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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Delivery across the Blood-Brain Barrier of Antisense Directed against Amyloid β: Reversal of Learning and Memory Deficits in Mice Overexpressing Amyloid Precursor Protein

William A. Banks, Susan A. Farr, Waseem Butt, Vijaya B. Kumar, Mark W. Franko and John E. Morley
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 1113-1121;
William A. Banks
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Susan A. Farr
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Waseem Butt
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Vijaya B. Kumar
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Mark W. Franko
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John E. Morley
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Abstract

Amyloid β protein (Aβ) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Aβ, can be reversed with i.c.v. injections of an Aβ antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with 32P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 ± 0.39 μl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 ± 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.

Footnotes

  • Send reprint requests to: Dr. John E. Morley, Saint Louis University Health Sciences Center, Division of Geriatric Medicine, 1402 S. Grand Blvd., Room M238, St. Louis, MO 63104. E-mail:morley{at}slu.edu

  • This study was supported by Veterans Affairs Merit Review, R0-1 MH54979, and R0-1 NS41863.

  • Abbreviations:
    CNS
    central nervous system
    BBB
    blood-brain barrier
    Aβ
    amyloid β protein
    APP
    amyloid precursor protein
    Olg
    phosphorothiolate oligonucleotide
    P-Olg
    oligonucleotide radioactively labeled with 32P
    LR-BSA
    lactated Ringer's solution containing 1% by volume of bovine serum albumin
    Expt
    exposure time
    Vi
    distribution volume in brain att = 0
    %Inj/g
    percentage of the dose injected i.v. taken up by each gram of brain
    CSF
    cerebrospinal fluid
    PE
    polyethylene
    OTS-1
    oligonucleotide transport system-1
    ANOVA
    analysis of variance
    • Received January 3, 2001.
    • Accepted February 16, 2001.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Delivery across the Blood-Brain Barrier of Antisense Directed against Amyloid β: Reversal of Learning and Memory Deficits in Mice Overexpressing Amyloid Precursor Protein

William A. Banks, Susan A. Farr, Waseem Butt, Vijaya B. Kumar, Mark W. Franko and John E. Morley
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1113-1121;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Delivery across the Blood-Brain Barrier of Antisense Directed against Amyloid β: Reversal of Learning and Memory Deficits in Mice Overexpressing Amyloid Precursor Protein

William A. Banks, Susan A. Farr, Waseem Butt, Vijaya B. Kumar, Mark W. Franko and John E. Morley
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1113-1121;
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