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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Intravenous Human Interleukin-1α Impairs Memory Processing in Mice: Dependence on Blood-Brain Barrier Transport into Posterior Division of the Septum

William A. Banks, Susan A. Farr, Michael E. La Scola and John E. Morley
Journal of Pharmacology and Experimental Therapeutics November 2001, 299 (2) 536-541;
William A. Banks
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Susan A. Farr
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Michael E. La Scola
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John E. Morley
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Abstract

Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1α (hIL-1α; mIL-1α) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1α to affect memory. Retention was impaired in a dose-dependent manner when hIL-1α was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1α was reversed by injecting a blocking antibody (Ab) specific for hIL-1α into the PDS. This shows that much of the memory impairment induced by hIL-1α depends on its ability to cross the BBB. Ab specific for mIL-1α was also effective in reversing memory impairment, showing that hIL-1α releases mIL-1α from endogenous stores. Whether the mIL-1α was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1α affects memory by releasing mIL-1α from endogenous stores and by crossing the BBB to act at sites within the PDS.

Footnotes

  • This study was supported by Veterans Affairs Merit review, R01 AA12743, and R01 NS41863.

  • Abbreviations:
    CNS
    central nervous system
    IL-1
    interleukin-1
    BBB
    blood-brain barrier
    hIL-1α
    human interleukin-1α
    mIL-1α
    murine interleukin-1α
    mIL-1β
    murine interleukin-1β
    PDS
    posterior division of the septum
    hIL-1β
    human interleukin-1β
    Ab
    antibody
    GS
    goat serum
    Ab-h1α
    blocking antibody specific for human IL-1α
    Ab-h1β
    blocking antibody specific for human IL-1β
    Ab-m1α
    blocking antibody specific for murine IL-1α
    Ab-m1β
    blocking antibody specific for murine IL-1β
    ND50
    concentration of antibody required to yield one-half-maximal inhibition of the [3H]thymidine incorporation by murine T-helper D10.G4.1 cells when the cytokine is present at a concentration just high enough to elicit a maximum response
    I-hIL-1β
    hIL-1β radioactively labeled with131I
    Ki
    unidirectional influx rate
    ANOVA
    analysis of variance
    NS
    normal saline
    CSF
    cerebrospinal fluid
    • Received June 22, 2001.
    • Accepted August 3, 2001.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 299 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 2
1 Nov 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Intravenous Human Interleukin-1α Impairs Memory Processing in Mice: Dependence on Blood-Brain Barrier Transport into Posterior Division of the Septum

William A. Banks, Susan A. Farr, Michael E. La Scola and John E. Morley
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 536-541;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Intravenous Human Interleukin-1α Impairs Memory Processing in Mice: Dependence on Blood-Brain Barrier Transport into Posterior Division of the Septum

William A. Banks, Susan A. Farr, Michael E. La Scola and John E. Morley
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 536-541;
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