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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activity-Dependent Neurotrophic Factor: Intranasal Administration of Femtomolar-Acting Peptides Improve Performance in a Water Maze

Illana Gozes, Eliezer Giladi, Albert Pinhasov, Amos Bardea and Douglas E. Brenneman
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 1091-1098;
Illana Gozes
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Eliezer Giladi
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Albert Pinhasov
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Amos Bardea
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Douglas E. Brenneman
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Abstract

Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. A nine-amino acid peptide derived from ADNF (Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala; ADNF-9) captured the activity of the parent protein and has been reported to protect cultured neurons from multiple neurotoxins. Antibodies recognizing ADNF-9 produced neuronal apoptosis, and identified an additional, structurally related, glia-derived peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAP). Previous comparative studies have characterized s.c.-injected NAP as most efficacious in protecting against developmental retardation and learning impairments in apolipoprotein E-deficient mice. This study was designed to assess 1) neuroprotection after intranasal administration of ADNF-9 and NAP to rats treated with the cholinotoxin ethylcholine aziridium; and 2) bioavailability and pharmacokinetics after intranasal administration. Results showed significant improvements in short-term spatial memory, as assessed in a water maze, after daily intranasal administration of 1 μg of peptide (ADNF-9 or NAP) per animal. However, a 5-day pretreatment with ADNF-9 did not improve performance measured after cessation of treatment. Compared with rats treated with ADNF-9, NAP-pretreated animals exhibited a significantly better performance. Furthermore, NAP (and not ADNF-9) protected against loss of choline acetyl transferase activity. Significant amounts of3H-labeled NAP reached the brain, remained intact 30 min after administration, and dissipated 60 min after administration. This study revealed efficacy for ADNF-related peptides in rodent models for neurodegeneration. The small size of the molecules, the low dosage required, the noninvasive administration route, and the demonstrated activity in a relevant paradigm suggest NAP as a lead compound for future drug design.

Footnotes

  • Send reprint requests to: Dr. Illana Gozes, Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: igozes{at}post.tau.ac.il

  • ↵1 This study was supported, in part, by the U.S.-Israel Binational Science Foundation, the Israel Science Foundation, and the Institute for the Study of Aging.

  • ↵2 I.G. is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

  • ↵3 This work is in partial fulfillment of the requirements for the Ph.D. degree of A.P.

  • Abbreviations:
    VIP
    vasoactive intestinal peptide
    ADNF
    activity-dependent neurotrophic factor
    ADNF-14
    Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala
    ADNF-9
    Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala
    hsp60
    heat shock protein 60
    NAP
    Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln
    AF64A
    ethylcholine aziridium
    ChAT
    choline acetyl transferase
    SNV
    stearyl-Nle17-VIP
    bFGF
    basic fibroblast growth factor
    • Received December 2, 1999.
    • Accepted February 22, 2000.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activity-Dependent Neurotrophic Factor: Intranasal Administration of Femtomolar-Acting Peptides Improve Performance in a Water Maze

Illana Gozes, Eliezer Giladi, Albert Pinhasov, Amos Bardea and Douglas E. Brenneman
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1091-1098;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activity-Dependent Neurotrophic Factor: Intranasal Administration of Femtomolar-Acting Peptides Improve Performance in a Water Maze

Illana Gozes, Eliezer Giladi, Albert Pinhasov, Amos Bardea and Douglas E. Brenneman
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1091-1098;
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