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      Diurnal Uptake of Circulating Interleukin-1α by Brain, Spinal Cord, Testis and Muscle

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          Abstract

          The effects, synthesis, and release of cytokines show diurnal patterns. We used recombinant human interleukin-1α radioactively labeled with <sup>125</sup>I (I-IL) to determine whether its uptake by brain, spinal cord, testis and muscle showed a diurnal rhythm when tested every 4 h in mice. Each tissue showed statistically significant diurnal variation in their uptakes of I-IL ranging from a nearly 10-fold difference for the spinal cord to less than a 2-fold difference for muscle. All nadirs occurred at either 04.00 or 24.00 h and all peaks at 08.00 or 12.00 h. The pharmacokinetics of intravenously injected I-IL did not show any significant variations in blood. Recombinant human tumor necrosis factor-α, which does not cross the blood-brain barrier, did not show a diurnal rhythm in its uptake by any of these tissues. This diurnal variation in the rate of uptake of cytokines by tissues could underlie differences in potency when given at different times of the day.

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          Most cited references 5

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          Murine tumor necrosis factor alpha is transported from blood to brain in the mouse.

          The cytokines are important components of the brain-immune axis. Recent work has shown that [125I]IL-1 alpha and [125I]IL-1 beta are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNF alpha) labeled with 125I (I-mTNF alpha) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNF alpha showed that this transport system was saturable, and lack of inhibition by IL-1 alpha, IL-1 beta, IL-6, or MIP-1 alpha showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the i.v. injection of I-mTNF alpha showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNF alpha in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNF alpha from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNF alpha is sequestered by the brain. The BBB was not disrupted by up to 50 micrograms kg-1 of mTNF alpha i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
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            Bidirectional transport of interleukin-1 alpha across the blood-brain barrier.

            Circulating interleukin-1 alpha (IL-1 alpha) has multiple effects on the central nervous system. We investigated the ability of radioiodinated IL-1 alpha (rIL-1 alpha) to cross the rodent blood-brain barrier and found its entry rate to be 43.9 times greater than that predicted by leakage alone. The rIL-1 alpha entered multiple regions of the brain, with over 40% entering at the cortex. The hypothalamus had the highest entry rate on a weight basis but only accounted for 2% of total entry. In all experiments, the entry rate of rIL-1 alpha greatly exceeded that of simultaneously injected radiolabeled albumin. The half-time disappearance of rIL-1 alpha from the brain after central injection was 21.9 min, a time that exceeds the reabsorption rate of cerebrospinal fluid. Pretreatment of animals with aluminum decreased both entry and exit rates, which is compatible with a saturable component of transport. Thus, rIL-1 alpha has access to many regions of the brain with bidirectional transport rates across the blood-brain barrier exceeding those predicted by nonspecific mechanisms.
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              Interleukin-1α in blood has direct access to cortical brain cells

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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                1998
                April 1998
                10 July 1998
                : 5
                : 1-2
                : 36-41
                Affiliations
                Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, La., USA
                Article
                26324 Neuroimmunomodulation 1998;5:36–41
                10.1159/000026324
                9698256
                © 1998 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
                Pages: 6
                Categories
                Original Paper

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