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Vol. 293, Issue 3, 1091-1098, June 2000
Department of Clinical Biochemistry, Sackler School of Medicine,
Tel Aviv University, Tel Aviv, Israel (I.G., E.G., A.P., A.B.); and
Section on Developmental and Molecular Pharmacology, Laboratory of
Developmental Neurobiology, National Institute for Child Health and
Human Development, National Institutes of Health, Bethesda, Maryland
(D.E.B.)
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 of
3H-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.
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