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      Attenuation of Canine Cerebral Vasospasm after Subarachnoid Hemorrhage by Protein Kinase C Inhibitors despite Augmented Phosphorylation of Myosin Light Chain

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          Abstract

          The purpose of the present study is to assess the roles of protein kinase C (PKC) isoforms, especially PKCδ and α, and 20-kD myosin light chain (MLC<sub>20</sub>) phosphorylation in the mechanism of cerebral vasospasm following subarachnoid hemorrhage (SAH). We had shown that those PKC isoforms are involved in the development of cerebral vasospasm. Using PKC isoform-specific inhibitors in a ‘two- hemorrhage’ canine model, we examined changes in the development of cerebral vasospasm, translocation of PKC isoforms and MLC<sub>20</sub> phosphorylation level in canine basilar arteries. A PKC inhibitor (5 µ M rottlerin for PKCδ or chelerythrine for PKCα) was injected into the cisterna magna on day 4 before the second hemorrhage. The treatment was continued daily until day 7. Rottlerin inhibited the initial phase of vasospasm and PKCδ translocation, but did not significantly inhibit PKCα translocation. Chelerythrine inhibited cerebral vasospasm, and the translocation of both PKCδ and α throughout the entire course of the study. Although cerebral vasospasm after SAH was inhibited by each PKC inhibitor, the MLC<sub>20</sub> phosphorylation level remained elevated as in the untreated hemorrhage-control study. We conclude that cerebral vasospasm following SAH depends on PKCδ and α, while the enhancement of MLC<sub>20</sub> phosphorylation contributes little to this form of vasospasm.

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          Most cited references 5

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          The molecular heterogeneity of protein kinase C and its implications for cellular regulation.

           Y Nishizuka (1988)
          Protein kinase C is now known to be a large family of proteins, with multiple subspecies that have subtle individual enzymological characteristics. Some members of the family exhibit distinct patterns of tissue expression and intracellular localization; different kinases probably have distinct functions in the processing and modulation of a variety of physiological and pathological responses to external signals.
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            Rottlerin, a novel protein kinase inhibitor.

            Rottlerin, a compound from Mallotus philippinensis, is shown to inhibit protein kinases with some specificity for PKC. To some extent, the novel inhibitor is able to differentiate between PKC isoenzymes, with IC50 values for PKC delta of 3-6 microM, PKC alpha,beta,gamma of 30-42 microM and PKC epsilon,eta,zeta of 80-100 microM. Inhibition of PKC appears, at least in part, to be due to a competition between rottlerin and ATP. Among the protein kinases tested, only CaM-kinase III is suppressed by rottlerin as effectively as PKC delta. The chemical structure of rottlerin might serve as a basis for the development of novel inhibitors with improved selectivity for a distinct PKC isoenzyme, such as PKC delta, or for CaM-kinase III.
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              Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cdelta.

              Phospholipid scramblase induces nonspecific bidirectional movement of phospholipids across the membrane during cell activation and has been proposed to mediate the appearance of phosphatidylserine (PS) in the plasma membrane outer leaflet during apoptosis, a cell surface change that is critical for apoptotic cell removal. We report here that protein kinase C (PKC) delta plays an important role in activated transbilayer movement of phospholipids and surface PS exposure by directly enhancing the activity of phospholipid scramblase. Specific inhibition of PKCdelta by rottlerin prevented both apoptosis- and activation-induced scramblase activity. PKCdelta was either selectively cleaved and activated in a caspase 3-dependent manner (during apoptosis) or translocated to the plasma membrane (in stimulated cells) and could directly phosphorylate scramblase immunoprecipitated from Jurkat cells. Furthermore, reconstitution of PKCdelta and scramblase, but not scramblase or PKCdelta alone in Chinese hamster ovary cells demonstrated enhanced scramblase activity.
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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
                2003
                April 2003
                19 June 2003
                : 40
                : 2
                : 169-178
                Affiliations
                aDepartment of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, and bDepartment of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
                Article
                70714 J Vasc Res 2003;40:169–178
                10.1159/000070714
                12808353
                © 2003 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, References: 27, Pages: 10
                Categories
                Research Paper

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