Activity-dependent neurotrophic factor: Structure-activity relationships of femtomolar-acting peptides

Douglas E. Brenneman*, Janet Hauser, Elaine Neale, Sara Rubinraut, Mati Fridkin, Ariane Davidson, Illana Gozes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)619-627
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume285
Issue number2
StatePublished - 1998

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