Activity-dependent neurotrophic factor: Intranasal administration of femtomolar-acting peptides improve performance in a water maze

Illana Gozes*, Eliezer Giladi, Albert Pinhasov, Amos Bardea, Douglas E. Brenneman

*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 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-pre-treated 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.

Original languageEnglish
Pages (from-to)1091-1098
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume293
Issue number3
StatePublished - Jun 2000

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