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Vol. 285, Issue 2, 619-627, May 1998
Section on Developmental and Molecular Pharmacology (D.E.B., J.H.),
Section on Cell Biology (E.N.), Laboratory of Developmental
Neurobiology, National Institute for Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland;
Department of Organic Chemistry (S.R., M.F.), The Weizmann Institute of
Science, Rehovot, Israel;
Department of Clinical Biochemistry (A.D.,
I.G.), Sackler School of Medicine, Tel Aviv University, Tel Aviv,
Israel
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
1013 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
-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.
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