PT  - JOURNAL ARTICLE
AU  - Brenneman, Douglas E.
AU  - Hauser, Janet
AU  - Neale, Elaine
AU  - Rubinraut, Sara
AU  - Fridkin, Mati
AU  - Davidson, Ariane
AU  - Gozes, Illana
TI  - Activity-Dependent Neurotrophic Factor: Structure-Activity Relationships of Femtomolar-Acting Peptides
DP  - 1998 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 619--627
VI  - 285
IP  - 2
4099  - http://jpet.aspetjournals.org/content/285/2/619.short
4100  - http://jpet.aspetjournals.org/content/285/2/619.full
SO  - J Pharmacol Exp Ther1998 May 01; 285
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics