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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Activity-Dependent Neurotrophic Factor: Structure-Activity Relationships of Femtomolar-Acting Peptides

Douglas E. Brenneman, Janet Hauser, Elaine Neale, Sara Rubinraut, Mati Fridkin, Ariane Davidson and Illana Gozes
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 619-627;
Douglas E. Brenneman
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Janet Hauser
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Elaine Neale
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Sara Rubinraut
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Mati Fridkin
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Ariane Davidson
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Illana Gozes
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Abstract

Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. A 14-amino acid peptide of ADNF (ADNF-14) has been reported that protects cultured neurons from multiple neurotoxins. Structure-activity relationships of peptides related to ADNF-14 now have been determined. A 9-amino acid core peptide (ADNF-9) has been identified that has greater potency and a broader effective concentration range (10−16 to 10−13 M) than ADNF or ADNF-14 in preventing cell death associated with tetrodotoxin treatment of cerebral cortical cultures. Deletions or conservative amino acid substitutions to ADNF-9 resulted in reduced potency, narrower effective concentration range and/or decreased efficacy. Removal of the N-terminal serine or the COOH-terminal isoleucine-proline-alanine from ADNF-9 produced a significant reduction in survival-promoting activity. Comparative studies of ADNF-9 action in mixed (glia plus neurons) vs.glia-depleted neuronal cultures indicated that ADNF-9 can act directly on neurons, although the potency of the peptide was 10,000-fold greater in mixed cultures. Kinetic studies showed that exposure to ADNF-9 for only 2 hr was sufficient to produce a 4-day protection against the cell-killing action of tetrodotoxin. Treatment with bafilomycin A1 (an inhibitor of receptor-mediated endocytosis) for 2 hr prevented the ADNF- and ADNF-9-mediated neuroprotection. ADNF-9, like ADNF-14, was neuroprotective against N-methyl-d-aspartate and the β-amyloid peptide (amino acids 25–35), and had a much broader range of effective concentrations than ADNF-14. These studies identify ADNF-9 as an attractive lead compound for the development of therapeutic agents against neurodegenerative diseases.

Footnotes

  • Send reprint requests to: Dr. Douglas E. Brenneman, Chief, Section on Developmental and Molecular Pharmacology, Laboratory of Developmental Neurobiology, National Institute for Child Health and Human Development, Building 49, Room 5A38, National Institutes of Health, Bethesda, MD 20892.

  • ↵1 Supported in part by the U.S.-Israel-Binational Science Foundation (BSF).

  • Abbreviations:
    ADNF
    activity-dependent neurotrophic factor
    TTX
    tetrodotoxin
    PBS
    phosphate-buffered saline
    NMDA
    N-methyl-d-aspartate
    VIP
    vasoactive intestinal peptide
    SDS
    sodium dodecyl sulfate
    hsp60
    heat shock protein 60
    BFA
    bafilomycin A1
    RME
    receptor-mediated endocytosis
    • Received August 14, 1997.
    • Accepted January 22, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Activity-Dependent Neurotrophic Factor: Structure-Activity Relationships of Femtomolar-Acting Peptides

Douglas E. Brenneman, Janet Hauser, Elaine Neale, Sara Rubinraut, Mati Fridkin, Ariane Davidson and Illana Gozes
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 619-627;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Activity-Dependent Neurotrophic Factor: Structure-Activity Relationships of Femtomolar-Acting Peptides

Douglas E. Brenneman, Janet Hauser, Elaine Neale, Sara Rubinraut, Mati Fridkin, Ariane Davidson and Illana Gozes
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 619-627;
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