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Tumor Necrosis Factor-α: The Next Marker of Stroke. DISEASE MARKERS 2022; 2022:2395269. [PMID: 35265224 PMCID: PMC8898850 DOI: 10.1155/2022/2395269] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/05/2022] [Accepted: 02/19/2022] [Indexed: 02/06/2023]
Abstract
Although there is no shortage of research on the markers for stroke, to our knowledge, there are no clear markers that can meet the needs of clinical prediction and treatment. The inflammatory cascade is a critical process that persists and functions throughout the stroke process, ultimately worsening stroke outcomes and increasing mortality. Numerous inflammatory factors, including tumor necrosis factor (TNF), are involved in this process. These inflammatory factors play a dual role during stroke, and their mechanisms are complex. As one of the representatives, TNF is the primary regulator of the immune system and plays an essential role in the spread of inflammation. In researches done over the last few years, tumor necrosis factor-alpha (TNF-α) has emerged as a potential marker for stroke because of its essential role in stroke. This review summarizes the latest research on TNF-α in stroke and explores its potential as a therapeutic target.
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Lee CH, Ahn JH, Chen BH, Kim DW, Sim H, Lee TK, Park JH, Won MH, Choi SY. Differences in TNF‑α and TNF‑R1 expression in damaged neurons and activated astrocytes of the hippocampal CA1 region between young and adult gerbils following transient forebrain ischemia. Mol Med Rep 2021; 24:625. [PMID: 34212986 PMCID: PMC8281367 DOI: 10.3892/mmr.2021.12264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 11/30/2022] Open
Abstract
Tumor necrosis factor (TNF)-α and TNF receptor 1 (TNF-R1) play diverse roles in modulating the neuronal damage induced by cerebral ischemia. The present study compared the time-dependent changes of TNF-α and TNF-R1 protein expression levels in the hippocampal subfield cornu ammonis 1 (CA1) between adult and young gerbils following transient forebrain ischemia (tFI), via western blot and immunohistochemistry analyses. In adult gerbils, delayed neuronal death of pyramidal neurons, the principal neurons in CA1, was recorded 4 days after tFI; however, in young gerbils, delayed neuronal death was recorded 7 days after tFI. TNF-α protein expression levels gradually increased in both groups following tFI; however, TNF-α expression was higher in young gerbils compared with adult gerbils. TNF-R1 protein expression levels markedly increased in both groups 1 day after tFI. Subsequently, TNF-R1 expression gradually decreased in young gerbils, whereas TNF-R1 expression levels were irregularly altered in adult gerbils following tFI. Notably, TNF-α immunoreactivity significantly increased in pyramidal neurons in both groups 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF-α immunoreactivity was rarely exhibited in pyramidal neurons 4 days after tFI due to neuronal death, suggesting that TNF-α immunoreactivity was newly expressed in astrocytes. In young gerbils, TNF-α immunoreactivity increased in pyramidal neurons 4 days after tFI, and TNF-α immunoreactivity was newly expressed in astrocytes. In addition, TNF-R1 immunoreactivity was exhibited in pyramidal cells of both sham groups, and significantly increased 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF-R1 immunoreactivity was rarely exhibited 4 days after tFI, and astrocytes newly expressed TNF-R1 immunoreactivity. In young gerbils, TNF-R1 immunoreactivity increased in pyramidal neurons 4 days after tFI; however, TNF-R1 immunoreactivity was not reported in pyramidal neurons and astrocytes thereafter. Taken together, the results of the present study suggest that different expression levels of TNF-α and TNF-R1 in ischemic CA1 between adult and young gerbils may be due to age-dependent differences of tFI-induced neuronal death.
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Affiliation(s)
- Choong Hyun Lee
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungnam 31116, Republic of Korea
| | - Ji Hyeon Ahn
- Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan, Gyeongnam 50510, Republic of Korea
| | - Bai Hui Chen
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Gangnung‑Wonju National University, Gangneung, Gangwon 25457, Republic of Korea
| | - Hyejin Sim
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Tae-Kyeong Lee
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Joon Ha Park
- Department of Anatomy, College of Korean Medicine, Dongguk University, Gyeongju, Gyeongbuk 38066, Republic of Korea
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Soo Young Choi
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
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Matheson R, Chida K, Lu H, Clendaniel V, Fisher M, Thomas A, Lo EH, Selim M, Shehadah A. Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke. Transl Stroke Res 2020; 11:1052-1063. [PMID: 32016769 DOI: 10.1007/s12975-020-00783-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 01/21/2020] [Accepted: 01/22/2020] [Indexed: 12/15/2022]
Abstract
Histone deacetylase 3 (HDAC3) has been implicated as neurotoxic in several neurodegenerative conditions. However, the role of HDAC3 in ischemic stroke has not been thoroughly explored. We tested the hypothesis that selective inhibition of HDAC3 after stroke affords neuroprotection. Adult male Wistar rats (n = 8/group) were subjected to 2 h of middle cerebral artery occlusion (MCAO), and randomly selected animals were treated intraperitoneally twice with either vehicle (1% Tween 80) or a selective HDAC3 inhibitor (RGFP966, 10 mg/kg) at 2 and 24 h after MCAO. Long-term behavioral tests were performed up to 28 days after MCAO. Another set of rats (n = 7/group) were sacrificed at 3 days for histological analysis. Immunostaining for HDAC3, acetyl-Histone 3 (AcH3), NeuN, TNF-alpha, toll-like receptor 4 (TLR4), cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), Akt, and TUNEL were performed. Selective HDAC3 inhibition improved long-term functional outcome (p < 0.05) and reduced infarct volume (p < 0.0001). HDAC3 inhibition increased levels of AcH3 in the ischemic brain (p = 0.016). Higher levels of AcH3 were significantly correlated with better neurological scores and smaller infarct volumes (r = 0.74, p = 0.002; r = 0.6, p = 0.02, respectively). The RGFP966 treatment reduced apoptosis-TUNEL+, cleaved caspase-3+, and cleaved PARP+ cells-and neuroinflammation-TNF-alpha+ and TLR4+ cells-in the ischemic border compared to vehicle control (p < 0.05). The RGFP966 treatment also increased Akt expression in the ipsilateral cortex (p < 0.001). Selective HDAC3 inhibition after stroke improves long-term neurological outcome and decreases infarct volume. The neuroprotective effects of HDAC3 inhibition are associated with a reduction in apoptosis and inflammation and upregulation of the Akt pathway.
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Affiliation(s)
- Rudy Matheson
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
| | - Kohei Chida
- Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
| | - Hui Lu
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.,Xuan Wu Hospital/Capital Medical University, Xicheng district, Beijing, 100053, People's Republic of China
| | - Victoria Clendaniel
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
| | - Marc Fisher
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Ajith Thomas
- Department of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Eng H Lo
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA
| | - Magdy Selim
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Amjad Shehadah
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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Montaner J, Ramiro L, Simats A, Hernández-Guillamon M, Delgado P, Bustamante A, Rosell A. Matrix metalloproteinases and ADAMs in stroke. Cell Mol Life Sci 2019; 76:3117-3140. [PMID: 31165904 PMCID: PMC11105215 DOI: 10.1007/s00018-019-03175-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 05/22/2019] [Accepted: 05/29/2019] [Indexed: 12/27/2022]
Abstract
Stroke is a leading cause of death and disability worldwide. However, after years of in-depth research, the pathophysiology of stroke is still not fully understood. Increasing evidence shows that matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinase" (ADAMs) participate in the neuro-inflammatory cascade that is triggered during stroke but also in recovery phases of the disease. This review covers the involvement of these proteins in brain injury following cerebral ischemia which has been widely studied in recent years, with efforts to modulate this group of proteins in neuroprotective therapies, together with their implication in neurorepair mechanisms. Moreover, the review also discusses the role of these proteins in specific forms of neurovascular disease, such as small vessel diseases and intracerebral hemorrhage. Finally, the potential use of MMPs and ADAMs as guiding biomarkers of brain injury and repair for decision-making in cases of stroke is also discussed.
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Affiliation(s)
- Joan Montaner
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain.
| | - Laura Ramiro
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
| | - Alba Simats
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
| | - Mar Hernández-Guillamon
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
| | - Pilar Delgado
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
| | - Alejandro Bustamante
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
| | - Anna Rosell
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain
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Yu Y, Cao Y, Bell B, Chen X, Weiss RM, Felder RB, Wei SG. Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats. Hypertension 2019; 74:63-72. [PMID: 31154904 DOI: 10.1161/hypertensionaha.119.12651] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
TNF-α (tumor necrosis factor-α) is initially synthesized as a transmembrane protein that is cleaved by TACE (TNF-α-converting enzyme) to release soluble TNF-α. The elevated level of TNF-α in the brain and circulation in heart failure (HF) suggests an increase in the TACE-mediated ectodomain shedding process. The present study sought to determine whether TACE is upregulated in cardiovascular/autonomic brain regions like subfornical organ and hypothalamic paraventricular nucleus in rats with ischemia-induced HF and whether TACE plays a role in TNF-α-driven sympathetic excitation. We found that TACE was expressed throughout the subfornical organ and paraventricular nucleus, with significantly higher levels in HF than in sham-operated (Sham) rats. Intracerebroventricular injection of recombinant TACE induced a mild increase in blood pressure, heart rate, and renal sympathetic nerve activity that peaked at 15 to 20 minutes in both Sham and HF rats. HF rats had a secondary prolonged increase in these variables that was prevented by the TNF-α inhibitor SPD304. Intracerebroventricular administration of the TACE inhibitor TNF-alpha protease inhibitor 1 decreased blood pressure, heart rate, and renal sympathetic nerve activity in Sham and HF rats, with an exaggerated reduction in heart rate and renal sympathetic nerve activity in the HF rats. Direct microinjection of TACE or TNF-alpha protease inhibitor 1 into paraventricular nucleus or subfornical organ of Sham and HF rats elicited blood pressure, heart rate, and renal sympathetic nerve activity responses similar to intracerebroventricular TACE or TNF-alpha protease inhibitor 1. Intracerebroventricular infusion of Ang II (angiotensin II) and IL (interleukin)-1β increased TACE expression in subfornical organ and paraventricular nucleus of normal rats. These data suggest that a TACE-mediated increase in soluble TNF-α in the brain contributes to sympathetic excitation in HF.
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Affiliation(s)
- Yang Yu
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine
| | - Yiling Cao
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine
| | - Balyssa Bell
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine
| | - Xiaolei Chen
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine
| | - Robert M Weiss
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine
| | - Robert B Felder
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine.,Veterans Affairs Medical Center, Iowa City, IA (R.B.F.)
| | - Shun-Guang Wei
- From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine.,Neuroscience Graduate Program (S.-G.W.), University of Iowa Carver College of Medicine
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Dimitriadis K, Wenzel M, Buchholz G, Straube A. Does Pretreatment with a Tumor Necrosis Factor Alpha-inhibitor Improve the Outcome After Ischemic Cerebral Infarction? A Case Report. Cureus 2019; 11:e4089. [PMID: 31032149 PMCID: PMC6472869 DOI: 10.7759/cureus.4089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Tumor necrosis factor-α (TNFα) plays a major role in inflammatory and vascular processes after cerebral ischemia. TNFa-Inhibitors have, on the one hand, been associated with thromboembolic events; on the other hand, they may prevent brain edema after stroke or injury. Here, we report on a 38-year old Caucasian male with a history of Crohn´s disease, treated with adalimumab, who presented without brain edema and only minor sequelae after a major ischemic stroke. This case report illustrates two interesting aspects: 1) the treatment with adalimumab could, in that case, be the etiology for the thromboembolic event; and (2) pretreatment with this TNFa-Inhibitor was the most likely reason why the formation of brain edema was suppressed.
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Affiliation(s)
- Konstantinos Dimitriadis
- Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Munich, DEU
| | - Michael Wenzel
- Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Munich, DEU
| | - Grete Buchholz
- Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Munich, DEU
| | - Andreas Straube
- Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Munich, DEU
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Venkat P, Yan T, Chopp M, Zacharek A, Ning R, Van Slyke P, Dumont D, Landschoot-Ward J, Liang L, Chen J. Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 Diabetic Rats. Cell Transplant 2018; 27:1744-1752. [PMID: 30124060 PMCID: PMC6300775 DOI: 10.1177/0963689718791568] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/24/2018] [Accepted: 06/27/2018] [Indexed: 12/02/2022] Open
Abstract
Angiopoietin-1 (Ang1) mediates vascular maturation and immune response. Diabetes decreases Ang1 expression and disrupts Ang1/Tie2 signaling activity. Vasculotide is an Ang1 mimetic peptide, and has anti-inflammatory effects. In this study, we test the hypothesis that vasculotide treatment induces neuroprotection and decreases inflammation after stroke in type 1 diabetic (T1DM) rats. T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with: 1) phosphate buffered saline (PBS); 2) vasculotide (3µg/kg, i.p. injection) administered half an hour prior to MCAo and at 8 and 24 hours after MCAo. Rats were sacrificed at 48 h after MCAo. Neurological function, infarct volume, hemorrhage, blood brain barrier (BBB) permeability and neuroinflammation were measured. Vasculotide treatment of T1DM-MCAo rats significantly improves functional outcome, decreases infarct volume and BBB permeability, but does not decrease brain hemorrhagic transformation compared with PBS-treated T1DM-MCAo rats. In the ischemic brain, Vasculotide treatment significantly decreases apoptosis, number of cleaved-caspase-3 positive cells, the expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF-α). Western blot analysis shows that vasculotide significantly decreases expression of receptor for advanced glycation end products (RAGE), MCP-1 and TNF-α in the ischemic brain compared with T1DM-MCAo rats. Vasculotide treatment in cultured primary cortical neurons (PCN) significantly decreases TLR4 expression compared with control. Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.
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Affiliation(s)
- Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
| | - Tao Yan
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
- Department of Physics, Oakland University, Rochester, MI, USA
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
| | - Ruizhuo Ning
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
- Department of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | | | - Daniel Dumont
- Department of Medical Biophysics, Sunnybrook Research Institute, University of Toronto, Canada
| | | | - Linlin Liang
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
- Reproductive Medical Center, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
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Immune Cells After Ischemic Stroke Onset: Roles, Migration, and Target Intervention. J Mol Neurosci 2018; 66:342-355. [DOI: 10.1007/s12031-018-1173-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 09/14/2018] [Indexed: 01/09/2023]
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Fidaleo M, Cavallucci V, Pani G. Nutrients, neurogenesis and brain ageing: From disease mechanisms to therapeutic opportunities. Biochem Pharmacol 2017; 141:63-76. [PMID: 28539263 DOI: 10.1016/j.bcp.2017.05.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/19/2017] [Indexed: 02/08/2023]
Abstract
Appreciation of the physiological relevance of mammalian adult neurogenesis has in recent years rapidly expanded from a phenomenon of homeostatic cell replacement and brain repair to the current view of a complex process involved in high order cognitive functions. In parallel, an array of endogenous or exogenous triggers of neurogenesis has also been identified, among which metabolic and nutritional cues have drawn significant attention. Converging evidence from animal and in vitro studies points to nutrient sensing and energy metabolism as major physiological determinants of neural stem cell fate, and modulators of the whole neurogenic process. While the cellular and molecular circuitries underlying metabolic regulation of neurogenesis are still incompletely understood, the key role of mitochondrial activity and dynamics, and the importance of autophagy have begun to be fully appreciated; moreover, nutrient-sensitive pathways and transducers such as the insulin-IGF cascade, the AMPK/mTOR axis and the transcription regulators CREB and Sirt-1 have been included, beside more established "developmental" signals like Notch and Wnt, in the molecular networks that dictate neural-stem-cell self-renewal, migration and differentiation in response to local and systemic inputs. Many of these nutrient-related cascades are deregulated in the contest of metabolic diseases and in ageing, and may contribute to impaired neurogenesis and thus to cognition defects observed in these conditions. Importantly, accumulating knowledge on the metabolic control of neurogenesis provides a theoretical framework for the trial of new or repurposed drugs capable of interfering with nutrient sensing as enhancers of neurogenesis in the context of neurodegeneration and brain senescence.
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Affiliation(s)
- Marco Fidaleo
- Institute of General Pathology, Università Cattolica School of Medicine, 00168 Rome, Italy
| | - Virve Cavallucci
- Institute of General Pathology, Università Cattolica School of Medicine, 00168 Rome, Italy
| | - Giovambattista Pani
- Institute of General Pathology, Università Cattolica School of Medicine, 00168 Rome, Italy.
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Baek AE, Sutton NR, Petrovic-Djergovic D, Liao H, Ray JJ, Park J, Kanthi Y, Pinsky DJ. Ischemic Cerebroprotection Conferred by Myeloid Lineage-Restricted or Global CD39 Transgene Expression. Circulation 2017; 135:2389-2402. [PMID: 28377485 DOI: 10.1161/circulationaha.116.023301] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 03/22/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Cerebral tissue damage after an ischemic event can be exacerbated by inflammation and thrombosis. Elevated extracellular ATP and ADP levels are associated with cellular injury, inflammation, and thrombosis. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39), an enzyme expressed on the plasmalemma of leukocytes and endothelial cells, suppresses platelet activation and leukocyte infiltration by phosphohydrolyzing ATP/ADP. To investigate the effects of increased CD39 in an in vivo cerebral ischemia model, we developed a transgenic mouse expressing human CD39 (hCD39). METHODS A floxed-stop sequence was inserted between the promoter and the hCD39 transcriptional start site, generating a mouse in which the expression of hCD39 can be controlled tissue-specifically using Cre recombinase mice. We generated mice that express hCD39 globally or in myeloid-lineage cells only. Cerebral ischemia was induced by middle cerebral artery occlusion. Infarct volumes were quantified by MRI after 48 hours. RESULTS Both global and transgenic hCD39- and myeloid lineage CD39-overexpressing mice (transgenic, n=9; myeloid lineage, n=6) demonstrated significantly smaller cerebral infarct volumes compared with wild-type mice. Leukocytes from ischemic and contralateral hemispheres were analyzed by flow cytometry. Although contralateral hemispheres had equal numbers of macrophages and neutrophils, ischemic hemispheres from transgenic mice had less infiltration (n=4). Transgenic mice showed less neurological deficit compared with wild-type mice (n=6). CONCLUSIONS This is the first report of transgenic overexpression of CD39 in mice imparting a protective phenotype after stroke, with reduced leukocyte infiltration, smaller infarct volumes, and decreased neurological deficit. CD39 overexpression, either globally or in myeloid lineage cells, quenches postischemic leukosequestration and reduces stroke-induced neurological injury.
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Affiliation(s)
- Amy E Baek
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Nadia R Sutton
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Danica Petrovic-Djergovic
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Hui Liao
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Jessica J Ray
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Joan Park
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - Yogendra Kanthi
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.)
| | - David J Pinsky
- From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.).
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Hsu LW, Shiao WC, Chang NC, Yu MC, Yen TL, Thomas PA, Jayakumar T, Sheu JR. The neuroprotective effects of Tao- Ren- Cheng- Qi Tang against embolic stroke in rats. Chin Med 2017; 12:7. [PMID: 28168001 PMCID: PMC5286857 DOI: 10.1186/s13020-017-0128-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 01/13/2017] [Indexed: 12/12/2022] Open
Abstract
Background Combinations of the traditional Chinese and Western medicines have been used to treat numerous diseases throughout the world, and there is a growing body of evidence showing that some of the herbs used in traditional Chinese medicine elicit significant pharmacological effects. The aim of this study was to demonstrate the neuroprotective effects of Tao-Ren-Cheng-Qi Tang (TRCQT) in combination with aspirin following middle cerebral artery occlusion (MCAO)—induced embolic stroke in rats. Methods A blood clot was embolized into the middle cerebral artery of rats to induce focal ischemic brain injury. After 24 h of MCAO occlusion, the rats were arbitrarily separated into five groups and subjected to different oral treatment processes with TRCQT and aspirin for 30 days before being evaluated in terms of their neurological behavior using a four-point system. The rats were sacrificed at 30 days after drug treatment and the infarct volumes were measured using a 2,3,5-triphenyltetrazolium chloride staining method. Tumor necrosis factor-α (TNF-α), c-Jun N-terminal kinases (JNK), activated caspase-3 and Bax were detected by western blot analysis. The apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. ROS generation was also measured by electron spin resonance spectrometry. Results Rats treated with TRCQT alone or in combination with aspirin showed a significantly reduced infarct volume (P < 0.001) and improved neurological outcome compared with those treated with distilled water. Rats treated with TRCQT alone (P = 0.021) or in combination with aspirin (P = 0.02) also showed significantly reduced MCAO-induced expression levels of TNF-α and pJNK (P < 0.001) in their ischemic regions. Rats treated with TRCQT alone or in combination with aspirin showed decreased apoptosis by a reduction in the number of TUNEL positive cells, which inhibited the expression of activated caspase-3 (P = 0.038) and Bax (P = 0.004; P = 0.003). TRCQT also led to a significant concentration-dependent reduction in the formation of hydroxyl radicals (P < 0.001). Conclusions TRCQT reduced brain infarct volume and improved neurological outcomes by reducing apoptosis, attenuating the expression of TNF-α and p-JNK, and reducing the formation of hydroxyl radicals in MCAO-induced embolic stroke of rats. Electronic supplementary material The online version of this article (doi:10.1186/s13020-017-0128-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ling-Wei Hsu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Cheng Shiao
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Internal Medicine, Yuan's General Hospital, Kaohsiung, Taiwan
| | - Nen-Chung Chang
- Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Meng-Che Yu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ting-Lin Yen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Philip Aloysius Thomas
- Department of Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirappalli, Tamil Nadu 620 001 India
| | - Thanasekaran Jayakumar
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Joen-Rong Sheu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan
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12
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Pan Q, He C, Liu H, Liao X, Dai B, Chen Y, Yang Y, Zhao B, Bihl J, Ma X. Microvascular endothelial cells-derived microvesicles imply in ischemic stroke by modulating astrocyte and blood brain barrier function and cerebral blood flow. Mol Brain 2016; 9:63. [PMID: 27267759 PMCID: PMC4897950 DOI: 10.1186/s13041-016-0243-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 05/25/2016] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Endothelial cell (EC) released microvesicles (EMVs) can affect various target cells by transferring carried genetic information. Astrocytes are the main components of the blood brain barrier (BBB) structure in the brain and participate in regulating BBB integrity and blood flow. The interactions between ECs and astrocytes are essential for BBB integrity in homeostasis and pathological conditions. Here, we studied the effects of human brain microvascular ECs released EMVs on astrocyte functions. Additionally, we investigated the effects of EMVs treated astrocytes on regulating BBB function and cerebral ischemic damage. RESULTS EMVs prepared from ECs cultured in normal condition (n-EMVs) or oxygen and glucose deprivation (OGD-EMVs) condition had diverse effects on astrocytes. The n-EMVs promoted, while the OGD-EMVs inhibited the proliferation of astrocytes via regulating PI3K/Akt pathway. Glial fibrillary acidic protein (GFAP) expression (marker of astrocyte activation) was up-regulated by n-EMVs, while down-regulated by OGD-EMVs. Meanwhile, n-EMVs inhibited but OGD-EMVs promoted the apoptosis of astrocytes accompanied by up/down-regulating the expression of Caspase-9 and Bcl-2. In the BBB model of ECs-astrocytes co-culture, the n-EMVs, conversely to OGD-EMVs, decreased the permeability of BBB accompanied with up-regulation of zonula occudens-1(ZO-1) and Claudin-5. In a transient cerebral ischemia mouse model, n-EMVs ameliorated, while OGD-EMVs aggravated, BBB disruption, local cerebral blood flow (CBF) reduction, infarct volume and neurological deficit score. CONCLUSIONS Our data suggest that EMVs diversely modulate astrocyte functions, BBB integrity and CBF, and could serve as a novel therapeutic target for ischemic stroke.
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Affiliation(s)
- Qunwen Pan
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Caixia He
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.,Guangdong Medical University, Zhanjiang, 524001, China
| | - Hua Liu
- College of Health Science, Wuhan Sports University, Wuhan, Hubei, 430000, China
| | - Xiaorong Liao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Bingyan Dai
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yanfang Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.,Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA.,Department of Neurology, Boonshoft School of Medicine, Wright State University, Dayton, OH, 45435, USA
| | - Yi Yang
- College of Health Science, Wuhan Sports University, Wuhan, Hubei, 430000, China
| | - Bin Zhao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Ji Bihl
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China. .,Department of Pharmacology and Toxicology, Wright State University, Dayton, OH, 45435, USA.
| | - Xiaotang Ma
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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13
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Wang Z, Wang L, Fan R, Zhou J, Zhong J. Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17. Comput Biol Chem 2015; 61:15-22. [PMID: 26709988 DOI: 10.1016/j.compbiolchem.2015.12.003] [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: 05/12/2015] [Revised: 10/07/2015] [Accepted: 12/06/2015] [Indexed: 11/29/2022]
Abstract
Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (Ki=92 and 47nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S=0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding.
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Affiliation(s)
- Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Lei Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Rong Fan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jie Zhou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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14
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WEI ZIJIAN, YU DESHUI, BI YUNLONG, CAO YANG. A disintegrin and metalloprotease 17 promotes microglial cell survival via epidermal growth factor receptor signalling following spinal cord injury. Mol Med Rep 2015; 12:63-70. [PMID: 25738567 PMCID: PMC4438914 DOI: 10.3892/mmr.2015.3395] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 12/12/2014] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) converting enzyme (TACE), also termed a disintegrin and metalloprotease 17 (ADAM17), is involved in multiple cell signalling pathways. Through the secretion of epidermal growth factor receptor (EGFR) ligands, ADAM17 can activate the EGFR and is involved in various downstream signalling pathways. The present study aimed to investigate whether ADAM17‑induced EGFR transactivation is involved in microglial cell survival following spinal cord injury (SCI). Reverse transcription quantitative polymerase chain reaction and western blot analysis revealed that ADAM17 was overexpressed in a mouse model following SCI. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that the viability of human microglia and oligodendrocytes were significantly reduced in a time- and dose-dependent manner following treatment with the ADAM17 antagonist, TNF protease inhibitor 2. Hoechst 33258 staining and flow cytometric analysis revealed that inhibiting ADAM17 increased the rate of cellular apoptosis in neuronal and glial cell cultures, which was accompanied by increased cleavage of caspase-3. Western blot analysis demonstrated that inhibiting ADAM17 resulted in a reduction in the phosphorylation of the EGFR signalling pathway components and thereby impaired functional recovery, inhibited cell viability and prompted microglial apoptosis following SCI. Pre-treatment with the EGFR inhibitor, AG1478, rescued the ADAM17‑mediated proliferation of microglial cells. These data demonstrated that ADAM17 contributed to microglial cell survival, predominantly by EGFR signalling, following SCI.
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Affiliation(s)
- ZIJIAN WEI
- Graduate School of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - DESHUI YU
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - YUNLONG BI
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - YANG CAO
- Department of Orthopedics, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
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15
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Wu D, Gu Q, Zhao N, Xia F, Li Z. Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-α converting enzyme as potential therapeutics for hepatitis. J Drug Target 2015; 23:936-42. [PMID: 26061299 DOI: 10.3109/1061186x.2015.1043916] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The human tumor necrosis factor-α converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 ± 5, 510 ± 46 and 320 ± 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE-inhibitor complex architecture.
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Affiliation(s)
- Dan Wu
- a Infectious Disease Department , The Shengjing Hospital of China Medical University , Shenyang , China
| | - Qiuhong Gu
- a Infectious Disease Department , The Shengjing Hospital of China Medical University , Shenyang , China
| | - Ning Zhao
- a Infectious Disease Department , The Shengjing Hospital of China Medical University , Shenyang , China
| | - Fei Xia
- a Infectious Disease Department , The Shengjing Hospital of China Medical University , Shenyang , China
| | - Zhiwei Li
- a Infectious Disease Department , The Shengjing Hospital of China Medical University , Shenyang , China
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16
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García-García PM, Getino-Melián MA, Domínguez-Pimentel V, Navarro-González JF. Inflammation in diabetic kidney disease. World J Diabetes 2014; 5:431-443. [PMID: 25126391 PMCID: PMC4127580 DOI: 10.4239/wjd.v5.i4.431] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 02/24/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.
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17
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Wang YF, Chen PY, Chang W, Zhu FQ, Xu LL, Wang SL, Chang LY, Luo J, Liu GJ. Clinical significance of tumor necrosis factor-α inhibitors in the treatment of sciatica: a systematic review and meta-analysis. PLoS One 2014; 9:e103147. [PMID: 25050851 PMCID: PMC4106891 DOI: 10.1371/journal.pone.0103147] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 06/26/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Currently, no satisfactory treatment is available for sciatica caused by herniated discs and/or spinal stenosis. The objective of this study is to assess the value of tumor necrosis factor (TNF)-α inhibitors in the treatment of sciatica. METHODS Without language restrictions, we searched PubMed, OVID, EMBASE, the Web of Science, the Clinical Trials Registers, the Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria. RESULTS Nine prospective randomized controlled trials (RCTs) and two before-after controlled trials involving 531 patients met our inclusion criteria and were included in this study. Our systematic assessment and meta-analysis demonstrated that in terms of the natural course of the disease, compared with the control condition, TNF-α inhibitors neither significantly relieved lower back and leg pain (both p > 0.05) nor enhanced the proportion of patients who felt overall satisfaction (global perceived effect (satisfaction)) or were able to return to work (return to work) (combined endpoint; p > 0.05) at the short-term, medium-term and long-term follow-ups. In addition, compared with the control condition, TNF-α inhibitors could reduce the risk ratio (RR) of discectomy or radicular block (combined endpoint; RR = 0.51, 95% CI 0.26 to 1.00, p = 0.049) at medium-term follow-up, but did not decrease RR at the short-term (RR = 0.64, 95% CI 0.17 to 2.40, p = 0.508) and long-term follow-ups (RR = 0.64, 95% CI 0.40 to 1.03, p = 0.065). CONCLUSION The currently available evidence demonstrated that other than reducing the RR of discectomy or radicular block (combined endpoint) at medium-term follow-up, TNF-α inhibitors showed limited clinical value in the treatment of sciatica caused by herniated discs and/or spinal stenosis.
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Affiliation(s)
- Yun Fu Wang
- Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Ping You Chen
- Medical Imaging Center, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Wei Chang
- Department of Spine Surgery, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Fi Qi Zhu
- Department of Neurology, Yuebei People’s Hospital Affiliated to Shantou University Medical College, Shaoguan City, Guangdong Province, China
| | - Li Li Xu
- Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Song Lin Wang
- Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Li Ying Chang
- Department of Neurology, Xiangyang Center Hospital Affiliated to Hubei University of Arts and Science, Xiangyang City, Hubei Province, China
| | - Jie Luo
- Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
| | - Guang Jian Liu
- Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China
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18
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Reduced inflammatory phenotype in microglia derived from neonatal rat spinal cord versus brain. PLoS One 2014; 9:e99443. [PMID: 24914808 PMCID: PMC4051776 DOI: 10.1371/journal.pone.0099443] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 05/15/2014] [Indexed: 12/22/2022] Open
Abstract
Microglia are the primary immune cells of the central nervous system (CNS). Membrane bound sensors on their processes monitor the extracellular environment and respond to perturbations of the CNS such as injury or infection. Once activated, microglia play a crucial role in determining neuronal survival. Recent studies suggest that microglial functional response properties vary across different regions of the CNS. However, the activation profiles of microglia derived from the spinal cord have not been evaluated against brain microglia in vitro. Here, we studied the morphological properties and secretion of inflammatory and trophic effectors by microglia derived from the brain or spinal cord of neonatal rats under basal culture conditions and after activation with lipopolysaccharide (LPS). Our results demonstrate that spinal microglia assume a less inflammatory phenotype after LPS activation, with reduced release of the inflammatory effectors tumor necrosis factor alpha, interleukin-1 beta, and nitric oxide, a less amoeboid morphology, and reduced phagocytosis relative to brain-derived microglia. Phenotypic differences between brain and spinal microglia are an important consideration when evaluating anti-inflammatory or immunomodulatory therapies for brain versus spinal injury.
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19
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Seifert HA, Pennypacker KR. Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res 2014; 5:543-53. [PMID: 24895236 DOI: 10.1007/s12975-014-0349-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 05/19/2014] [Accepted: 05/21/2014] [Indexed: 12/21/2022]
Abstract
Despite extensive research into stroke pathology, there have not been any major recent advancements in stroke therapeutics. Animal models of cerebral ischemia and clinical data have been used to investigate the progressive neural injury that occurs after an initial ischemic insult. This has lead researchers to focus more on the peripheral immune response that is generated as a result of cerebral ischemia. The therapies that have been developed as a result of this research thus far have proven ineffective in clinical trials. The failure of these therapeutics in clinical trials is thought to be due to the broad immunosuppression elicited as a result of the treatments and the cerebral ischemia itself. Emerging evidence indicates a more selective modulation of the immune system following stroke could be beneficial. The spleen has been shown to exacerbate neural injury following experimental stroke and would provide a strong therapeutic target. Selecting facets of the immune system to target would allow the protective and regenerative properties of the immune response to remain intact while blunting the pro-inflammatory response generated towards the injured brain.
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Affiliation(s)
- Hilary A Seifert
- Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd., MDC Box 8, Tampa, FL, 33612, USA
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20
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Sun L, Qiang R, Yang Y, Jiang ZL, Wang GH, Zhao GW, Ren TJ, Jiang R, Xu LH. L-serine treatment may improve neurorestoration of rats after permanent focal cerebral ischemia potentially through improvement of neurorepair. PLoS One 2014; 9:e93405. [PMID: 24671106 PMCID: PMC3966884 DOI: 10.1371/journal.pone.0093405] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 03/04/2014] [Indexed: 01/07/2023] Open
Abstract
The present study was conducted to clarify whether treatment with L-serine can improve the brain repair and neurorestoration of rats after permanent middle cerebral artery occlusion (pMCAO). After pMCAO, the neurological functions, brain lesion volume, and cortical injury were determined. GDNF, NGF, NCAM L1, tenascin-C, and Nogo-A levels were measured. Proliferation and differentiation of the neural stem cells (NSCs) and proliferation of the microvessels in the ischemic boundary zone of the cortex were evaluated. Treatment with L-serine (168 mg/kg body weight, i.p.) began 3 h after pMCAO and was repeated every 12 h for 7 days or until the end of the experiment. L-Serine treatment: 1) reduced the lesion volume and neuronal loss; 2) improved the recovery of neurological functions; 3) elevated the expression of nerve growth-related factors; and 4) facilitated the proliferation of endogenous NSCs and microvessels activated after pMCAO and increased the number of new-born neurons. 5) D-cycloserine, an inhibitor of serine hydroxymethyltransferase, blunted the effects of L-serine on NSC proliferation, differentiation, microvascular proliferation. In conclusions, L-serine treatment in pMCAO rats can reduce brain injury and facilitate neurorestoration which is partly associated with the improvement of proliferation of NSCs and microvessels, reconstruction of neurovascular units and resultant neurorepair. The effects of L-serine on endogenous NSC proliferation and microvascular proliferation are partly mediated by the action of L-serine as a substrate for the production of one-carbon groups used for purine and pyrimidine synthesis and modulation of the expression of some nerve growth-related factors.
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Affiliation(s)
- Li Sun
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
| | - Ren Qiang
- Department of Infectious Diseases, The Third People's Hospital of Nantong, Jiangsu, China
| | - Yao Yang
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
- * E-mail: (ZLJ); (YY)
| | - Zheng-Lin Jiang
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
- Department of Neurology, Affiliated Hospital, Nantong University, Jiangsu, China
- * E-mail: (ZLJ); (YY)
| | - Guo-Hua Wang
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
| | - Guang-Wei Zhao
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
- Department of Neurology, Affiliated Hospital, Nantong University, Jiangsu, China
| | - Tao-Jie Ren
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
- Department of Neurology, Affiliated Hospital, Nantong University, Jiangsu, China
| | - Rui Jiang
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
| | - Li-Hua Xu
- Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China
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21
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Vidal PM, Lemmens E, Avila A, Vangansewinkel T, Chalaris A, Rose-John S, Hendrix S. ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice. Cell Death Dis 2013; 4:e954. [PMID: 24336074 PMCID: PMC3877539 DOI: 10.1038/cddis.2013.466] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 10/16/2013] [Accepted: 10/23/2013] [Indexed: 02/05/2023]
Abstract
A disintegrin and metalloprotease 17 (ADAM17) is a sheddase with important substrates including tumor necrosis factor-α (TNF-α) and its receptors, the p75 neurotrophin receptor (p75NTR), and members of the epidermal growth factor family. The rationale of this study was to inhibit ADAM17-induced shedding of soluble TNF-α in order to reduce detrimental inflammation after spinal cord injury (SCI). However, using the specific ADAM17 blocker BMS-561392 in neuronal and glial cell cultures, we show that proper functioning of ADAM17 is vital for oligodendrocyte and microglia survival in a p44 MAPK-dependent manner. In contrast, genetic ablation of ADAM17 specifically increases microglial death. Surprisingly, although blocking ADAM17 in vivo does not substantially change the ratio between membrane-bound and soluble TNF-α, it increases expression of the pro-apoptotic marker Bax and microglial apoptosis while impairing functional recovery after SCI. These data suggest that ADAM17 is a key survival factor for microglial cells after SCI.
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Affiliation(s)
- P M Vidal
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - E Lemmens
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - A Avila
- 1] Department of Physiology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium [2] Developmental Neurology Unit, GIGA-Neurosciences, University of Liège, Liège, Belgium [3] Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Liège, Belgium
| | - T Vangansewinkel
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - A Chalaris
- Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
| | - S Rose-John
- Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
| | - S Hendrix
- Department of Morphology & Biomedical Research Institute, Hasselt University, Hasselt, Belgium
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Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013; 2013:746068. [PMID: 24223607 PMCID: PMC3810327 DOI: 10.1155/2013/746068] [Citation(s) in RCA: 294] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 08/06/2013] [Accepted: 08/28/2013] [Indexed: 12/18/2022]
Abstract
Stroke is a leading cause of death worldwide. Ischemic stroke is caused by blockage of blood vessels in the brain leading to tissue death, while intracerebral hemorrhage (ICH) occurs when a blood vessel ruptures, exposing the brain to blood components. Both are associated with glial toxicity and neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), continually sample the environment for signs of injury and infection. Under homeostatic conditions, they have a ramified morphology and phagocytose debris. After stroke, microglia become activated, obtain an amoeboid morphology, and release inflammatory cytokines (the M1 phenotype). However, microglia can also be alternatively activated, performing crucial roles in limiting inflammation and phagocytosing tissue debris (the M2 phenotype). In rodent models, microglial activation occurs very early after stroke and ICH; however, their specific roles in injury and repair remain unclear. This review summarizes the literature on microglial responses after ischemic stroke and ICH, highlighting the mediators of microglial activation and potential therapeutic targets for each condition.
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Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor α antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation 2013; 10:103. [PMID: 23962089 PMCID: PMC3765285 DOI: 10.1186/1742-2094-10-103] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 08/02/2013] [Indexed: 01/04/2023] Open
Abstract
Background Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-α) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed. Methods Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-α concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-α antibody, CNTO5048, or vehicle. Results After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024). Conclusions Post-injury treatment with the TNF-α antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.
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Affiliation(s)
- Beilei Lei
- Multidisciplinary Neuroprotection Laboratories, Durham, NC 27710, USA
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Improvement in regional CBF by L-serine contributes to its neuroprotective effect in rats after focal cerebral ischemia. PLoS One 2013; 8:e67044. [PMID: 23825613 PMCID: PMC3692549 DOI: 10.1371/journal.pone.0067044] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 05/13/2013] [Indexed: 11/19/2022] Open
Abstract
To investigate the mechanisms underlying the neuroprotective effect of L-serine, permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery while monitoring cerebral blood flow (CBF). Rats were divided into control and L-serine-treated groups after middle cerebral artery occlusion. The neurological deficit score and brain infarct volume were assessed. Nissl staining was used to quantify the cortical injury. L-serine and D-serine levels in the ischemic cortex were analyzed with high performance liquid chromatography. We found that L-serine treatment: 1) reduced the neurological deficit score, infarct volume and cortical neuron loss in a dose-dependent manner; 2) improved CBF in the cortex, and this effect was inhibited in the presence of apamin plus charybdotoxin while the alleviation of both neurological deficit score and infarct volume was blocked; and 3) increased the amount of L-serine and D-serine in the cortex, and inhibition of the conversion of L-serine into D-serine by aminooxyacetic acid did not affect the reduction of neurological deficit score and infarct volume by L-serine. In conclusion, improvement in regional CBF by L-serine may contribute to its neuroprotective effect on the ischemic brain, potentially through vasodilation which is mediated by the small- and intermediate-conductance Ca2+-activated K+ channels on the cerebral blood vessel endothelium.
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Changes in platelet GPIbα and ADAM17 during the acute stage of atherosclerotic ischemic stroke among Chinese. ACTA ACUST UNITED AC 2013; 33:438-442. [DOI: 10.1007/s11596-013-1138-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Indexed: 12/21/2022]
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26
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Choi JY, Park HJ, Lee YJ, Byun J, Youn YS, Choi JH, Woo SY, Kang JL. Upregulation of Mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammation. J Pharmacol Exp Ther 2013; 344:447-58. [PMID: 23197771 DOI: 10.1124/jpet.112.199778] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Toll-like receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor κB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Mer-neutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury.
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MESH Headings
- ADAM Proteins/antagonists & inhibitors
- ADAM17 Protein
- Animals
- Blotting, Western
- Bronchoalveolar Lavage Fluid/chemistry
- Bronchoalveolar Lavage Fluid/cytology
- Bronchoalveolar Lavage Fluid/immunology
- Cell Count
- Cells, Cultured
- Dipeptides/administration & dosage
- Dipeptides/therapeutic use
- Electrophoretic Mobility Shift Assay
- Enzyme Activation
- Enzyme Induction
- Enzyme-Linked Immunosorbent Assay
- Hydroxamic Acids/administration & dosage
- Hydroxamic Acids/therapeutic use
- Lipopolysaccharides/pharmacology
- Lung/drug effects
- Lung/enzymology
- Lung/metabolism
- Lung/pathology
- Macrophages, Alveolar/drug effects
- Macrophages, Alveolar/enzymology
- Macrophages, Peritoneal/drug effects
- Macrophages, Peritoneal/enzymology
- Male
- Mice
- Mice, Inbred BALB C
- Phosphorylation
- Pneumonia, Bacterial/drug therapy
- Pneumonia, Bacterial/enzymology
- Pneumonia, Bacterial/pathology
- Proto-Oncogene Proteins/biosynthesis
- Proto-Oncogene Proteins/metabolism
- RNA/metabolism
- Receptor Protein-Tyrosine Kinases/biosynthesis
- Receptor Protein-Tyrosine Kinases/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects
- Up-Regulation
- c-Mer Tyrosine Kinase
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Affiliation(s)
- Ji-Yeon Choi
- Department of Physiology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
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27
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Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 2012; 120:3793-802. [DOI: 10.1182/blood-2012-02-412726] [Citation(s) in RCA: 286] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abstract
The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell–dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4+ T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A–blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A–positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.
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Abstract
Inflammation is a hallmark of stroke pathology. The cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, modulate tissue injury in experimental stroke and are therefore potential targets in future stroke therapy. The effect of these cytokines on infarct evolution depends on their availability in the ischemic penumbra in the early phase after stroke onset, corresponding to the therapeutic window (<4.5 hours), which is similar in human and experimental stroke. This review summarizes a large body of literature on the spatiotemporal and cellular production of TNF, IL-1, and IL-6, focusing on the early phase in experimental and human stroke. We also review studies of cytokines in blood and cerebrospinal fluid in stroke. Tumor necrosis factor and IL-1 are upregulated early in peri-infarct microglia. Newer literature suggests that IL-6 is produced by microglia, in addition to neurons. Tumor necrosis factor- and IL-1-producing macrophages infiltrate the infarct and peri-infarct with a delay. This information is discussed in the context of suggestions that neuronal sensitivity to ischemia may be modulated by cytokines. The fact that TNF and IL-1, and suppossedly also IL-6, are produced by microglia within the therapeutic window place these cells centrally in potential future stroke therapy.
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Affiliation(s)
- Kate Lykke Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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RODRIGUES MARIACAROLINAO, DMITRIEV DMITRIY, RODRIGUES ANTONIO, GLOVER LORENE, SANBERG PAULR, ALLICKSON JULIEG, KUZMIN-NICHOLS NICOLE, TAJIRI NAOKI, SHINOZUKA KAZUTAKA, GARBUZOVA-DAVIS SVITLANA, KANEKO YUJI, BORLONGAN CESARV. Menstrual blood transplantation for ischemic stroke: Therapeutic mechanisms and practical issues. Interv Med Appl Sci 2012; 4:59-68. [PMID: 25267932 PMCID: PMC4177033 DOI: 10.1556/imas.4.2012.2.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Cerebrovascular diseases are a major cause of death and long-term disability in developed countries. Tissue plasmin activator (tPA) is the only approved therapy for ischemic stroke, strongly limited by the short therapeutic window and hemorrhagic complications, therefore excluding most patients from its benefits. The rescue of the penumbra area of the ischemic infarct is decisive for functional recovery after stroke. Inflammation is a key feature in the penumbra area and it plays a dual role, improving injury in early phases but impairing neural survival at later stages. Stem cells can be opportunely used to modulate inflammation, abrogate cell death and, therefore, preserve neural function. We here discuss the possible role of stem cells derived from menstrual blood as restorative treatment for stroke. We highlight the availability, proliferative capacity, pluripotentiality and angiogenic features of these cells and explore their present and future experimental and clinical applications.
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Affiliation(s)
- MARIA CAROLINA O. RODRIGUES
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
- Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - DMITRIY DMITRIEV
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - ANTONIO RODRIGUES
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
- Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - LOREN E. GLOVER
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - PAUL R. SANBERG
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | | | | | - NAOKI TAJIRI
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - KAZUTAKA SHINOZUKA
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - SVITLANA GARBUZOVA-DAVIS
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - YUJI KANEKO
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
| | - CESAR V. BORLONGAN
- Department of Neurosurgery and Brain Repair, University of South Florida, College of Medicine, Tampa, FL, USA
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Tauchi R, Imagama S, Natori T, Ohgomori T, Muramoto A, Shinjo R, Matsuyama Y, Ishiguro N, Kadomatsu K. The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. J Neuroinflammation 2012; 9:53. [PMID: 22420304 PMCID: PMC3334708 DOI: 10.1186/1742-2094-9-53] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2011] [Accepted: 03/15/2012] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Chondroitin sulfate proteoglycans are major inhibitory molecules for neural plasticity under both physiological and pathological conditions. The chondroitin sulfate degrading enzyme chondroitinase ABC promotes functional recovery after spinal cord injury, and restores experience-dependent plasticity, such as ocular dominance plasticity and fear erasure plasticity, in adult rodents. These data suggest that the sugar chain in a proteoglycan moiety is essential for the inhibitory activity of proteoglycans. However, the significance of the core protein has not been studied extensively. Furthermore, considering that chondroitinase ABC is derived from bacteria, a mammalian endogenous enzyme which can inactivate the proteoglycans' activity is desirable for clinical use. METHODS The degradation activity of ADAMTS-4 was estimated for the core proteins of chondroitin sulfate proteoglycans, that is, brevican, neurocan and phosphacan. To evaluate the biological significance of ADMATS-4 activity, an in vitro neurite growth assay and an in vivo neuronal injury model, spinal cord contusion injury, were employed. RESULTS ADAMTS-4 digested proteoglycans, and reversed their inhibition of neurite outgrowth. Local administration of ADAMTS-4 significantly promoted motor function recovery after spinal cord injury. Supporting these findings, the ADAMTS-4-treated spinal cord exhibited enhanced axonal regeneration/sprouting after spinal cord injury. CONCLUSIONS Our data suggest that the core protein in a proteoglycan moiety is also important for the inhibition of neural plasticity, and provides a potentially safer tool for the treatment of neuronal injuries.
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Affiliation(s)
- Ryoji Tauchi
- Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
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Lapchak PA. Identifying Vascular Targets to Treat Hemorrhagic Stroke. Transl Stroke Res 2012. [DOI: 10.1007/978-1-4419-9530-8_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Combination treatment with low-dose Niaspan and tissue plasminogen activator provides neuroprotection after embolic stroke in rats. J Neurol Sci 2011; 309:96-101. [PMID: 21802695 DOI: 10.1016/j.jns.2011.07.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 06/29/2011] [Accepted: 07/06/2011] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Niaspan, an extended-release formulation of niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. We have previously demonstrated that Niaspan (40 mg/kg) administered at 2h after stroke induces neuroprotection, while low dose Niaspan (20mg/kg) does not reduce infarct volume. Tissue plasminogen activator (tPA) is an effective therapy for acute stroke, but its use remains limited by a narrow therapeutic window. We have previously demonstrated that intravenous administration of tPA 4h after stroke in rats does not reduce infarct volume. In this study, we tested whether combination treatment with low-dose Niaspan (20mg/kg) and tPA administered 4h after embolic stroke in a rat model reduces infarct volume and provides neuroprotection. METHODS Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with low-dose Niaspan (20mg/kg) alone (n = 7), tPA (10mg/kg) alone (n = 7), combination of low-dose Niaspan and tPA (n = 7), or saline control (n = 9), 4h after stroke. A battery of functional outcome tests was performed. Rats were sacrificed at 7 days after MCAo and lesion volumes were measured. To investigate the underlying mechanism of combination treatment neuroprotective effect, deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), cleaved caspase-3, tumor necrosis factor alpha (TNF-alpha), and toll-like receptor 4 (TLR-4) immunostaining were performed. RESULTS Combination treatment with low-dose Niaspan and tPA significantly improved functional outcome compared to the saline control group (p<0.05), while treatment with Niaspan or tPA alone did not significantly improve functional outcome compared to saline control group. Additionally, combination treatment significantly reduced infarct volume compared to saline control group (p = 0.006) and infarct volume was significantly correlated with functional outcome (p = 0.0008; r = 0.63). Monotherapy with Niaspan or tPA did not significantly decrease infarct volume compared to saline control group. Combination treatment reduced apoptosis as measured by significant reduction in the number of TUNEL-positive cells and cleaved caspase-3 expression in the ischemic brain compared to saline control group (p<0.05). Combination treatment also significantly reduced the expression of TNF-alpha and TLR-4 in the ischemic brain compared to Niaspan, tPA and saline treatment groups (p<0.05). A significant interaction between Niaspan and tPA on the TNF-alpha expression was detected (p<0.05), indicating a synergy effect in the combination treatment group. CONCLUSION Treatment of stroke with combination of low-dose Niaspan and tPA at 4h after embolic stroke reduces infarct volume, improves neurological outcome and provides neuroprotection. The neuroprotective effects of combination treatment were associated with reduction of apoptosis and attenuation of TNF-alpha and TLR-4 expression.
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Recent progress in cell therapy for basal ganglia disorders with emphasis on menstrual blood transplantation in stroke. Neurosci Biobehav Rev 2011; 36:177-90. [PMID: 21645544 DOI: 10.1016/j.neubiorev.2011.05.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 04/25/2011] [Accepted: 05/20/2011] [Indexed: 12/13/2022]
Abstract
Cerebrovascular diseases are the third leading cause of death and the primary cause of long-term disability in the United States. The only approved therapy for stroke is tPA, strongly limited by the short therapeutic window and hemorrhagic complications, therefore excluding most patients from its benefits. Parkinson's and Huntington's disease are the other two most studied basal ganglia diseases and, as stroke, have very limited treatment options. Inflammation is a key feature in central nervous system disorders and it plays a dual role, either improving injury in early phases or impairing neural survival at later stages. Stem cells can be opportunely used to modulate inflammation, abrogate cell death and, therefore, preserve neural function. We here discuss the role of stem cells as restorative treatments for basal ganglia disorders, including Parkinson's disease, Huntington's disease and stroke, with special emphasis to the recently investigated menstrual blood stem cells. We highlight the availability, proliferative capacity, pluripotentiality and angiogenic features of these cells and explore their present and future experimental and clinical applications.
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Lapchak PA, Wu Q. Vascular Dysfunction in Brain Hemorrhage: Translational Pathways to Developing New Treatments from Old Targets. JOURNAL OF NEUROLOGY & NEUROPHYSIOLOGY 2011; 2011:S1-e001. [PMID: 22400125 PMCID: PMC3293216 DOI: 10.4172/2155-9562.s1-e001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hemorrhagic stroke which is a form of stroke that affects 20% of all stroke patients is a devastating condition for which new treatments must be developed. Current treatment methods are quite insufficient to reduce long term morbidity and high mortality rate, up to 50%, associated with bleeding into critical brain structures, into ventricular spaces and within the subarachnoid space. During the last 10-15 years, significant advances in the understanding of important mechanisms that contribute to cell death and clinical deficits have been made. The most important observations revolve around a key set of basic mechanisms that are altered in brain bleeding models, including activation of membrane metalloproteinases, oxidative stress and both inflammatory and coagulation pathways. Moreover, it is now becoming apparent that brain hemorrhage can activate the ischemic stroke cascade in neurons, glial cells and the vascular compartment. The activation of multiple pathways allows comes the opportunity to intervene pharmacologically using monotherapy or combination therapy. Ultimately, combination therapy or pleiotropic compounds with multi-target activities should prove to be more efficacious than any single therapy alone. This article provides a comprehensive look at possible targets for small molecule intervention as well as some new approaches that result in metabolic down-regulation or inhibition of multiple pathways simultaneously.
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Affiliation(s)
- Paul A. Lapchak
- Director of Translational Research, Cedars-Sinai Medical Center, Department of Neurology, Davis Research Building, D- 2091, 110 N, George Burns Road, Los Angeles, CA 90048 USA
| | - Qiang Wu
- Project Scientist, Cedars-Sinai Medical Center, Department of Neurology, Davis Research Building, D-2094E, 110 N. George Burns Road, Los Angeles, CA 90048 USA
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Liu WH, Chang LS. Suppression of ADAM17-mediated Lyn/Akt pathways induces apoptosis of human leukemia U937 cells: Bungarus multicinctus protease inhibitor-like protein-1 uncovers the cytotoxic mechanism. J Biol Chem 2010; 285:30506-15. [PMID: 20679348 DOI: 10.1074/jbc.m110.156257] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Cell surface proteases have been demonstrated to play an important role in facilitating cell invasion into the extracellular matrix and may contribute significantly to extracellular matrix degradation by metastatic cancer cells. Abundant expression of these enzymes is associated with poor prognosis. Thus, protease inhibitors that repress cell surface proteases may be applicable to cancer therapy. Because soybean Kunitz-type trypsin inhibitor has been found to induce apoptotic death of human leukemia Jurkat cells, anti-leukemia activity of Bungarus multicinctus protease inhibitor-like protein-1 (PILP-1) is thus examined. PILP-1 induced apoptosis of human leukemia U937 cells, characteristic of loss of mitochondrial membrane potential, degradation of procaspase-8, and production of t-Bid. FADD down-regulation neither restored viability of PILP-1-treated cells nor attenuated production of active caspase-8 and t-Bid in PILP-1-treated cells, suggesting that the death receptor-mediated pathway was not involved in the cytotoxicity of PILP-1. It was found that PILP-1-evoked p38 MAPK activation and ERK inactivation led to PILP-1-induced cell death and down-regulation of ADAM17. Knockdown of ADAM17 by siRNA induced death of U937 cells and inactivation of Lyn and Akt. Immunoprecipitation suggested that ADAM17 and Lyn form complexes. Overexpression of ADAM17, LynY507F (gain of function), and constitutively active Akt suppressed the cytotoxic effects of PILP-1. PILP-1-elicited inactivation of Lyn and Akt was abrogated in cells with overexpressed ADAM17 or LynY507F. Taken together, our data indicate that ADAM17-mediated activation of Lyn/Akt maintains the viability of U937 cells and that suppression of the pathway is responsible for PILP-1-induced apoptosis.
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Affiliation(s)
- Wen-Hsin Liu
- From the Institute of Biomedical Sciences, National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
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Abstract
This review focuses on the role of ADAM-17 in disease. Since its debut as the tumor necrosis factor converting enzyme (TACE), ADAM-17 has been reported to be an indispensible regulator of almost every cellular event from proliferation to migration. The central role of ADAM-17 in cell regulation is rooted in its diverse array of substrates: cytokines, growth factors, and their receptors as well as adhesion molecules are activated or inactivated by their cleavage with ADAM-17. It is therefore not surprising that ADAM-17 is implicated in numerous human diseases including cancer, heart disease, diabetes, rheumatoid arthritis, kidney fibrosis, Alzheimer's disease, and is a promising target for future treatments. The specific role of ADAM-17 in the pathophysiology of these diseases is very complex and depends on the cellular context. To exploit the therapeutic potential of ADAM-17, it is important to understand how its activity is regulated and how specific organs and cells can be targeted to inactivate or activate the enzyme.
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Affiliation(s)
- Monika Gooz
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
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37
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Niaspan treatment induces neuroprotection after stroke. Neurobiol Dis 2010; 40:277-83. [PMID: 20554037 DOI: 10.1016/j.nbd.2010.05.034] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Revised: 05/26/2010] [Accepted: 05/30/2010] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION Niaspan, an extended-release formulation of Niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. In this study, we tested whether Niaspan administered acutely after stroke is neuroprotective. METHODS Adult male rats (n=8/group) were subjected to 2h of middle cerebral artery occlusion (MCAo) and treated with or without different doses of Niaspan (20, 40 or 80 mg/kg) at 2 and 24h after MCAo. A battery of functional outcome tests was performed, and serum HDL and triglycerides were measured. Rats were sacrificed at 7 days after MCAo and lesion volumes were measured. The optimal dose of Niaspan treatment of stroke was chosen for immunostaining: deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), cleaved caspase-3, tumor necrosis factor alpha (TNF-alpha), vascular endothelial growth factor (VEGF) and phosphorylated phosphatidylinositol 3-kinase (p-PI3K). Another set of rats (n=4/group) were killed at 7 days after MCAo for Western blot assay. RESULTS Niaspan dose-dependently reduced infarct volume and improved functional outcome after stroke. No significant difference in HDL and triglyceride levels was detected between Niaspan treatments and MCAo control groups. Niaspan treatment significantly decreased the number of TUNEL-positive cells (105+/-17) and cleaved caspase-3 expression (381+/-33) in the ischemic brain compared to MCAo control (165+/-18; 650+/-61, respectively; p<or=0.05). Niaspan treatment significantly reduced the expression of TNF-alpha (9.7+/-1.1% vs. 16+/-2.2%; p<or=0.05) and negative correlations were observed between the functional tests and the expression of TNF-alpha (r=-0.71, p<or=0.05). Niaspan treatment also significantly increased the expression of VEGF (5.2+/-0.9%) and PI3K/Akt (0.381+/-0.04%) in the ischemic brain compared with non-treated MCAo control (2.6+/-0.4%; 0.24+/-0.03, respectively; p<or=0.05). The functional outcome was positively correlated with p-PI3K (r=0.7, p<or=0.05). CONCLUSIONS Treatment of stroke with Niaspan at 2h after MCAo reduces infarct volume and improves neurological outcome and provides neuroprotection. The neuroprotective effects of Niaspan were associated with reduction of apoptosis and attenuation of TNF-alpha expression. VEGF and the PI3K/Akt pathway may contribute to the Niaspan-induced neuroprotection after stroke.
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Yamashita A, Kunimatsu T, Yamada K, Kojo A, Yamamoto T, Sato S, Onozuka M. Hypothermic and normothermic ischemia-reperfusion activate microglia differently in hippocampal formation. ACTA ACUST UNITED AC 2010; 73:73-80. [DOI: 10.1679/aohc.73.73] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Anzu Yamashita
- Research Center of Brain and Oral Science, Kanagawa Dental College
- Department of Human Biology, Kanagawa Dental College
| | - Teruhito Kunimatsu
- Division of Dental Anesthesiology, Department of Comprehensive Dentistry, Kanagawa Dental College, Yokohama Dental and Medical Clinic and Clinical Training Center
| | - Kentaro Yamada
- Research Center of Brain and Oral Science, Kanagawa Dental College
- Department of Physiology and Neuroscience, Kanagawa Dental College
| | - Akiko Kojo
- Department of Physiology and Neuroscience, Kanagawa Dental College
| | - Toshiharu Yamamoto
- Research Center of Brain and Oral Science, Kanagawa Dental College
- Department of Human Biology, Kanagawa Dental College
| | - Sadao Sato
- Research Center of Brain and Oral Science, Kanagawa Dental College
- Department of Craniofacial Growth and Development Dentistry, Kanagawa Dental College
| | - Minoru Onozuka
- Research Center of Brain and Oral Science, Kanagawa Dental College
- Department of Physiology and Neuroscience, Kanagawa Dental College
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Badiola N, Malagelada C, Llecha N, Hidalgo J, Comella JX, Sabriá J, Rodríguez-Alvarez J. Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol Dis 2009; 35:438-47. [PMID: 19555759 DOI: 10.1016/j.nbd.2009.06.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 05/22/2009] [Accepted: 06/16/2009] [Indexed: 01/08/2023] Open
Abstract
TNF-alpha has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-alpha in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-alpha is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-alpha-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-alpha receptor 1, we show that the activation of both caspase-3 and -8 by TNF-alpha is mediated by TNF-alpha receptor 1. The pro-apoptotic role of TNF-alpha in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-alpha or TNF-alpha receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-alpha/TNF-alpha receptor 1.
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Affiliation(s)
- Nahuai Badiola
- Institut de Neurociencies, Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Spain
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Abstract
Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial- not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglial-derived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.
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41
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Ridder D, Schwaninger M. NF-κB signaling in cerebral ischemia. Neuroscience 2009; 158:995-1006. [DOI: 10.1016/j.neuroscience.2008.07.007] [Citation(s) in RCA: 294] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 06/27/2008] [Accepted: 07/03/2008] [Indexed: 01/04/2023]
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ADAM 17 endopeptidase. CLASS 3 HYDROLASES 2009. [PMCID: PMC7123059 DOI: 10.1007/978-3-540-85705-1_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008; 5:45. [PMID: 18925972 PMCID: PMC2577641 DOI: 10.1186/1742-2094-5-45] [Citation(s) in RCA: 634] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Accepted: 10/17/2008] [Indexed: 12/31/2022] Open
Abstract
The role of tumor necrosis factor (TNF) as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1) is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF) or transmembrane TNF (tmTNF), with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.
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Affiliation(s)
- Melissa K McCoy
- Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA.
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Specific targeting of metzincin family members with small-molecule inhibitors: Progress toward a multifarious challenge. Bioorg Med Chem 2008; 16:8781-94. [DOI: 10.1016/j.bmc.2008.08.058] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Revised: 08/22/2008] [Accepted: 08/26/2008] [Indexed: 12/20/2022]
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Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. ACTA ACUST UNITED AC 2008; 4:300-9. [PMID: 18414459 DOI: 10.1038/ncprheum0797] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Accepted: 02/19/2008] [Indexed: 12/13/2022]
Abstract
The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis.
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Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19:433-42. [PMID: 18256353 DOI: 10.1681/asn.2007091048] [Citation(s) in RCA: 658] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Juan F Navarro-González
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010 Santa Cruz de Tenerife, Spain.
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Rosenzweig HL, Minami M, Lessov NS, Coste SC, Stevens SL, Henshall DC, Meller R, Simon RP, Stenzel-Poore MP. Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance. J Cereb Blood Flow Metab 2007; 27:1663-74. [PMID: 17327883 DOI: 10.1038/sj.jcbfm.9600464] [Citation(s) in RCA: 124] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.
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Affiliation(s)
- Holly L Rosenzweig
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA
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Lapchak PA, Araujo DM. Advances in hemorrhagic stroke therapy: conventional and novel approaches. Expert Opin Emerg Drugs 2007; 12:389-406. [PMID: 17874968 DOI: 10.1517/14728214.12.3.389] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may require a multifaceted approach, such as combining drugs with diverse mechanisms of action. Because of the substantial benefit of factor VIIa in reducing hemorrhage volume, it should be considered as a prime drug candidate included in combination therapy as an off-label use if the FAST trial proves that the risk of thromboembolic events is not increased with drug administration. Other promising drugs that may be considered in combination include uncompetitive NMDA receptor antagonists (such as memantine), antioxidants, metalloprotease inhibitors, statins and erythropoietin analogs, all of which have been shown to reduce hemorrhage and behavioral deficits in one or more animal models.
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Affiliation(s)
- Paul A Lapchak
- University of California San Diego, Department of Neuroscience, MTF 316, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA.
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Davis RL, Buck DJ, Saffarian N, Stevens CW. The opioid antagonist, beta-funaltrexamine, inhibits chemokine expression in human astroglial cells. J Neuroimmunol 2007; 186:141-9. [PMID: 17475341 PMCID: PMC1948894 DOI: 10.1016/j.jneuroim.2007.03.021] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2006] [Revised: 03/22/2007] [Accepted: 03/28/2007] [Indexed: 11/19/2022]
Abstract
Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)alpha induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-kappaB], we determined that NF-kappaB activation is instrumental in TNFalpha-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFalpha stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFalpha-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor beta-funaltrexamine (beta-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFalpha-induced CXCL10 expression. Rather, beta-FNA dose-dependently inhibited TNFalpha-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and beta-FNA each reduced TNFalpha-induced nuclear translocation of NF-kappaB p65. These data show that beta-FNA and fentanyl inhibit TNFalpha-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFalpha-induced CXCL10 expression by fentanyl and beta-FNA is not directly related to a reduction in NF-kappaB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, beta-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.
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Affiliation(s)
- Randall L Davis
- Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, 1111 W. 17th Street, Tulsa, Oklahoma 74107, USA.
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Doherty GH. Developmental switch in the effects of TNFα on ventral midbrain dopaminergic neurons. Neurosci Res 2007; 57:296-305. [PMID: 17150272 DOI: 10.1016/j.neures.2006.10.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2006] [Revised: 10/27/2006] [Accepted: 10/30/2006] [Indexed: 12/22/2022]
Abstract
The cytokine tumour necrosis factor-alpha (TNFalpha) has been implicated in the pathogenesis of neurodegenerative conditions as well as in the establishment of neural networks during development. This study investigated the in vitro effects of TNFalpha on embryonic dopaminergic neurons of the ventral mesencephalon. TNFalpha treatment enhanced the number of dopaminergic neurons in cultures derived from E12.5 mice embryos in a dose-dependent manner. In order to achieve this effect TNFalpha signalled via NF-kappaB. This enhancement in cell number was found to be due to TNFalpha promoting the differentiation of dopaminergic neurons rather than to an increase in cell survival. In contrast, TNFalpha-treated cultures derived from E14 or E16 mice demonstrated a decrease in dopaminergic neurons, and this loss was negated by pharmacological inhibition of caspases. The data presented demonstrate that during embryonic development, dopaminergic ventral mesencephalic neurons switch their in vitro response to TNFalpha from neurotrophic to neurotoxic. This is the first report of a population of neurons exhibiting this switch in TNFalpha responsiveness during neurodevelopment.
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Affiliation(s)
- G H Doherty
- School of Biology, University of St Andrews, Bute Medical Buildings, St Mary's Quad, St Andrews, Fife, Scotland, UK.
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