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      Lysophosphatidic Acid Reduces Microregional Oxygen Supply/Consumption Balance after Cerebral Ischemia-Reperfusion

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          Abstract

          Background: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. Objective: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O<sub>2</sub> supply/consumption balance after cerebral ischemia-reperfusion. Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C<sup>14</sup>-iodoantipyrine autoradiographic technique. Regional small-vessel (20–60 µm in diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. Results: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O<sub>2</sub> consumption to the contralateral cortex. However, microregional O<sub>2</sub> supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O<sub>2</sub> saturation (43 of 80 veins with O<sub>2</sub> saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O<sub>2</sub> extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O<sub>2</sub> saturations in the reperfused region (76 of 80 veins with O<sub>2</sub> saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). Conclusion: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.

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          Most cited references 32

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          Is Open Access

          Ischemic stroke: experimental models and reality

          The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel (“ischemic stroke”) eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models.
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            Lysophosphatidic Acid signaling in the nervous system.

            The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.
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              Pathobiology of injury after stroke: the neurovascular unit and beyond.

              Throughout the history of research on stroke pathophysiology, focus has shifted from purely vascular concepts to the insight that a complex interplay of biochemical and molecular mechanisms involving practically any cell type of the brain ("neurovascular unit") partakes in either salvage or demise of the tissue after a stroke. In addition, it was realized that peripheral immune cells play important roles, not only after their invasion into the brain but also because of stroke-induced effects on the immune system that can result in infections. Indeed, outcome of stroke patients is not only dictated by nonmodifiable factors, such as severity of stroke, age, or premorbidity, but also by modifiable factors largely related to medical complications, such as infections and possibly sarcopenia. The highly successful concept of stroke units attests to the benefits of treating stroke comprehensively. Breakthroughs in improving outcome after stroke will only result from approaches that target not only the brain, but also systemic effects of stroke. © 2012 New York Academy of Sciences.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2020
                July 2020
                20 May 2020
                : 57
                : 4
                : 178-184
                Affiliations
                aDepartment of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
                bDepartment of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
                Author notes
                *Dr. Harvey R. Weiss, Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854 (USA), hweiss@rwjms.rutgers.edu
                Article
                506011 J Vasc Res 2020;57:178–184
                10.1159/000506011
                32434183
                © 2020 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, Pages: 7
                Categories
                Research Article

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