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

Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein tha t is neuroprotective at femtomolar concentrations. A nine-amino acid peptid e derived from ADNF (Ser-Ala-Leu-Leu-Arg-Ser-lle-Pro-Ala; ADNF-9) captured the activity of the parent protein and has been reported to protect culture d neurons from multiple neurotoxins. Antibodies recognizing ADNF-9 produced neuronal apoptosis, and identified an additional, structurally related, gl ia-derived peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAP). Previous compara tive studies have characterized s.c.-injected NAP as most efficacious in pr otecting against developmental retardation and learning impairments in apol ipoprotein E-deficient mice. This study was designed to assess 1) neuroprot ection after intranasal administration of ADNF-9 and NAP to rats treated wi th the cholinotoxin ethylcholine aziridium; and 2) bioavailability and phar macokinetics after intranasal administration. Results showed significant im provements in short-term spatial memory, as assessed in a water maze, after daily intranasal administration of 1 mu g of peptide (ADNF-9 or NAP) per a nimal. However, a 5-day pretreatment with ADNF-9 did not improve performanc e measured after cessation of treatment. Compared with rats treated with AD NF-9, NAP-pretreated animals exhibited a significantly better performance. Furthermore, NAP land not ADNF-9) protected against loss of choline acetyl transferase activity. Significant amounts of H-3-labeled NAP reached the br ain, remained intact 30 min after administration, and dissipated 60 min aft er administration. This study revealed efficacy for ADNF-related peptides i n rodent models far neurodegeneration. The small size of the molecules, the low dosage required, the noninvasive administration route, and the demonst rated activity in a relevant paradigm suggest NAP as a lead compound for fu ture drug design.