted retinal ganglion cell loss in the chronic phase of ischemia. This investigation sheds light on the temporal dynamic of bradykinin type 2 receptor effects in ischemia, pointing to a therapeutic potential in the subacute and chronic phases of ischemic injury.
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Affiliation(s)
- Helena Justić
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Anja Barić
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Martina Ratko
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Iva Šimunić
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Marin Radmilović
- Sestre milosrdnice University Hospital Center, Department of Ophthalmology, Zagreb, Croatia
| | - Marta Pongrac
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Siniša Škokić
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Marina Dobrivojević Radmilović
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
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Zhou J, Zhang L, Peng J, Zhang X, Zhang F, Wu Y, Huang A, Du F, Liao Y, He Y, Xie Y, Gu L, Kuang C, Ou W, Xie M, Tu T, Pang J, Zhang D, Guo K, Feng Y, Yin S, Cao Y, Li T, Jiang Y. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab 2024; 36:2054-2068.e14. [PMID: 38906140 DOI: 10.1016/j.cmet.2024.05.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 09/11/2023] [Accepted: 05/23/2024] [Indexed: 06/23/2024]
Abstract
Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptor that regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 has been previously implicated in the pathogenesis of neurodegenerative disorders, but there are inconsistencies in its functions. Therefore, whether and how LRP1 maintains brain homeostasis remains to be clarified. Here, we report that astrocytic LRP1 promotes astrocyte-to-neuron mitochondria transfer by reducing lactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucose uptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocytic LRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in a mouse model of ischemic stroke. Furthermore, we examined lactate levels in human patients with stroke. Cerebrospinal fluid (CSF) lactate was elevated in stroke patients and inversely correlated with astrocytic mitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.
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Affiliation(s)
- Jian Zhou
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Lifang Zhang
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Jianhua Peng
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Academician (Expert) Workstation of Sichuan Province, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Xianhui Zhang
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Fan Zhang
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yuanyuan Wu
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - An Huang
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Fengling Du
- Department of Neonatology, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yuyan Liao
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yijing He
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yuke Xie
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Long Gu
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Chenghao Kuang
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Wei Ou
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Maodi Xie
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tianqi Tu
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Jinwei Pang
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Dingkun Zhang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kecheng Guo
- Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yue Feng
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Department of Nuclear Medicine, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Shigang Yin
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Yang Cao
- Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Tao Li
- Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yong Jiang
- Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
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Hu S, Wang D, Liu W, Wang Y, Chen J, Cai X. Apelin receptor dimer: Classification, future prospects, and pathophysiological perspectives. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167257. [PMID: 38795836 DOI: 10.1016/j.bbadis.2024.167257] [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: 02/08/2024] [Revised: 04/25/2024] [Accepted: 05/17/2024] [Indexed: 05/28/2024]
Abstract
Apelin receptor (APJ), a member of the class A family of G protein-coupled receptor (GPCR), plays a crucial role in regulating cardiovascular and central nervous systems function. APJ influences the onset and progression of various diseases such as hypertension, atherosclerosis, and cerebral stroke, making it an important target for drug development. Our preliminary findings indicate that APJ can form homodimers, heterodimers, or even higher-order oligomers, which participate in different signaling pathways and have distinct functions compared with monomers. APJ homodimers can serve as neuroprotectors against, and provide new pharmaceutical targets for vascular dementia (VD). This review article aims to summarize the structural characteristics of APJ dimers and their roles in physiology and pathology, as well as explore their potential pharmacological applications.
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Affiliation(s)
- Shujuan Hu
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261042, PR China
| | - Dexiu Wang
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261042, PR China
| | - Wenkai Liu
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261042, PR China
| | - Yixiang Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261042, PR China
| | - Jing Chen
- Neurobiology Institute, Jining Medical University, Jining, Shandong 272067, PR China; Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
| | - Xin Cai
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261042, PR China.
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Jin ZL, Gao WY, Guo F, Liao SJ, Hu MZ, Yu T, Yu SZ, Shi Q. Ring Finger Protein 146-mediated Long-chain Fatty-acid-Coenzyme a Ligase 4 Ubiquitination Regulates Ferroptosis-induced Neuronal Damage in Ischemic Stroke. Neuroscience 2023; 529:148-161. [PMID: 37591333 DOI: 10.1016/j.neuroscience.2023.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/19/2023]
Abstract
Ischemic stroke (IS) is one of the leading causes of disability and death worldwide. Long-chain fatty-acid-coenzyme A ligase 4 (ACSL4) is a critical isozyme for ferroptosis that participates in the progression of IS. RING finger protein 146 (RNF146) is an E3 ligase predicted to interact with ACSL4 and regulated by activating transcription factor 3 (ATF3). The molecular mechanism of the RNF146/ACSL4 axis in IS is still unclear. Oxygen-glucose deprivation/reperfusion (OGD/R) treatment was used as the in vitro model, and middle cerebral artery occlusion (MCAO) mice were established for the in vivo model for IS. The protein level of ACSL4 was monitored by Western blot during ischemic injury. RNF146 was overexpressed in vitro and in vivo. The interaction of RNF146 and ACSL4 was determined by co-immunoprecipitation (Co-IP) assay. Chromatin immunoprecipitation (ChIP) assay and luciferase assay were utilized to determine the regulation of ATF3 on RNF146. Ferroptosis was evaluated by the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), Fe2+, and protein levels of related genes including ACSL4, SLC7A11, and GPX4. ACSL4 was downregulated upon OGD treatment and then increased by re-oxygenation. RNF146 was responsible for the ubiquitination and degradation of ACSL4 protein. RNF146 overexpression could prevent the stimulation of OGD/R-induced LDH, MDA, and Fe2+ levels and ferroptosis-related gene expression. ATF3 could activate the transcription and expression of RNF146, leading to the inhibition of OGD/R-induced neuron ferroptosis. The ATF3-mediated RNF146 could alleviate neuronal damage in IS by regulating ACSL4 ubiquitination and ferroptosis, providing a novel theoretical basis for exploring therapeutic targets and strategies.
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Affiliation(s)
- Zheng-Long Jin
- Department of Neurology, Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University, Jiangmen 529000, Guangdong Province, PR China
| | - Wen-Ying Gao
- Department of TCM Pediatrics, Jiangmen Maternal and Child Health Hospital, Jiangmen 529030, Guangdong Province, PR China
| | - Fu Guo
- Department of Neurology, Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University, Jiangmen 529000, Guangdong Province, PR China
| | - Shao-Jun Liao
- Department of Spine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, PR China
| | - Ming-Zhe Hu
- Department of Neurology, The Affiliated Hospital of Shandong University of TCM, Jinan 250000, Shandong Province, PR China
| | - Tao Yu
- Department of Neurology, Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University, Jiangmen 529000, Guangdong Province, PR China
| | - Shang-Zhen Yu
- Department of Neurology, Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University, Jiangmen 529000, Guangdong Province, PR China
| | - Qing Shi
- Department of Neurology, Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University, Jiangmen 529000, Guangdong Province, PR China.
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Metwally SAH, Paruchuri SS, Yu L, Capuk O, Pennock N, Sun D, Song S. Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke. Int J Mol Sci 2023; 24:13289. [PMID: 37686096 PMCID: PMC10488118 DOI: 10.3390/ijms241713289] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H+ extrusion protein Na+/H+ exchanger-1 (NHE1) plays an important role in stroke-induced inflammation and white matter injury. In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. Post-stroke HOE642 and Rimeporide treatments accelerated motor and cognitive function recovery without affecting the initial ischemic infarct, neuronal damage, or reactive astrogliosis. However, the delayed administration of NHE1 blockers after ischemic stroke significantly reduced microglial inflammatory activation while enhanced oligodendrogenesis and white matter myelination, with an increased proliferation and decreased apoptosis of the oligodendrocytes. Our findings suggest that NHE1 protein plays an important role in microglia-mediated inflammation and white matter damage. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy.
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Affiliation(s)
- Shamseldin Ayman Hassan Metwally
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Satya Siri Paruchuri
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Lauren Yu
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Okan Capuk
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Nicholas Pennock
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Dandan Sun
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15213, USA
| | - Shanshan Song
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; (S.A.H.M.); (S.S.P.); (L.Y.); (O.C.); (N.P.)
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15213, USA
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Delgardo M, Tang AJ, Tudor T, Pascual-Leone A, Connolly ES. Role of gC1qR as a modulator of endothelial cell permeability and contributor to post-stroke inflammation and edema formation. Front Cell Neurosci 2023; 17:1123365. [PMID: 37383840 PMCID: PMC10294424 DOI: 10.3389/fncel.2023.1123365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. A serious risk of acute ischemic stroke (AIS) arises after the stroke event, due to inflammation and edema formation. Inflammation and edema in the brain are mediated by bradykinin, the formation of which is dependent upon a multi-ligand receptor protein called gC1qR. There are currently no preventive treatments for the secondary damage of AIS produced by inflammation and edema. This review aims to summarize recent research regarding the role of gC1qR in bradykinin formation, its role in inflammation and edema following ischemic injury, and potential therapeutic approaches to preventing post-stroke inflammation and edema formation.
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Vespakinin-M, a natural peptide from Vespa magnifica, promotes functional recovery in stroke mice. Commun Biol 2022; 5:74. [PMID: 35058552 PMCID: PMC8776894 DOI: 10.1038/s42003-022-03024-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Acute ischemic stroke triggers complex systemic pathological responses for which the exploration of drug resources remains a challenge. Wasp venom extracted from Vespa magnifica (Smith, 1852) is most commonly used to treat rheumatoid arthritis as well as neurological disorders. Vespakinin-M (VK), a natural peptide from wasp venom, has remained largely unexplored for stroke. Herein, we first confirmed the structure, stability, toxicity and distribution of VK as well as its penetration into the blood–brain barrier. VK (150 and 300 µg/kg, i.p.) was administered to improve stroke constructed by middle cerebral artery occlusion in mice. Our results indicate that VK promote functional recovery in mice after ischemia stroke, including an improvement of neurological impairment, reduction of infarct volume, maintenance of blood-brain barrier integrity, and an obstruction of the inflammatory response and oxidative stress. In addition, VK treatment led to reduced neuroinflammation and apoptosis associated with the activation of PI3K–AKT and inhibition of IκBα–NF-κB signaling pathways. Simultaneously, we confirmed that VK can combine with bradykinin receptor 2 (B2R) as detected by molecular docking, the B2R antagonist HOE140 could counteract the neuro-protective effects of VK on stroke in mice. Overall, targeting the VK–B2R interaction can be considered as a practical strategy for stroke therapy. Zhao et al establish the structure, stability, toxicity and distribution of vespakinin-M (VK) as well as its penetration into the blood–brain barrier in mice. They go on to show that VK promotes functional recovery in mice after ischemia stroke and shed light on the potential underlying mechanisms, which together indicates the potential therapeutic value of targeting VK in stroke therapy.
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Bhat EA, Sajjad N, Banawas S, Khan J. Human CALHM5: Insight in large pore lipid gating ATP channel and associated neurological pathologies. Mol Cell Biochem 2021; 476:3711-3718. [PMID: 34089472 DOI: 10.1007/s11010-021-04198-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 05/27/2021] [Indexed: 10/21/2022]
Abstract
Recently calcium homeostasis modulators (CALHMs) are identified as ATP release channels play crucial role in functioning of neurons including gustatory signaling and neuronal excitability. Pathologies of Alzheimer's disease and depression have been associated with the dysfunction of CALHMs. Recently, CALHMs has been emerged as an important therapeutic research particularly in neurobiological studies. CALHM1 is most extensively studied among CALHMs and is an ATP and ion channel that is activated by membrane depolarization or removal of extracellular Ca2+. Despite the emerged role of CALHM5 shown by an recently assembled data; however, the neuronal function remains obscure until the first Cryo-EM structure of CALHM5 was recently solved by various research group which acts as a template to study the hidden functional properties of the CALHM5 protein based on structure function mechanism. It provides insight in some of the different pathophysiological roles. CALHM5 structure showed an abnormally large pore channel structure assembled as an undecamer with four transmembrane helices (TM1-TM4), an N-terminal helix (NTH), an extracellular loop region and an intracellular C-terminal domain (CTD) that consists of three α-helices CH1-3. The TM1 and NTH were always poorly defined among all CALHMs; however, these regions were well defined in CALHM5 channel structure. In this context, this review will provide insight in structure, function and mechanism to understand its significant role in pathological diseases particularly in Alzheimer's disease. Moreover, it focuses on CALHM5 structure and recent associated properties based on Cryo-EM research.
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Affiliation(s)
- Eijaz Ahmed Bhat
- Life Science Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, P.R. China. .,Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
| | - Nasreena Sajjad
- Department of Biochemistry, University of Kashmir, Hazratbal, Jammu and Kashmir, India
| | - Saeed Banawas
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Kingdom of Saudi Arabia. .,Health and Basic Sciences Research Center, Majmaah University, Majmaah, 11952, Saudi Arabia. .,Departments of Biomedical Sciences, Oregon State University, Corvallis, OR, 97331, USA.
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Kingdom of Saudi Arabia.,Health and Basic Sciences Research Center, Majmaah University, Majmaah, 11952, Saudi Arabia
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Yu R, Kim NS, Li Y, Jeong JY, Park SJ, Zhou B, Oh WJ. Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice. Transl Stroke Res 2021; 13:142-159. [PMID: 33978913 PMCID: PMC8766426 DOI: 10.1007/s12975-021-00914-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 12/18/2022]
Abstract
Post-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Recently, axon guidance molecules were revealed as key players in injured vessel remodeling. One such molecule, Semaphorin 3E (Sema3E), and its receptor, Plexin-D1, control vascular development by regulating vascular endothelial growth factor (VEGF) signaling. In this study, using a mouse model of transient brain infarction, we aimed to investigate whether Sema3E-Plexin-D1 signaling was involved in cerebrovascular remodeling after ischemic injury. We found that ischemic damage rapidly induced Sema3e expression in the neurons of peri-infarct regions, followed by Plexin-D1 upregulation in remodeling vessels. Interestingly, Plexin-D1 reemergence was concurrent with brain vessels entering an active angiogenic process. In line with this, Plxnd1 ablation worsened neurological deficits, infarct volume, neuronal survival rate, and blood flow recovery. Furthermore, reduced and abnormal vascular morphogenesis was caused by aberrantly increased VEGF signaling. In Plxnd1 knockout mice, we observed significant extravasation of intravenously administered tracers in the brain parenchyma, junctional protein downregulation, and mislocalization in regenerating vessels. This suggested that the absence of Sema3E-Plexin-D1 signaling is associated with blood–brain barrier (BBB) impairment. Finally, the abnormal behavioral performance, aberrant vascular phenotype, and BBB breakdown defects in Plxnd1 knockout mice were restored following the inhibition of VEGF signaling during vascular remodeling. These findings demonstrate that Sema3E-Plexin-D1 signaling can promote functional recovery by downregulating VEGF signaling in the injured adult brain.
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Affiliation(s)
- Ri Yu
- Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.,College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Nam-Suk Kim
- Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Yan Li
- Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Jin-Young Jeong
- Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.,Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, 42988, Republic of Korea
| | - Sang-Joon Park
- College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Bin Zhou
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Won-Jong Oh
- Neurovascular Biology Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
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10
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Kinins and Kinin Receptors in Cardiovascular and Renal Diseases. Pharmaceuticals (Basel) 2021; 14:ph14030240. [PMID: 33800422 PMCID: PMC8000381 DOI: 10.3390/ph14030240] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 12/11/2022] Open
Abstract
This review addresses the physiological role of the kallikrein–kinin system in arteries, heart and kidney and the consequences of kallikrein and kinin actions in diseases affecting these organs, especially ischemic and diabetic diseases. Emphasis is put on pharmacological and genetic studies targeting kallikrein; ACE/kininase II; and the two kinin receptors, B1 (B1R) and B2 (B2R), distinguished through the work of Domenico Regoli and his collaborators. Potential therapeutic interest and limitations of the pharmacological manipulation of B1R or B2R activity in cardiovascular and renal diseases are discussed. This discussion addresses either the activation or inhibition of these receptors, based on recent clinical and experimental studies.
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11
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Cui Y, Zhang Y, Zhao X, Shao L, Liu G, Sun C, Xu R, Zhang Z. ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun 2021; 93:312-321. [PMID: 33444733 DOI: 10.1016/j.bbi.2021.01.003] [Citation(s) in RCA: 337] [Impact Index Per Article: 84.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 12/13/2020] [Accepted: 01/06/2021] [Indexed: 12/22/2022] Open
Abstract
Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme for polyunsaturated fatty acids (PUFAs) metabolism that dictates ferroptosis sensitivity. The role of ACSL4 in the progression of ischemic stroke is unclear. Here, we found that ACSL4 expression was suppressed in the early phase of ischemic stroke and this suppression was induced by HIF-1α. Knockdown of ACSL4 protected mice against brain ischemia, whereas, forced overexpression of ACSL4 exacerbated ischemic brain injury. ACSL4 promoted neuronal death via enhancing lipid peroxidation, a marker of ferroptosis. Moreover, knockdown of ACSL4 inhibited proinflammatory cytokine production in microglia. These data identify ACSL4 as a novel regulator of neuronal death and neuroinflammation, and interventions of ACSL4 expression may provide a potential therapeutic target in ischemic stroke.
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Affiliation(s)
- Yu Cui
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Ningxia Road 308, Qingdao 266071, Shandong, China
| | - Yan Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China
| | - Xiaolong Zhao
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China
| | - Liming Shao
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China
| | - Guoping Liu
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China
| | - Chengjian Sun
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China
| | - Rui Xu
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China.
| | - Zhaolong Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao 266000, Shandong, China.
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12
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Wu X, Lin L, Qin J, Wang L, Wang H, Zou Y, Zhu X, Hong Y, Zhang Y, Liu Y, Xin C, Xu S, Ye S, Zhang J, Xiong Z, Zhu L, Li H, Chen J, She Z. CARD3 Promotes Cerebral Ischemia-Reperfusion Injury Via Activation of TAK1. J Am Heart Assoc 2020; 9:e014920. [PMID: 32349637 PMCID: PMC7428569 DOI: 10.1161/jaha.119.014920] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/23/2020] [Indexed: 02/07/2023]
Abstract
Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia-reperfusion (I-R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time-dependent manner during I-R injury. Further animal study revealed that, relative to control mice, CARD3-knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron-specific CARD3-overexpressing transgenic (CARD3-TG) mice exhibited increased I-R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor-β-activated kinase 1) was enhanced in CARD3-TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3-TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z-7-oxozeaenol. Conclusions These results indicate that CARD3 promotes I-R injury via activation of TAK1, which not only reveals a novel regulatory axis of I-R induced brain injury but also provides a new potential therapeutic approach for I-R injury.
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Affiliation(s)
- Xiaolin Wu
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Lijin Lin
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Juan‐Juan Qin
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Lifen Wang
- Operating TheaterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hao Wang
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Yichun Zou
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Xueyong Zhu
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Ying Hong
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Yan Zhang
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Ye Liu
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Can Xin
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Shuangxiang Xu
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Shengda Ye
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Jianjian Zhang
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Zhongwei Xiong
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
| | - Lihua Zhu
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Hongliang Li
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
| | - Jincao Chen
- Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanPR China
- Department of NeurosurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhi‐Gang She
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPR China
- Basic Medical SchoolWuhan UniversityWuhanPR China
- Institute of Model Animals of Wuhan UniversityWuhanPR China
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13
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Liu S, Jin R, Xiao AY, Zhong W, Li G. Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke. Brain Behav Immun 2019; 82:13-24. [PMID: 31356925 PMCID: PMC6800638 DOI: 10.1016/j.bbi.2019.07.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/15/2019] [Accepted: 07/25/2019] [Indexed: 01/26/2023] Open
Abstract
White matter damage is an important contributor to long-term neurological deficit after stroke. Our previous study has shown that inhibition of CD147 ameliorates acute ischemic stroke in mice. In this study, we aimed to investigate whether inhibition of CD147 promotes white matter repair and long-term functional recovery after ischemic stroke.Male adult C57BL/6 mice were subjected to transient (1-h) middle cerebral artery occlusion (tMCAO). Anti-CD147 function-blocking antibody (αCD147) was injected intravenously once daily for 3 days beginning 4 h after onset of ischemia. Sensorimotor and cognitive functions were evaluated up to 28 days after stroke. We found that αCD147 treatment not only prevented neuronal and oligodendrocyte cell death in the acute phase, but also profoundly protected white matter integrity and reduced brain atrophy and tissue loss in the late phase, leading to improved sensorimotor and cognitive functions for at least 28 days after stroke. Mechanistically, we found that αCD147 treatment increased the number of proliferating NG2(+)/PDGFRα(+) oligodendrocyte precursor cells (OPCs) and newly generated mature APC(+)/Sox10(+) oligodendrocytes after stroke, possibly through upregulation of SDF-1/CXCR4 axis in OPCs. In conclusion, inhibition of CD147 promotes long-term functional recovery after stroke, at least in part, by enhancing oligodendrogenesis and white matter repair.
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Affiliation(s)
- Shan Liu
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Rong Jin
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Adam Y Xiao
- The Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA
| | - Wei Zhong
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Guohong Li
- From the Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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14
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Sörensen-Zender I, Chen R, Rong S, David S, Melk A, Haller H, Schmitt R. Binding to carboxypeptidase M mediates protective effects of fibrinopeptide Bβ 15-42. Transl Res 2019; 213:124-135. [PMID: 31401267 DOI: 10.1016/j.trsl.2019.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 02/03/2023]
Abstract
During fibrinolysis a 28-amino-acid peptide is generated besides other degradation products of fibrin. This peptide, called Bβ15-42, which is cleaved by plasmin from the end of the fibrin Bβ-chain, is protective in myocardial and renal ischemia/reperfusion injury and improves the outcome in experimental sepsis. Bβ15-42 has been shown to mediate different beneficial effects in endothelial cells through binding to vascular endothelial-cadherin. Here, we provide in vitro and in vivo evidence that Bβ15-42 has additional cell protective activity in tubular cells, which is caused by a distinct mechanism. As vascular endothelial-cadherin is not expressed by tubular cells we used ligand-receptor capture technology LRC-TriCEPS to search for tubular cell surface receptors and identified carboxypeptidase M (CBPM) as a novel binding partner of Bβ15-42. Silencing CBPM with siRNA reduced the protective potential of Bβ15-42 against tubular cell stress. Bβ15-42 inhibited the enzymatic activity of CBPM and modified the impact of CBPM on bradykinin signaling. We conclude that beneficial properties of Bβ15-42 are not restricted to endothelial cells but are also active in epithelial cells where cytoprotection depends on CBPM binding.
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Affiliation(s)
| | - Rongjun Chen
- Department of Nephrology and Hypertension, Medical School Hannover, Germany
| | - Song Rong
- Department of Nephrology and Hypertension, Medical School Hannover, Germany
| | - Sascha David
- Department of Nephrology and Hypertension, Medical School Hannover, Germany
| | - Anette Melk
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Medical School Hannover, Germany
| | - Roland Schmitt
- Department of Nephrology and Hypertension, Medical School Hannover, Germany
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15
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Li X, Cheng S, Hu H, Zhang X, Xu J, Wang R, Zhang P. Progranulin protects against cerebral ischemia-reperfusion (I/R) injury by inhibiting necroptosis and oxidative stress. Biochem Biophys Res Commun 2019; 521:569-576. [PMID: 31679689 DOI: 10.1016/j.bbrc.2019.09.111] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 09/26/2019] [Indexed: 10/25/2022]
Abstract
Ischemic stroke is a leading cause of mortality and disability worldwide. Nevertheless, its molecular mechanisms have not yet been adequately illustrated. Progranulin (PGRN) is a secreted glycoprotein with pleiotropic functions. In the present study, we found that PGRN expression was markedly reduced in mice after stroke onset through middle cerebral artery occlusion (MCAO). We also showed that necroptosis was a mechanism underlying cerebral I/R injury. Importantly, PGRN knockdown in vivo significantly promoted the infarction volume and neurological deficits scores in mice after MCAO surgery. Necroptosis induced by MCAO was further accelerated by PGRN knockdown, as evidenced by the promoted expression of phosphorylated receptor-interacting protein (RIP) 1 kinase (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL), which was accompanied with increased expression of cleaved Caspase-8 and Caspase-3. However, PGRN over-expression was neuroprotective. Additionally, PGRN-regulated ischemic stroke was related to ROS accumulation that MCAO-mice with PGRN knockdown exhibited severe oxidative stress, as proved by the aggravated malondialdehyde (MDA) and lipid peroxidation (LPO) contents, and the decreased superoxide dismutase (SOD) activity. However, PGRN over-expression in mice with cerebral ischemia showed anti-oxidative effects. Finally, PGRN was found to attenuate oxidative damage partly via its regulatory effects on necroptosis. Therefore, promoting PGRN expression could reduced cerebral I/R-induced brain injury by suppressing neroptosis and associated reactive oxygen species (ROS) production. These data elucidated that PGRN might provide an effective therapeutic treatment for ischemic stroke.
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Affiliation(s)
- Xiaogang Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Shaoli Cheng
- Basic Medical Experimental Teaching Center, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Hao Hu
- Basic Medical Experimental Teaching Center, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xiaotian Zhang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Jiehua Xu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Rui Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Pengbo Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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16
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Ji B, Wang Q, Xue Q, Li W, Li X, Wu Y. The Dual Role of Kinin/Kinin Receptors System in Alzheimer's Disease. Front Mol Neurosci 2019; 12:234. [PMID: 31632239 PMCID: PMC6779775 DOI: 10.3389/fnmol.2019.00234] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 09/13/2019] [Indexed: 11/30/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive spatial disorientation, learning and memory deficits, responsible for 60%–80% of all dementias. However, the pathological mechanism of AD remains unknown. Numerous studies revealed that kinin/kinin receptors system (KKS) may be involved in the pathophysiology of AD. In this review article, we summarized the roles of KKS in neuroinflammation, cerebrovascular impairment, tau phosphorylation, and amyloid β (Aβ) generation in AD. Moreover, we provide new insights into the mechanistic link between KKS and AD, and highlight the KKS as a potential therapeutic target for AD treatment.
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Affiliation(s)
- Bingyuan Ji
- Neurobiology Institute, School of Mental Health, Jining Medical University, Jining, China
| | - Qinqin Wang
- Neurobiology Institute, School of Mental Health, Jining Medical University, Jining, China
| | - Qingjie Xue
- Department of Pathogenic Biology, Jining Medical University, Jining, China
| | - Wenfu Li
- Neurobiology Institute, School of Mental Health, Jining Medical University, Jining, China
| | - Xuezhi Li
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.,Shandong Key Laboratory of Behavioral Medicine, School of Mental Health, Jining Medical University, Jining, China
| | - Yili Wu
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.,Shandong Key Laboratory of Behavioral Medicine, School of Mental Health, Jining Medical University, Jining, China
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17
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Liu Q, Zhang Y. PRDX1 enhances cerebral ischemia-reperfusion injury through activation of TLR4-regulated inflammation and apoptosis. Biochem Biophys Res Commun 2019; 519:453-461. [PMID: 31526567 DOI: 10.1016/j.bbrc.2019.08.077] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 08/13/2019] [Indexed: 02/07/2023]
Abstract
Stroke is still a leading cause of death across the world. Despite various signals or molecules that contribute to the pathophysiological process have been investigated, the exact molecular mechanisms revealing stroke damage still remain to be explored. Peroxiredoxin 1 (PRDX1) has been identified as a stress-induced macrophage redox protein with multiple functions. Although PRDX1 is a critical factor related to the regulation of immunity, inflammation, apoptosis and oxidative stress, its effects on cerebral ischemia-reperfusion (I-R) injury were presently unclear. In the study, by using a mouse model of I-R injury, we found that PRDX1 expression was up-regulated during I-R injury in a time-dependent manner. Additionally, PRDX1-knockout mice showed reduced infarction area and alleviated neuropathological scores with decreased brain water contents. Furthermore, cell death and inflammatory response in mice with cerebral I-R injury were markedly attenuated by PRDX1 knockout, which were associated with the blockage of Caspase-3 and nuclear factor-κB (NF-κB) signaling pathways. Mechanistically, PRDX1-regulated cerebral I-R injury was through the promotion of toll-like receptor-4 (TLR4), as proved by the evidence that TLR4 suppression abrogated the exacerbated effect of TLR4 on inflammatory response and apoptosis in oxygen and glucose deprivation (OGD)-treated primary microglial cells. These data demonstrated that PRDX1 contributed to cerebral stroke by interacting with TLR4, providing an effective therapeutic approach for cerebral I-R injury.
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Affiliation(s)
- Qiang Liu
- Department of Neurology, Yan'an University Affiliated Hospital, Yan'an, Shannxi, 716000, China
| | - Yuan Zhang
- Department of EMG Evoked Potential Chamber, Heze Municipal Hospital, Shandong Province, Heze City, Shandong Province, 274000, China.
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18
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Wang L, Wu D, Xu Z. USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the inhibition of TAK1 signaling. Biochem Biophys Res Commun 2019; 516:1272-1278. [PMID: 31301769 DOI: 10.1016/j.bbrc.2019.06.042] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 06/08/2019] [Indexed: 12/11/2022]
Abstract
Cerebral ischemia is a leading cause of death and long-term disability in the world. Multiple signaling pathways play essential roles in the process. Therefore, identifying the unknown important modulators of these pathways may supply promising therapeutic targets for the treatment of cerebral ischemia. Ubiquitin-specific protease 10 (USP10) is a member of the ubiquitin-specific protease family of cysteine proteases with enzymatic activity to cleave ubiquitin from ubiquitin-conjugated protein substrates, and is involved in multiple pathologies. However, the effects of USP10 in cerebral ischemia-reperfusion (I/R) injury remain unclear. Here, we reported that USP10 expression was markedly decreased in wild type (WT) mice after cerebral I/R injury. USP10 knockout (KO) mice showed significantly elevated infarct size and the neurological deficit score after cerebral I/R operation. USP10 deletion also promoted inflammatory response in ischemic penumbra of cortical regions by further accelerating nuclear factor κB (NF-κB) signaling pathway. In addition, apoptosis was markedly induced in USP10-knockout mice after cerebral I/R injury compared to the WT mice. The c-Jun N-terminal kinase-mitogen-activated protein kinase (JNK-MAPK) signaling induced by cerebral I/R injury was further aggravated in USP10-KO mice. Finally, USP10 was found to display protective effects against cerebral I/R injury through direct interaction with transforming growth factor β-activated kinase 1 (TAK1). Thus, USP10 might be a protective factor in cerebral I/R injury. Modulation of USP10/TAK1 might be a promising strategy to prevent this pathological process.
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Affiliation(s)
- Lei Wang
- Department of Neurology, The Second People's Hospital of Dongying, Shandong Province, 257335, China
| | - Dongchuan Wu
- Department of Neurology, People's Hospital of Dongying City, Dongying, Shandong Province, 257091, China
| | - Zongrong Xu
- Department of Neurology, People's Hospital of Dongying City, Dongying, Shandong Province, 257091, China.
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19
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Ma Z, Dong Q, Lyu B, Wang J, Quan Y, Gong S. The expression of bradykinin and its receptors in spinal cord ischemia-reperfusion injury rat model. Life Sci 2019; 218:340-345. [DOI: 10.1016/j.lfs.2018.12.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 12/11/2018] [Accepted: 12/19/2018] [Indexed: 11/15/2022]
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20
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Alexander-Curtis M, Pauls R, Chao J, Volpi JJ, Bath PM, Verdoorn TA. Human tissue kallikrein in the treatment of acute ischemic stroke. Ther Adv Neurol Disord 2019; 12:1756286418821918. [PMID: 30719079 PMCID: PMC6348491 DOI: 10.1177/1756286418821918] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/24/2018] [Indexed: 01/08/2023] Open
Abstract
Acute ischemic stroke (AIS) remains a major cause of death and disability throughout the world. The most severe form of stroke results from large vessel occlusion of the major branches of the Circle of Willis. The treatment strategies currently available in western countries for large vessel occlusion involve rapid restoration of blood flow through removal of the offending blood clot using mechanical or pharmacological means (e.g. tissue plasma activator; tPA). This review assesses prospects for a novel pharmacological approach to enhance the availability of the natural enzyme tissue kallikrein (KLK1), an important regulator of local blood flow. KLK1 is responsible for the generation of kinins (bradykinin and kallidin), which promote local vasodilation and long-term vascularization. Moreover, KLK1 has been used clinically as a direct treatment for multiple diseases associated with impaired local blood flow including AIS. A form of human KLK1 isolated from human urine is approved in the People's Republic of China for subacute treatment of AIS. Here we review the rationale for using KLK1 as an additional pharmacological treatment for AIS by providing the biochemical mechanism as well as the human clinical data that support this approach.
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Affiliation(s)
| | - Rick Pauls
- DiaMedica Therapeutics, Minneapolis, MN, USA
| | - Julie Chao
- Medical University of South Carolina, Department of Biochemistry and Molecular Biology, Charleston, SC, USA
| | - John J Volpi
- Houston Methodist, Stanley H. Appel Department of Neurology, Houston, TX, USA
| | - Philip M Bath
- Stroke Trials Unit, University of Nottingham, City Hospital Campus, Nottingham, UK
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21
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Tuazon JP, Castelli V, Lee JY, Desideri GB, Stuppia L, Cimini AM, Borlongan CV. Neural Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:79-91. [PMID: 31898782 DOI: 10.1007/978-3-030-31206-0_4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neural stem cell (NSC) transplantation has provided the basis for the development of potentially powerful new therapeutic cell-based strategies for a broad spectrum of clinical diseases, including stroke, psychiatric illnesses such as fetal alcohol spectrum disorders, and cancer. Here, we discuss pertinent preclinical investigations involving NSCs, including how NSCs can ameliorate these diseases, the current barriers hindering NSC-based treatments, and future directions for NSC research. There are still many translational requirements to overcome before clinical therapeutic applications, such as establishing optimal dosing, route of delivery, and timing regimens and understanding the exact mechanism by which transplanted NSCs lead to enhanced recovery. Such critical lab-to-clinic investigations will be necessary in order to refine NSC-based therapies for debilitating human disorders.
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Affiliation(s)
- Julian P Tuazon
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Vanessa Castelli
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | - Jea-Young Lee
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
| | | | - Liborio Stuppia
- Department of Psychological, Humanistic and Territorial Sciences, University G. D'Annunzio, Chieti, Italy
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, PA, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA.
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22
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Zhang JY, Bai QK, Zhang YD. Pretreatment with simvastatin upregulates expression of BK-2R and CD11b in the ischemic penumbra of rats. J Biomed Res 2018; 32:354-360. [PMID: 29784898 PMCID: PMC6163114 DOI: 10.7555/jbr.32.20160152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment in preventing cerebral ischemia/reperfusion injury in rats using a model of middle cerebral artery occlusion (MCAO). Rats were pretreated with simvastatin 14 days prior to MCAO induction. At 3, 24, and 48 hours after reperfusion, bradykinin levels in the ischemic penumbra were assayed by ELISA, mRNA levels of bradykinin B2 receptors (BK-2Rs) and CD11b were measured by fluorescent quantitative real-time PCR (RT-PCR), and co-expression of microglia and BK-2Rs was determined by immunofluorescence. Simvastatin had no effect on bradykinin expression in the ischemic penumbra at any time point. However, the levels of BK-2R and CD11b mRNA in the ischemic penumbra, which were significantly decreased 3 hours after ischemia-reperfusion, were increased in simvastatin-pretreated rats. Moreover, the co-expression of BK-2Rs and microglia was confirmed by immunofluorescence analysis. These results suggest that the beneficial effects of simvastatin pretreatment before cerebral ischemia/reperfusion injury in rats may be partially due to increased expression of BK-2R and CD11b in the ischemic penumbra.
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Affiliation(s)
- Jian-Ying Zhang
- Department of Neurology, Pudong People's Hospital, Shanghai 201299, China
| | - Qing-Ke Bai
- Department of Neurology, Pudong People's Hospital, Shanghai 201299, China
| | - Ying-Dong Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
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23
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Zhang SR, Piepke M, Chu HX, Broughton BR, Shim R, Wong CH, Lee S, Evans MA, Vinh A, Sakkal S, Arumugam TV, Magnus T, Huber S, Gelderblom M, Drummond GR, Sobey CG, Kim HA. IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke. JCI Insight 2018; 3:121560. [PMID: 30232272 DOI: 10.1172/jci.insight.121560] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/07/2018] [Indexed: 12/15/2022] Open
Abstract
Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.
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Affiliation(s)
- Shenpeng R Zhang
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Marius Piepke
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hannah X Chu
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Brad Rs Broughton
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Raymond Shim
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Connie Hy Wong
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Seyoung Lee
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Megan A Evans
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Antony Vinh
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Samy Sakkal
- College of Health and Biomedicine, Victoria University, Western Centre for Health, Research and Education, St. Albans, Victoria, Australia
| | - Thiruma V Arumugam
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Tim Magnus
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Grant R Drummond
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Hyun Ah Kim
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
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24
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Song S, Wang S, Pigott VM, Jiang T, Foley LM, Mishra A, Nayak R, Zhu W, Begum G, Shi Y, Carney KE, Hitchens TK, Shull GE, Sun D. Selective role of Na + /H + exchanger in Cx3cr1 + microglial activation, white matter demyelination, and post-stroke function recovery. Glia 2018; 66:2279-2298. [PMID: 30043461 DOI: 10.1002/glia.23456] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 03/27/2018] [Accepted: 04/24/2018] [Indexed: 12/22/2022]
Abstract
Na+ /H+ exchanger (NHE1) activation is required for multiple microglial functions. We investigated effects of selective deletion of microglial Nhe1 in Cx3cr1-CreER ;Nhe1f/f mice on neuroinflammation and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)-treated mice at 48 hr and 14 days post-stroke. However, the Tam-treated mice showed significantly higher survival rate and faster neurological function recovery during day 1-14 post-stroke. Deletion of microglial Nhe1 prevented the elevation of CD11b+ /CD45low-med microglia in the ischemic hemisphere at day 3 post-stroke, but stimulated expression of Ym1, CD68, TGF-β, IL-10, decreased expression of CD86 and IL-1β, and reduced GFAP+ reactive astrocytes. Moreover, at day 14 post-stroke, enhanced white matter myelination was detected in the microglial Nhe1 deleted mice. In comparison, neuronal Nhe1-null mice (the CamKII-Cre+/- ;Nhe1f/f mice) showed a significant reduction in both acute and subacute infarct volume, along with increased survival rate and moderate neurological function recovery. However, these neuronal Nhe1-null mice did not exhibit reduced activation of CD11b+ /CD45low-med microglia or CD11b+ /CD45hi macrophages in the ischemic brains, and they exhibited no reductions in white matter lesions. Taken together, this study demonstrated that deletion of microglial and neuronal Nhe1 had differential effects on ischemic brain damage. Microglial NHE1 is involved in pro-inflammatory responses during post-stroke brain tissue repair. In contrast, neuronal NHE1 activation is directly associated with the acute ischemic neuronal injury but not inflammation. Our study reveals that NHE1 protein is a potential therapeutic target critical for differential regulation of ischemic neuronal injury, demyelination and tissue repair.
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Affiliation(s)
- Shanshan Song
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Shaoxia Wang
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Victoria M Pigott
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Tong Jiang
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Lesley M Foley
- Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Abhishek Mishra
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Rachana Nayak
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Wen Zhu
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Gulnaz Begum
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Yejie Shi
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Karen E Carney
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - T Kevin Hitchens
- Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
| | - Gary E Shull
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, 45267
| | - Dandan Sun
- Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213.,Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania
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25
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Gauberti M, Potzeha F, Vivien D, Martinez de Lizarrondo S. Impact of Bradykinin Generation During Thrombolysis in Ischemic Stroke. Front Med (Lausanne) 2018; 5:195. [PMID: 30018956 PMCID: PMC6037726 DOI: 10.3389/fmed.2018.00195] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/14/2018] [Indexed: 12/22/2022] Open
Abstract
Ischemic stroke is one of the leading causes of death and disability worldwide. Current medical management in the acute phase is based on the activation of the fibrinolytic cascade by intravenous injection of a plasminogen activator (such as tissue-type plasminogen activator, tPA) that promotes restauration of the cerebral blood flow and improves stroke outcome. Unfortunately, the use of tPA is associated with deleterious effects such as hemorrhagic transformation, symptomatic brain edema, and angioedema, which limit the efficacy of this therapeutic strategy. Preclinical and clinical evidence suggests that intravenous thrombolysis generates large amounts of bradykinin, a peptide with potent pro-inflammatory, and pro-edematous effects. This tPA-triggered generation of bradykinin could participate in the deleterious effects of thrombolysis and is a potential target to improve neurological outcome in tPA-treated patients. The present review aims at summarizing current evidence linking thrombolysis, bradykinin generation, and neurovascular damage.
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Affiliation(s)
- Maxime Gauberti
- Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale UMR-S U1237, "Physiopathology and Imaging of Neurological Disorders" PhIND, Caen, France.,Department of Diagnostic Imaging and Interventional Radiology, Centre Hospitalier Universitaire Caen Côte de Nacre, Caen, France
| | - Fanny Potzeha
- Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale UMR-S U1237, "Physiopathology and Imaging of Neurological Disorders" PhIND, Caen, France
| | - Denis Vivien
- Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale UMR-S U1237, "Physiopathology and Imaging of Neurological Disorders" PhIND, Caen, France.,Department of Clinical Research, Centre Hospitalier Universitaire Caen, Caen, France
| | - Sara Martinez de Lizarrondo
- Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale UMR-S U1237, "Physiopathology and Imaging of Neurological Disorders" PhIND, Caen, France
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26
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Nokkari A, Abou-El-Hassan H, Mechref Y, Mondello S, Kindy MS, Jaffa AA, Kobeissy F. Implication of the Kallikrein-Kinin system in neurological disorders: Quest for potential biomarkers and mechanisms. Prog Neurobiol 2018; 165-167:26-50. [PMID: 29355711 PMCID: PMC6026079 DOI: 10.1016/j.pneurobio.2018.01.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 01/15/2018] [Indexed: 01/06/2023]
Abstract
Neurological disorders represent major health concerns in terms of comorbidity and mortality worldwide. Despite a tremendous increase in our understanding of the pathophysiological processes involved in disease progression and prevention, the accumulated knowledge so far resulted in relatively moderate translational benefits in terms of therapeutic interventions and enhanced clinical outcomes. Aiming at specific neural molecular pathways, different strategies have been geared to target the development and progression of such disorders. The kallikrein-kinin system (KKS) is among the most delineated candidate systems due to its ubiquitous roles mediating several of the pathophysiological features of these neurological disorders as well as being implicated in regulating various brain functions. Several experimental KKS models revealed that the inhibition or stimulation of the two receptors of the KKS system (B1R and B2R) can exhibit neuroprotective and/or adverse pathological outcomes. This updated review provides background details of the KKS components and their functions in different neurological disorders including temporal lobe epilepsy, traumatic brain injury, stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis and glioma. Finally, this work will highlight the putative roles of the KKS components as potential neurotherapeutic targets and provide future perspectives on the possibility of translating these findings into potential clinical biomarkers in neurological disease.
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Affiliation(s)
- Amaly Nokkari
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon
| | - Hadi Abou-El-Hassan
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Mark S Kindy
- Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA; James A. Haley VA Medical Center, Tampa, FL, USA
| | - Ayad A Jaffa
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon; Department of Medicine, Medical University of South, Charleston, SC, USA.
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon; Center for Neuroproteomics & Biomarkers Research, Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
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27
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The Long-Term Outcome Comparison of Different Time-Delayed Kallikrein Treatments in a Mouse Cerebral Ischemic Model. Stem Cells Int 2018; 2018:1706982. [PMID: 29760720 PMCID: PMC5907522 DOI: 10.1155/2018/1706982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/23/2017] [Accepted: 10/10/2017] [Indexed: 11/18/2022] Open
Abstract
Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long-term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3β-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO) until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3β-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein.
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28
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Ferrero H, Larrayoz IM, Gil-Bea FJ, Martínez A, Ramírez MJ. Adrenomedullin, a Novel Target for Neurodegenerative Diseases. Mol Neurobiol 2018; 55:8799-8814. [PMID: 29600350 DOI: 10.1007/s12035-018-1031-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 03/22/2018] [Indexed: 01/18/2023]
Abstract
Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer's disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.
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Affiliation(s)
- Hilda Ferrero
- Department of Pharmacology and Toxicology, and IdiSNA, Navarra Institute for Health Research, University of Navarra, Pamplona, Spain
| | - Ignacio M Larrayoz
- Biomarkers and Molecular Signaling, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - Francisco J Gil-Bea
- Department of Pharmacology and Toxicology, and IdiSNA, Navarra Institute for Health Research, University of Navarra, Pamplona, Spain
- Neuroscience Area, Biodonostia Health Research Institute, CIBERNED, San Sebastian, Spain
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain
| | - María J Ramírez
- Department of Pharmacology and Toxicology, and IdiSNA, Navarra Institute for Health Research, University of Navarra, Pamplona, Spain.
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29
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Neuroprotection of bradykinin/bradykinin B2 receptor system in cerebral ischemia. Biomed Pharmacother 2017; 94:1057-1063. [DOI: 10.1016/j.biopha.2017.08.042] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 08/07/2017] [Accepted: 08/07/2017] [Indexed: 12/17/2022] Open
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30
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Desposito D, Zadigue G, Taveau C, Adam C, Alhenc-Gelas F, Bouby N, Roussel R. Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice. Sci Rep 2017; 7:9410. [PMID: 28842604 PMCID: PMC5572700 DOI: 10.1038/s41598-017-09721-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 07/10/2017] [Indexed: 12/28/2022] Open
Abstract
Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemia-reperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK−/−). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK−/− mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R-agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42–52% and IS by 66–71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes.
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Affiliation(s)
- Dorinne Desposito
- INSERM U 1138, Cordeliers Research Center, Paris, France.,Paris Descartes University, Paris, France.,Pierre et Marie Curie University, Paris, France
| | | | - Christopher Taveau
- INSERM U 1138, Cordeliers Research Center, Paris, France.,Paris Descartes University, Paris, France.,Pierre et Marie Curie University, Paris, France
| | - Clovis Adam
- Anatomopathology Department, Kremlin-Bicêtre Hospital, Paris, France
| | - François Alhenc-Gelas
- INSERM U 1138, Cordeliers Research Center, Paris, France.,Paris Descartes University, Paris, France.,Pierre et Marie Curie University, Paris, France
| | - Nadine Bouby
- INSERM U 1138, Cordeliers Research Center, Paris, France. .,Paris Descartes University, Paris, France. .,Pierre et Marie Curie University, Paris, France.
| | - Ronan Roussel
- INSERM U 1138, Cordeliers Research Center, Paris, France.,Denis Diderot University, Paris, France.,Diabetology, Endocrinology and Nutrition Department, DHU FIRE, Bichat Hospital, AP-HP, Paris, France
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31
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Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 2017; 158:94-131. [PMID: 28743464 DOI: 10.1016/j.pneurobio.2017.07.004] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 07/18/2017] [Accepted: 07/18/2017] [Indexed: 12/13/2022]
Abstract
Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.
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32
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Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke. J Neurosci 2017; 37:5648-5658. [PMID: 28483976 DOI: 10.1523/jneurosci.3811-16.2017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 04/25/2017] [Accepted: 05/01/2017] [Indexed: 12/12/2022] Open
Abstract
The voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy.SIGNIFICANCE STATEMENT Kv2.1 is a critical regulator of apoptosis in central neurons. It has not been determined, however, whether the cell death-enabling function of this K+ channel can be selectively targeted to improve neuronal survival following injury in vivo The experiments presented here demonstrate that the cell death-specific role of Kv2.1 can be uniquely modulated to provide neuroprotection in an animal model of acute ischemic stroke. We thus reveal a novel therapeutic strategy for neurological disorders that are accompanied by Kv2.1-facilitated forms of cell death.
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33
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Ji B, Liu H, Zhang R, Jiang Y, Wang C, Li S, Chen J, Bai B. Novel signaling of dynorphin at κ-opioid receptor/bradykinin B2 receptor heterodimers. Cell Signal 2017; 31:66-78. [PMID: 28069442 DOI: 10.1016/j.cellsig.2017.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 12/19/2016] [Accepted: 01/04/2017] [Indexed: 01/06/2023]
Abstract
The κ-opioid receptor (KOR) and bradykinin B2 receptor (B2R) are involved in a variety of important physiological processes and share many similar characteristics in terms of their distribution and functions in the nervous system. We first demonstrated the endogenous expression of KOR and B2R in human SH-SY5Y cells and their co-localization on the membrane of human embryonic kidney 293 (HEK293) cells. Bioluminescence and fluorescence resonance energy transfer and the proximity ligation assay were exploited to demonstrate the formation of functional KOR and B2R heteromers in transfected cells. KOR/B2R heteromers triggered dynorphin A (1-13)-induced Gαs/protein kinase A signaling pathway activity, including upregulation of intracellular cAMP levels and cAMP-response element luciferase reporter activity, resulting in increased cAMP-response element-binding protein (CREB) phosphorylation, which could be dampened by the protein kinase A (PKA) inhibitor H89. This indicated that the co-existence of KOR and B2R is critical for CREB phosphorylation. In addition, dynorphin A (1-13) induced a significantly higher rate of proliferation in HEK293-KOR/B2R and human SH-SY5Y cells than in the control group. These results indicate that KOR can form a heterodimer with B2R and this leads to increased protein kinase A activity by the CREB signaling pathway, leading to a significant increase in cell proliferation. The nature of this signaling pathway has significant implications for the role of dynorphin in the regulation of neuroprotective effects.
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Affiliation(s)
- Bingyuan Ji
- School of Life Science, Shandong Agricultural University, Taian 271018, PR China; Neurobiology Institute, Jining Medical University, Jining 272067, PR China
| | - Haiqing Liu
- Department of Physiology, Taishan Medical College, Taian 271000, PR China
| | - Rumin Zhang
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China
| | - Yunlu Jiang
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China
| | - Chunmei Wang
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China
| | - Sheng Li
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China
| | - Jing Chen
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China; Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK.
| | - Bo Bai
- Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
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Tissue Kallikrein Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the B2R-ERK1/2-CREB-Bcl-2 Signaling Pathway in Diabetic Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:1843201. [PMID: 27446506 PMCID: PMC4944080 DOI: 10.1155/2016/1843201] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/06/2016] [Indexed: 01/06/2023]
Abstract
Diabetes mellitus (DM) substantially increases the risk of ischemic stroke and reduces the tolerance to ischemic insults. Tissue kallikrein (TK) has been demonstrated to protect neurons from ischemia/reperfusion (I/R) injury in orthoglycemic model by activating the bradykinin B2 receptor (B2R). Considering the differential effects of B2R or bradykinin B1 receptor (B1R) on cardioprotection and neuroprotection in I/R with or without diabetes, this study was designed to investigate the role of TK during cerebral I/R injury in streptozotocin-induced diabetic rats. Intravenous injection of TK inhibited apoptosis in neurons, alleviated edema and inflammatory reactions after focal cerebral I/R, significantly reduced the infarct volume, and improved functional recovery. These beneficial effects were accompanied by activation of the extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding (CREB), and Bcl-2 signal proteins. Inhibition of the B2R or ERK1/2 pathway abated the effects of TK, whereas an antagonist of B1R enhanced the effects. These findings reveal that the neuroprotective effect of TK against cerebral I/R injury in streptozotocin-induced diabetic rats mainly involves the enhancement of B2R and ERK1/2-CREB-Bcl-2 signaling pathway activity.
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35
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Nascimento IC, Glaser T, Nery AA, Pillat MM, Pesquero JB, Ulrich H. Kinin-B1 and B2 receptor activity in proliferation and neural phenotype determination of mouse embryonic stem cells. Cytometry A 2015; 87:989-1000. [PMID: 26243460 DOI: 10.1002/cyto.a.22726] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The kinins bradykinin and des-arg(9) -bradykinin cleaved from kininogen precursors by kallikreins exert their biological actions by stimulating kinin-B2 and B1 receptors, respectively. In vitro models of neural differentiation such as P19 embryonal carcinoma cells and neural progenitor cells have suggested the involvement of B2 receptors in neural differentiation and phenotype determination; however, the involvement of B1 receptors in these processes has not been established. Here, we show that B1 and B2 receptors are differentially expressed in mouse embryonic E14Tg2A stem cells undergoing neural differentiation. Proliferation and differentiation assays, performed in the presence of receptor subtype-selective agonists and antagonists, revealed that B1 receptor activity is required for the proliferation of embryonic and differentiating cells as well as for neuronal maturation at later stages of differentiation, while the B2 receptor acts on neural phenotype choice, promoting neurogenesis over gliogenesis. Besides the elucidation of bradykinin functions in an in vitro model reflecting early embryogenesis and neurogenesis, this study contributes to the understanding of B1 receptor functions in this process.
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Affiliation(s)
- Isis C Nascimento
- Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Talita Glaser
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Arthur A Nery
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Micheli M Pillat
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
| | - João B Pesquero
- Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
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36
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Li M, Guo S, Zhang P, Gong J, Zheng A, Zhang Y, Li H. Vinexin-β deficiency protects against cerebral ischaemia/reperfusion injury by inhibiting neuronal apoptosis. J Neurochem 2015; 134:211-21. [PMID: 25824575 DOI: 10.1111/jnc.13110] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 03/25/2015] [Accepted: 03/26/2015] [Indexed: 01/09/2023]
Abstract
Vinexin-β is an adaptor protein that regulates cell adhesion, cytoskeletal organization and signal transduction. Our previous work showed that Vinexin-β protects against cardiac hypertrophy. However, its function in stroke is largely unknown. In the present study, we observed a significant increase in Vinexin-β expression in both human intracerebral haemorrhage and mouse cerebral ischaemia/reperfusion (I/R) injury model, indicating that Vinexin-β is involved in stroke. Next, using Vinexin-β knockout mice, we further demonstrated that Vinexin-β deficiency significantly protected against cerebral I/R injury, as demonstrated by a dramatic decrease in the infarct volume and an improvement in neurological function. Additionally, immunofluorescence and western blotting showed that the deletion of Vinexin-β attenuated neuronal apoptosis. Mechanically, we found that Akt signalling was up-regulated in the brains of the Vinexin-β knockout mice compared with those of the WT control mice after ischaemic injury. Taken together, our results demonstrate that the deletion of Vinexin-β potently protects against ischaemic injury by inhibiting neuronal apoptosis, and this effect may occur via the up-regulation of Akt signalling. Our findings revealed that Vinexin-β acts as a novel modulator of ischaemic injury, suggesting that Vinexin-β may represent an attractive therapeutic target for the prevention of stroke.
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Affiliation(s)
- Mingchang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Sen Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Peng Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Jun Gong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,College of Life Sciences, Wuhan University, Wuhan, China
| | - Ankang Zheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Yan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China
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Negraes PD, Trujillo CA, Pillat MM, Teng YD, Ulrich H. Roles of kinins in the nervous system. Cell Transplant 2015; 24:613-23. [PMID: 25839228 DOI: 10.3727/096368915x687778] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The kallikrein-kinin system (KKS) is an endogenous pathway involved in many biological processes. Although primarily related to blood pressure control and inflammation, its activation goes beyond these effects. Neurogenesis and neuroprotection might be stimulated by bradykinin being of great interest for clinical applications following brain injury. This peptide is also an important player in spinal cord injury pathophysiology and recovery, in which bradykinin receptor blockers represent substantial therapeutic potential. Here, we highlight the participation of kinin receptors and especially bradykinin in mediating ischemia pathophysiology in the central and peripheral nervous systems. Moreover, we explore the recent advances on mechanistic and therapeutic targets for biological, pathological, and neural repair processes involving kinins.
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Affiliation(s)
- Priscilla D Negraes
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
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Kim HA, Whittle SC, Lee S, Chu HX, Zhang SR, Wei Z, Arumugam TV, Vinh A, Drummond GR, Sobey CG. Brain immune cell composition and functional outcome after cerebral ischemia: comparison of two mouse strains. Front Cell Neurosci 2014; 8:365. [PMID: 25477780 PMCID: PMC4237143 DOI: 10.3389/fncel.2014.00365] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 10/16/2014] [Indexed: 11/13/2022] Open
Abstract
Inflammatory cells may contribute to secondary brain injury following cerebral ischemia. The C57Bl/6 mouse strain is known to exhibit a T helper 1-prone, pro-inflammatory type response to injury, whereas the FVB strain is relatively T helper 2-prone, or anti-inflammatory, in its immune response. We tested whether stroke outcome is more severe in C57Bl/6 than FVB mice. Male mice of each strain underwent sham surgery or 1 h occlusion of the middle cerebral artery followed by 23 h of reperfusion. Despite no difference in infarct size, C57Bl/6 mice displayed markedly greater functional deficits than FVB mice after stroke, as assessed by neurological scoring and hanging wire test. Total numbers of CD45(+) leukocytes tended to be larger in the brains of C57Bl/6 than FVB mice after stroke, but there were marked differences in leukocyte composition between the two mouse strains. The inflammatory response in C57Bl/6 mice primarily involved T and B lymphocytes, whereas neutrophils, monocytes and macrophages were more prominent in FVB mice. Our data are consistent with the concept that functional outcome after stroke is dependent on the immune cell composition which develops following ischemic brain injury.
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Affiliation(s)
- Hyun Ah Kim
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | | | - Seyoung Lee
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | - Hannah X Chu
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | - Shenpeng R Zhang
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | - Zihui Wei
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | - Thiruma V Arumugam
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore ; School of Pharmacy, Sungkyunkwan University Suwon, South Korea ; School of Biomedical Sciences, The University of Queensland St Lucia, QLD, Australia
| | - Anthony Vinh
- Department of Pharmacology, Monash University Clayton, VIC, Australia
| | - Grant R Drummond
- Department of Pharmacology, Monash University Clayton, VIC, Australia ; Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University Clayton, VIC, Australia
| | - Christopher G Sobey
- Department of Pharmacology, Monash University Clayton, VIC, Australia ; Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University Clayton, VIC, Australia
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39
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Chao J, Bledsoe G, Chao L. Kallikrein-kinin in stem cell therapy. World J Stem Cells 2014; 6:448-457. [PMID: 25258666 PMCID: PMC4172673 DOI: 10.4252/wjsc.v6.i4.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
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40
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Chen HZ, Guo S, Li ZZ, Lu Y, Jiang DS, Zhang R, Lei H, Gao L, Zhang X, Zhang Y, Wang L, Zhu LH, Xiang M, Zhou Y, Wan Q, Dong H, Liu DP, Li H. A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. J Neurosci 2014; 34:11897-11912. [PMID: 25186738 PMCID: PMC6608458 DOI: 10.1523/jneurosci.1545-14.2014] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 07/02/2014] [Accepted: 07/11/2014] [Indexed: 01/21/2023] Open
Abstract
The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.
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Affiliation(s)
- Hou-Zao Chen
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Sen Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Zuo-Zhi Li
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Yanyun Lu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Ding-Sheng Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Ran Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Hao Lei
- Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China
| | - Lu Gao
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaofei Zhang
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Lang Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Li-Hua Zhu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Mei Xiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
| | - Yan Zhou
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Qi Wan
- State Key Laboratory of Virology, Department of Immunology and Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China, and
| | - Hailong Dong
- Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - De-Pei Liu
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China,
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China,
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41
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Xiang M, Wang L, Guo S, Lu YY, Lei H, Jiang DS, Zhang Y, Liu Y, Zhou Y, Zhang XD, Li H. Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury. J Neurochem 2014; 129:988-1001. [PMID: 24528256 DOI: 10.1111/jnc.12682] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 02/07/2014] [Accepted: 02/12/2014] [Indexed: 12/26/2022]
Abstract
Interferon regulatory factor 8 (IRF8), a transcriptional regulator in the IRF family, has been implicated in innate immunity, immune cell differentiation and tumour cell apoptosis. In the present study, we found that IRF8 is constitutively expressed in the brain and suppressed after cerebral ischaemia in a time-dependent manner. IRF8 knockout (IRF8-KO) mice, wild type (WT) mice, neuron-specific IRF8 transgenic (TG) mice and non-transgenic mice were used in a transient cerebral ischaemic model. The IRF8 knockout mice exhibited aggravated apoptosis, inflammation and oxidative injury in the ischaemic brain, eventually leading to poorer stroke outcomes, whereas neuron-specific IRF8 transgenic mice showed a marked inhibition of apoptosis and improved stroke outcomes. To model ischaemia/reperfusion conditions in vitro, primary cortical neurons were cultured and subjected to transient oxygen and glucose deprivation for 60 min. Similar to the in vivo study, IRF8 knockdown by Ad-shIRF8 resulted in increased apoptosis, whereas IRF8 over-expression by Ad-IRF8 significantly decreased neuronal apoptosis. These data indicate that IRF8 is strongly protective in ischaemic stroke by regulating neuronal apoptosis, the inflammatory response and oxidative stress. In the present study, we found that the transcriptional factor IRF8 plays a protective role in the cerebral ischaemic-reperfusion injury by attenuating neuronal apoptosis, oxidative stress and inflammation. Besides the known function of IRF8 in regulating the inflammatory gene expression, we first demonstrated that IRF8 can directly modulate apoptosis and oxidative stress by controlling the relative genes expression.
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Affiliation(s)
- Mei Xiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China
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42
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Pereira RL, Felizardo RJF, Cenedeze MA, Hiyane MI, Bassi EJ, Amano MT, Origassa CST, Silva RC, Aguiar CF, Carneiro SM, Pesquero JB, Araújo RC, Keller ADC, Monteiro RC, Moura IC, Pacheco-Silva A, Câmara NOS. Balance between the two kinin receptors in the progression of experimental focal and segmental glomerulosclerosis in mice. Dis Model Mech 2014; 7:701-10. [PMID: 24742784 PMCID: PMC4036477 DOI: 10.1242/dmm.014548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end-stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation, whereas the role of its receptor 2 (B2RBK; also known as BDKRB2) in FSGS has not been studied. FSGS was induced in wild-type and B2RBK-knockout mice by a single intravenous injection of Adriamycin (ADM). In order to further modulate the kinin receptors, the animals were also treated with the B2RBK antagonist HOE-140 and the B1RBK antagonist DALBK. Here, we show that the blockage of B2RBK with HOE-140 protects mice from the development of FSGS, including podocyte foot process effacement and the re-establishment of slit-diaphragm-related proteins. However, B2RBK-knockout mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was upregulated after the injection of ADM and this upregulation was exacerbated in B2RBK-knockout animals. Furthermore, treatment with HOE-140 downregulated the B1RBK receptor. The blockage of B1RBK in B2RBK-knockout animals promoted FSGS regression, with a less-inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in an FSGS model and suggest a possible cross-talk between them in the progression of disease.
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Affiliation(s)
- Rafael Luiz Pereira
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil. Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo 05508-000, Brazil
| | - Raphael José Ferreira Felizardo
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil
| | - Marcos Antônio Cenedeze
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil
| | - Meire Ioshie Hiyane
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo 05508-000, Brazil
| | - Enio José Bassi
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil
| | - Mariane Tami Amano
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil
| | - Clarice Sylvia Taemi Origassa
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil
| | - Reinaldo Correia Silva
- Laboratory of Clinical and Experimental Immunology, Translational Medicine Division, Federal University of São Paulo, São Paulo 04039-002, Brazil
| | - Cristhiane Fávero Aguiar
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo 05508-000, Brazil
| | - Sylvia Mendes Carneiro
- Laboratory of Cellular Biology, Instituto Butantan, Av. Vital Brazil 1500, São Paulo 05503-900, Brazil
| | - João Bosco Pesquero
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
| | - Ronaldo Carvalho Araújo
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
| | - Alexandre de Castro Keller
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
| | - Renato C Monteiro
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 699, Paris 75870, France
| | - Ivan Cruz Moura
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 699, Paris 75870, France
| | - Alvaro Pacheco-Silva
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil. Instituto Israelita de Ensino e Pesquisa Albert Einstein, Renal Transplantation Unit, Albert Einstein Hospital, São Paulo 05521-000, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, Brazil. Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo 05508-000, Brazil.
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Allen RS, Sayeed I, Cale HA, Morrison KC, Boatright JH, Pardue MT, Stein DG. Severity of middle cerebral artery occlusion determines retinal deficits in rats. Exp Neurol 2014; 254:206-15. [PMID: 24518488 DOI: 10.1016/j.expneurol.2014.02.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 01/16/2014] [Accepted: 02/02/2014] [Indexed: 10/25/2022]
Abstract
Middle cerebral artery occlusion (MCAO) using the intraluminal suture technique is a common model used to study cerebral ischemia in rodents. Due to the proximity of the ophthalmic artery to the middle cerebral artery, MCAO blocks both arteries, causing both cerebral ischemia and retinal ischemia. While previous studies have shown retinal dysfunction at 48h post-MCAO, we investigated whether these retinal function deficits persist until 9days and whether they correlate with central neurological deficits. Rats received 90min of transient MCAO followed by electroretinography at 2 and 9days to assess retinal function. Retinal damage was assessed with cresyl violet staining, immunohistochemistry for glial fibrillary acidic protein (GFAP) and glutamine synthetase, and TUNEL staining. Rats showed behavioral deficits as assessed with neuroscore that correlated with cerebral infarct size and retinal function at 2days. Two days after surgery, rats with moderate MCAO (neuroscore <5) exhibited delays in electroretinogram implicit time, while rats with severe MCAO (neuroscore ≥5) exhibited reductions in amplitude. Glutamine synthetase was upregulated in Müller cells 3days after MCAO in both severe and moderate animals; however, retinal ganglion cell death was only observed in MCAO retinas from severe animals. By 9days after MCAO, both glutamine synthetase labeling and electroretinograms had returned to normal levels in moderate animals. Early retinal function deficits correlated with behavioral deficits. However, retinal function decreases were transient, and selective retinal cell loss was observed only with severe ischemia, suggesting that the retina is less susceptible to MCAO than the brain. Temporary retinal deficits caused by MCAO are likely due to ischemia-induced increases in extracellular glutamate that impair signal conduction, but resolve by 9days after MCAO.
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Affiliation(s)
- Rachael S Allen
- Emergency Medicine, Emory University, Atlanta, GA 30322, USA; Ophthalmology, Emory University, Atlanta, GA 30322, USA.
| | - Iqbal Sayeed
- Emergency Medicine, Emory University, Atlanta, GA 30322, USA.
| | - Heather A Cale
- Emergency Medicine, Emory University, Atlanta, GA 30322, USA.
| | | | | | - Machelle T Pardue
- Ophthalmology, Emory University, Atlanta, GA 30322, USA; Rehab R&D Center of Excellence, Atlanta VA Medical Center, Decatur, GA 30033, USA.
| | - Donald G Stein
- Emergency Medicine, Emory University, Atlanta, GA 30322, USA.
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IRF4 is a novel mediator for neuronal survival in ischaemic stroke. Cell Death Differ 2014; 21:888-903. [PMID: 24510125 PMCID: PMC4013523 DOI: 10.1038/cdd.2014.9] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 12/19/2013] [Accepted: 01/03/2014] [Indexed: 01/04/2023] Open
Abstract
Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4–SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4–SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
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Kränkel N, Madeddu P. Helping the circulatory system heal itself: manipulating kinin signaling to promote neovascularization. Expert Rev Cardiovasc Ther 2014; 7:215-9. [DOI: 10.1586/14779072.7.3.215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Chao J, Bledsoe G, Chao L. Tissue kallikrein-kinin therapy in hypertension and organ damage. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2014; 69:37-57. [PMID: 25130039 DOI: 10.1007/978-3-319-06683-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Tissue kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, tissue kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and gamma-epithelial Na channel. The tissue kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment tissue kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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47
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Duehrkop C, Rieben R. Ischemia/reperfusion injury: effect of simultaneous inhibition of plasma cascade systems versus specific complement inhibition. Biochem Pharmacol 2013; 88:12-22. [PMID: 24384116 DOI: 10.1016/j.bcp.2013.12.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 11/25/2013] [Accepted: 12/16/2013] [Indexed: 02/06/2023]
Abstract
Ischemia/reperfusion injury (IRI) may occur from ischemia due to thrombotic occlusion, trauma or surgical interventions, including transplantation, with subsequent reestablishment of circulation. Time-dependent molecular and structural changes result from the deprivation of blood and oxygen in the affected tissue during ischemia. Upon restoration of blood flow a multifaceted network of plasma cascades is activated, including the complement-, coagulation-, kinin-, and fibrinolytic system, which plays a major role in the reperfusion-triggered inflammatory process. The plasma cascade systems are therefore promising therapeutic targets for attenuation of IRI. Earlier studies showed beneficial effects through inhibition of the complement system using specific complement inhibitors. However, pivotal roles in IRI are also attributed to other cascades. This raises the question, whether drugs, such as C1 esterase inhibitor, which regulate more than one cascade at a time, have a higher therapeutic potential. The present review discusses different therapeutic approaches ranging from specific complement inhibition to simultaneous inhibition of plasma cascade systems for reduction of IRI, gives an overview of the plasma cascade systems in IRI as well as highlights recent findings in this field.
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Affiliation(s)
- Claudia Duehrkop
- Department of Clinical Research, University of Bern, Murtenstrasse 50, P.O. Box 44, CH-3010 Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Switzerland
| | - Robert Rieben
- Department of Clinical Research, University of Bern, Murtenstrasse 50, P.O. Box 44, CH-3010 Bern, Switzerland.
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48
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Mindin is a critical mediator of ischemic brain injury in an experimental stroke model. Exp Neurol 2013; 247:506-16. [DOI: 10.1016/j.expneurol.2013.01.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2012] [Revised: 12/14/2012] [Accepted: 01/18/2013] [Indexed: 11/23/2022]
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49
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Lu YY, Li ZZ, Jiang DS, Wang L, Zhang Y, Chen K, Zhang XF, Liu Y, Fan GC, Chen Y, Yang Q, Zhou Y, Zhang XD, Liu DP, Li H. TRAF1 is a critical regulator of cerebral ischaemia-reperfusion injury and neuronal death. Nat Commun 2013; 4:2852. [PMID: 24284943 PMCID: PMC3868160 DOI: 10.1038/ncomms3852] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Accepted: 10/31/2013] [Indexed: 01/08/2023] Open
Abstract
Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.
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Affiliation(s)
- Yan-Yun Lu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China
- These authors contributed equally to this work
| | - Zuo-Zhi Li
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
- These authors contributed equally to this work
| | - Ding-Sheng Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China
- These authors contributed equally to this work
| | - Lang Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China
| | - Yan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China
| | - Ke Chen
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Xiao-Fei Zhang
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yi Liu
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Guo-Chang Fan
- Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267-0575, USA
| | - Yingjie Chen
- Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Qinglin Yang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-3360, USA
| | - Yan Zhou
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Xiao-Dong Zhang
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - De-Pei Liu
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China
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50
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Albert-Weißenberger C, Sirén AL, Kleinschnitz C. Ischemic stroke and traumatic brain injury: the role of the kallikrein-kinin system. Prog Neurobiol 2012; 101-102:65-82. [PMID: 23274649 DOI: 10.1016/j.pneurobio.2012.11.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 11/15/2012] [Accepted: 11/20/2012] [Indexed: 12/16/2022]
Abstract
Acute ischemic stroke and traumatic brain injury are a major cause of mortality and morbidity. Due to the paucity of therapies, there is a pressing clinical demand for new treatment options. Successful therapeutic strategies for these conditions must target multiple pathophysiological mechanisms occurring at different stages of brain injury. In this respect, the kallikrein-kinin system is an ideal target linking key pathological hallmarks of ischemic and traumatic brain damage such as edema formation, inflammation, and thrombosis. In particular, the kinin receptors, plasma kallikrein, and coagulation factor XIIa are highly attractive candidates for pharmacological development, as kinin receptor antagonists or inhibitors of plasma kallikrein and coagulation factor XIIa are neuroprotective in animal models of stroke and traumatic brain injury. Nevertheless, conflicting preclinical evaluation as well as limited and inconclusive data from clinical trials suggest caution when transferring observations made in animals into the human situation. This review summarizes current evidence on the pathological significance of the kallikrein-kinin system during ischemic and traumatic brain damage, with a particular focus on experimental data derived from animal models. Experimental findings are also compared with human data if available, and potential therapeutic implications are discussed.
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