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      Hypothalamic Response to Experimental Allergic Encephalomyelitis: Role of Substance P

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          Abstract

          Adjuvant-induced arthritis (AA) is thought to be a model for experimental chronic stress that has as main features decreased adrenocorticotropin hormone (ACTH) plasma levels and a rise in median eminence content of arginine vasopressin (AVP) due to the activity of substance P. In experimental allergic encephalomyelitis (EAE), another chronic stress model, the role of substance P action is not clear. In this paper we tried to clarify the role of substance P in Lewis rats, which are susceptible to this disease. EAE was induced using myelin basic protein plus complete Freund’s adjuvant injected into the hind limbs. One day later injections of an antagonist to substance P (RP 67580), saline, and substance P were administered daily for 12–14 days through a stainless steel cannula into the lateral ventricle of the brain, and then the rats were killed. The rats were divided into groups of controls, sham, diseased controls (no intracerebroventricular injections) and EAE (injected intracerebroventricularly). Plasma was used for the quantification of ACTH and corticosterone but not AVP which was assayed in hypothalamic median eminence extracts. In noninjected diseased rats the plasma levels of ACTH and corticosterone were significantly higher than in noninjected control rats, whereas the AVP concentrations in the median eminence were unchanged. The substance P antagonist did not affect the levels of these hormones in plasma or the median eminence. Substance P decreased the plasma levels of ACTH and corticosterone but did not increase the median eminence content of vasopressin. Administration of the antagonist 30 min before an equivalent dose of substance P increased the plasma levels of the two hormones, but did not change the content of AVP. Based on the lack of response to the antagonist RP 67580 we suggest that the substance P has different roles in EAE and AA at least in the later stages of EAE (after 11 days of immunization).

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          Most cited references 12

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          IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35-55 induced experimental autoimmune encephalomyelitis.

          We investigated the role of IL-6 in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE) using IL-6-deficient mice and found that IL-6-deficient mice were resistant to active induction of EAE, but that the treatment of those mice with IL-6 during the preclinical phase caused typical EAE. We also found that both wild-type and IL-6-deficient mice were resistant to passive transfer of EAE by lymphocytes from IL-6-deficient mice, but that passive transfer of lymphocytes from wild-type mice induced typical EAE in IL-6-deficient mice. Histological abnormalities of the central nervous system (CNS) in those IL-6-deficient mice with EAE were similar to those in wild-type mice with EAE. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed no difference in the production of inflammatory cytokines such as IL-1beta, IL-2, TNF-alpha, and IFN-gamma in the CNS of IL-6-deficient mice with EAE as compared to the CNS of wild-type mice with EAE. These results indicated that IL-6 might be an important factor in the induction phase, but might have little influence on the effector phase of EAE. We further estimated the production of cytokines in MOG-stimulated lymph node (LN) cells by enzyme-linked immunosorbent assay. Increased IL-4 and IL-10 production and reduced IL-2 and IFN-gamma production were observed in LN cells from IL-6-deficient mice as compared to LN cells from wild-type mice. These results suggested that a shift of T cell responses from Thl to Th2 might explain the resistance of IL-6-deficient mice to EAE. Taken together, IL-6 may play a crucial role in the induction phase of EAE by modulating Th1/Th2 balance.
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            Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids

             FA Antoni,  DW Mason (1989)
            Lewis rats with experimental allergic encephalomyelitis (EAE), induced either by the subcutaneous injection of guinea pig myelin basic protein (MBP) or by the adoptive transfer of MBP-primed spleen cells, suffer from a single episode of paralysis from which they recover spontaneously. Animals developing EAE were found to have greatly elevated levels of corticosterone in the blood. This endogenous increase in steroid production was accompanied by lymphopenia and depressed delayed-type hypersensitivity responses to OVA, indicating that rats with EAE are immunosuppressed in an antigen-nonspecific fashion. Adrenalectomized rats given subcutaneous implants of corticosterone to maintain basal steroid levels invariably died when EAE was induced. However, if the steroid replacement therapy was adjusted to mimic the hormone levels that were observed in intact rats developing EAE, then the disease followed a nonfatal course closely resembling that seen in the nonadrenalectomized controls. Replacement therapy that achieved serum corticosterone levels slightly higher than those found in intact rats with EAE virtually suppressed the disease completely. It is concluded that endogenous corticosterone release in rats with EAE plays an essential role in the spontaneous recovery that is observed in this condition. However, the subsequent refractory phase that is characteristic of rats that have recovered from EAE induced by active immunization with MBP is not associated with chronically elevated corticosterone levels. This finding is discussed in the light of other data that suggest that unlike the spontaneous recovery, the refractory state has an immunological basis rather than an endocrinological basis.
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              Biological effects of single and repeated swimming stress in male rats: beneficial effects of glucocorticoids.

               E Gürsoy,  M Kalimi,  Y. Hu (2000)
              We have examined the biological effects of single (45 min at 22 degrees C) and repeated swimming stress (45 min at 22 degrees C for 7 d) using male Sprague-Dawley rats. Repeated swimming for a week resulted in a significant inhibition in total body weight (25%) as compared to control unstressed animals. There was significant increase in adrenal and kidney relative weight and decreases in relative thymus weight in repeated swimming-stressed animals as compared to control animals. Repeated swimming stress resulted in almost threefold increase in plasma corticosterone levels with concomitant dramatic decrease in total glucocorticoid receptor (GR) levels in liver, thymus, and heart as compared to control unstressed animals. Interestingly, single swimming stress resulted in a significant elevation in lipid peroxidation levels in the liver and heart. In contrast, there was no change in the lipid per oxidation levels in the liver and heart between chronic stressed and control unstressed animals. Finally, both single and repeated swimming-stress animals had almost 50% reduction in plasma triglyceride levels as compared to control unstressed animals. It is concluded that elevated plasma corticosterone levels by downregulating GR during repeated swimming stress exerts beneficial effects in rats by retarding the total body weight gain and lowering plasma triglyceride levels without affecting free-radicals-induced oxidative stress.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2004
                October 2003
                17 October 2003
                : 11
                : 1
                : 28-35
                Affiliations
                aDepartamento de Patologia Clínica, Núcleo de Medicina e Cirurgia Experimental, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, Brasil; bInstitut de Physique Biologique, cInstitut National de la Santé et de la Recherche Médicale (Inserm U-398), Faculté de Médecine et dHôpital de Hautepierre, Strasbourg, France
                Article
                72966 Neuroimmunomodulation 2004;11:28–35
                10.1159/000072966
                14557676
                © 2004 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, References: 40, Pages: 8
                Categories
                Original Paper

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