Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis

doi:10.1016/J.PATHOPHYS.2009.12.001

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Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis

Journal Article•DOI•

Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis

Prabal Deb¹, Suash Sharma², Hassan Km•Institutions (2)

Armed Forces Medical College¹, Georgia Regents University²

01 Jun 2010-Pathophysiology (Elsevier)-Vol. 17, Iss: 3, pp 197-218

TL;DR: The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, with emphasis on potential novel targets for designing newer therapeutic modalities.

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About: This article is published in Pathophysiology.The article was published on 2010-06-01. It has received 492 citations till now. The article focuses on the topics: Ischemic cascade & Stroke.

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Journal Article•DOI•

Reactive Oxygen Species in Metabolic and Inflammatory Signaling.

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Steven J. Forrester¹, Daniel S. Kikuchi¹, Marina S. Hernandes¹, Qian Xu¹, Kathy K. Griendling¹ - Show less +1 more•Institutions (1)

Emory University¹

16 Mar 2018-Circulation Research

TL;DR: The role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke is highlighted and the balance ROS signaling plays in both physiology and pathophysiology is understood.

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Abstract: Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases.

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1,011 citations

Journal Article•DOI•

The Pharmacological Potential of Rutin.

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Aditya Ganeshpurkar¹, Ajay Saluja¹•Institutions (1)

Gujarat Technological University¹

01 Feb 2017-Journal of The Saudi Pharmaceutical Society

TL;DR: The present review highlights current information and health-promoting effects of rutin and safety pharmacology issues and SAR of the same have also been discussed.

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Abstract: The contemporary scientific community has presently recognized flavonoids to be a unique class of therapeutic molecules due to their diverse therapeutic properties. Of these, rutin, also known as vitamin P or rutoside, has been explored for a number of pharmacological effects. Tea leaves, apples, and many more possess rutin as one of the active constituents. Today, rutin has been observed for its nutraceutical effect. The present review highlights current information and health-promoting effects of rutin. Along with this, safety pharmacology issues and SAR of the same have also been discussed.

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737 citations

Cites background from "Pathophysiologic mechanisms of acut..."

...Oxidative stress and inflammation are two of the pathological events observed after ‘ischemic injury’ in the brain (Deb et al., 2010)....
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Journal Article•DOI•

Stroke and the immune system: from pathophysiology to new therapeutic strategies

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Richard Macrez¹, Carine Ali¹, Olivier Toutirais¹, Brigitte Le Mauff¹, Gilles Defer², Ulrich Dirnagl², Denis Vivien¹ - Show less +3 more•Institutions (2)

French Institute of Health and Medical Research¹, Charité²

01 May 2011-Lancet Neurology

TL;DR: Development of novel and effective therapeutic strategies for stroke will require further investigation of pathways in the immune system and inflammatory responses in terms of their temporal profile (before, during, and after stroke) and risk-to-benefit therapeutic ratio of modulating them.

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Abstract: Summary Stroke is the second most common cause of death worldwide and a major cause of acquired disability in adults. Despite tremendous progress in understanding the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed, with the exception of thrombolysis, which only benefits a small proportion of patients. Systemic and local immune responses have important roles in causing stroke and are implicated in the primary and secondary progression of ischaemic lesions, as well as in repair, recovery, and overall outcome after a stroke. However, potential therapeutic targets in the immune system and inflammatory responses have not been well characterised. Development of novel and effective therapeutic strategies for stroke will require further investigation of these pathways in terms of their temporal profile (before, during, and after stroke) and risk-to-benefit therapeutic ratio of modulating them.

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411 citations

Journal Article•DOI•

The role of extracellular histone in organ injury

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Eleanor Silk¹, Hailin Zhao¹, Hao Weng², Daqing Ma¹•Institutions (2)

Imperial College London¹, Shanghai Jiao Tong University²

25 May 2017-Cell Death and Disease

TL;DR: Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ injury but warrant further research to inform future clinical applications.

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Abstract: Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved across species Within the nucleus, they provide structural stability to chromatin and regulate gene expression Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil extracellular traps, and all three can be detected in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion injury and autoimmune disease Once in the extracellular space, histones act as damage-associated molecular pattern proteins, activating the immune system and causing further cytotoxicity They interact with Toll-like receptors (TLRs), complement and the phospholipids of cell membranes inducing endothelial and epithelial cytotoxicity, TLR2/TLR4/TLR9 activation and pro-inflammatory cytokine/chemokine release via MyD88, NFκB and NLRP3 inflammasome-dependent pathways Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ injury but warrant further research to inform future clinical applications

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212 citations

Cites background from "Pathophysiologic mechanisms of acut..."

...Thrombo-embolism of the cerebral arteries results in acutely reduced cerebral perfusion, and if prolonged, irreversible inflammatory neuronal injury.(74) In vivo animal studies conducted to characterise the release and functional role of extracellular nucleosomes(53) show that animals exposed to moderate hypoxia (6% over 24 h), demonstrate a threefold rise in circulating levels of nucleosomes compared with control animals....
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Journal Article•DOI•

Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke.

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M. Angels Font, Adrià Arboix, Jerzy Krupinski

31 Jul 2010-Current Cardiology Reviews

TL;DR: These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region, and the origin of newly formed vessels and the pathogenic role of neovascularization and neurogenesis are important unresolved issues in the understanding of the mechanisms after stroke.

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Abstract: Only very little is know about the neurovascular niche after cardioembolic stroke. Three processes implicated in neurorepair: angiogenesis, neurogenesis and synaptic plasticity, would be naturally produced in adult brains, but also could be stimulated through endogen neurorepair phenomena. Angiogenesis stimulation generates new vessels with the aim to increase collateral circulation. Neurogenesis is controlled by intrinsic genetic mechanisms and growth factors but also ambiental factors are important. The leading process of the migrating neural progenitor cells (NPCs) is closely associated with blood vessels, suggesting that this interaction provides directional guidance to the NPCs. These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region. DNA microarray technology and blood genomic profiling in human stroke provided tools to investigate the expression of thousands of genes. Critical comparison of gene expression profiles after stroke in humans with those in animal models should lead to a better understanding of the pathophysiology of brain ischaemia. Probably the most important part of early recovery after stroke is limited capacity of penumbra/infarct neurones to recover. It became more clear in the last years, that penumbra is not just passively dying over time but it is also actively recovering. This initial plasticity in majority contributes towards later neurogenesis, angiogenesis and final recovery. Penumbra is a principal target in acute phase of stroke. Thus, the origin of newly formed vessels and the pathogenic role of neovascularization and neurogenesis are important unresolved issues in our understanding of the mechanisms after stroke. Biomaterials for promoting brain protection, repair and regeneration are new hot target. Recently developed biomaterials can enable and increase the target delivery of drugs or therapeutic proteins to the brain, allow cell or tissue transplants to be effectively delivered to the brain and help to rebuild damaged circuits. These new approaches are gaining clear importance because nanotechnology allows better control over material-cell interactions that induce specific developmental processes and cellular responses including differentiation, migration and outgrowth.

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204 citations

Cites background from "Pathophysiologic mechanisms of acut..."

..., the serine protease tissue-type plasminogen activator (tPA), utility of which is limited by short therapeutic window [54]....
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References

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Atherosclerosis — An Inflammatory Disease

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Russell Ross¹•Institutions (1)

University of Washington¹

14 Jan 1999-The New England Journal of Medicine

TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.

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Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

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Journal Article•DOI•

Atherosclerosis--an inflammatory disease.

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P L Weissberg, M R Bennett

17 Jun 1999-The New England Journal of Medicine

6,810 citations

"Pathophysiologic mechanisms of acut..." refers background in this paper

...Experimental studies have shown that inhibition of the inflammatory process has lead to control of the extent of injury, an aspect which has gained paramount importance in understanding stroke and management of cases thereof [4,54,55]....
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...There is increasing evidence that an inflammatory proess is the central dogma in the development and progression f atherosclerosis, a common entity underlying the pathoenesis of cerebral and cardiac ischemia [4]....
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...effect of complex interplay among monocytes, lipoproteins, platelets, lymphocytes, and smooth muscle cells in the intimal layer [4]....
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Journal Article•DOI•

Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells

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Vincenzo Pasceri¹, Vincenzo Pasceri², James T. Willerson², James T. Willerson¹, Edward T.H. Yeh - Show less +1 more•Institutions (2)

University of Texas Health Science Center at Houston¹, St Lukes Episcopal Hospital²

31 Oct 2000-Circulation

TL;DR: The hypothesis that CRP may play a direct role in promoting the inflammatory component of atherosclerosis and present a potential target for the treatment of Atherosclerosis is supported.

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Abstract: Background—The acute-phase reactant C-reactive protein (CRP) is an important risk factor for coronary heart disease. However, the possible effects of CRP on vascular cells are not known. Methods and Results—We tested the effects of CRP on expression of adhesion molecules in both human umbilical vein and coronary artery endothelial cells. Expression of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and E-selectin was assessed by flow cytometry. Incubation with recombinant human CRP (10 μg/mL) for 24 hours induced an ≈10-fold increase in expression of ICAM-1 and a significant expression of VCAM-1, whereas a 6-hour incubation induced significant E-selectin expression. Adhesion molecule induction was similar to that observed in endothelial cells activated with interleukin-1β. In coronary artery endothelial cells, induction of ICAM-1 and VCAM-1 was already present at 5 μg/mL and reached a maximum at 50 μg/mL, at which point a substantial increase in expression of E-selectin...

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1,946 citations

"Pathophysiologic mechanisms of acut..." refers background in this paper

...Interleukin-6: Cerebral ischemia is a potential bioactivator of IL-6 mRNA, especially in middle cerebral artery occlusion (MCAO) in animal models....
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...Angiotensin II has proinflammatory effects via augentation of expression of VCAM-1, MCP-1, and IL-6, and ncreased production of reactive oxygen species, which can e countered by angiotensin converting enzyme inhibitors or ngiotensin II receptor blockers for having anti-inflammatory ffect [138]....
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...CRP may be elevated in a number of cariovascular risk factors like increasing age, smoking, body ass index, lipid levels, and hypertension, while hypertenion itself may have a proinflammatory role mediated by ICAM-1 and IL-6 [128]....
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...Cytokine targets: Dual, anti-inflammatory and proinflamatory, effects of TNF- and of IL-6, have been the primary oncern in using strategies directed against these cytokines....
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...Acute phase reactants and body temperature In the normal condition body tends to respond to various issue injury, including inflammatory and infective condiions, by means of cytokines, primarily IL-6 and IL-1....
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Journal Article•DOI•

p53 Has a Direct Apoptogenic Role at the Mitochondria

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Motohiro Mihara¹, Susan Erster¹, Alex Zaika¹, Oleksi Petrenko¹, Thomas Chittenden², Petr Pancoska³, Ute M. Moll¹ - Show less +3 more•Institutions (3)

Stony Brook University¹, ImmunoGen, Inc.², University of Illinois at Chicago³

01 Mar 2003-Molecular Cell

TL;DR: Evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes is provided and it is shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release.

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1,751 citations

"Pathophysiologic mechanisms of acut..." refers background in this paper

...Prominent among these, include p53 [29], JNK (of MAPK family [30]), c-jun [31], p38 [32] and cyclin dependant kinase 5 (cdk-5) [33], which are potential targets for therapeutic intervention....
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Journal Article•DOI•

Glutamate-mediated astrocyte-neuron signalling.

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Vladimir Parpura¹, Trent A. Basarsky¹, Fang Liu¹, Ksenija Jeftinija¹, Srdija Jeftinija¹, Philip G. Haydon¹ - Show less +2 more•Institutions (1)

Iowa State University¹

30 Jun 1994-Nature

TL;DR: Astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate, and an NMDA (N-methyl-d-aspartate) receptor-mediated increase in neuronal calcium is demonstrated.

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Abstract: NEUROTRANSMITTER released from neurons is known to signal to neighbouring neurons and glia1–3 Here we demonstrate an additional signalling pathway in which glutamate is released from astrocytes and causes an NMDA (N-methyl-d-aspartate) receptor-mediated increase in neuronal calcium. Internal calcium was elevated and glutamate release stimulated by application of the neuro-ligand bradykinin to cultured astrocytes. Elevation of astrocyte internal calcium was also sufficient to induce glutamate release. To determine whether this released glutamate signals to neurons, we studied astrocyte–neuron co-cultures. Bradykinin significantly increased calcium levels in neurons co-cultured with astrocytes, but not in solitary neurons. The glutamate receptor antagonists d-2-amino-5-phosphonopentanoic acid and d-glutamylglycine prevented bradykinin-induced neuronal calcium elevation. When single astrocytes were directly stimulated to increase internal calcium and release glutamate, calcium levels of adjacent neurons were increased; this increase could be blocked by d-glutamylglycine. Thus, astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate.

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1,662 citations

"Pathophysiologic mechanisms of acut..." refers background in this paper

...Release of excitatory neurotransmitter, glutamate, to modulate activity in nearby neurons occur through six known mechanisms: (i) reversal of uptake by plasma membrane glutamate transporters [9], (ii) anion channel opening induced by cell swelling [10], (iii) Ca2+dependent exocytosis [11], (iv) glutamate exchange via the cystine–glutamate antiporter [12], (v) release through ionotropic purinergic receptors [13], and (vi) functional unpaired connexons, ‘hemichannels’, on the cell surface [14]....
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