Introduction

Vasoactive intestinal peptide (VIP), which was originally discovered in the intestine as a 28–amino acid peptide and shown to induce vasodilation, was later found to be a major brain peptide with neuroprotective activities in vivo [1–5]. To exert neuroprotective activity in the brain, VIP requires glial cells that secrete protective proteins such as activity-dependent neurotrophic factor (ADNF [6]). ADNF, isolated by sequential chromatographic methods, was named activity-dependent neurotrophic factor because it protects neurons from death associated with the blockade of electrical activity.

ADNF is a 14-kDa protein, and structure-activity studies have identified femtomolar-active neuroprotective peptides, ADNF-14 (VLGGGSALLRSIPA) [6] and ADNF-9 (SALLRSIPA) [7]. ADNF-9 exhibits protective activity in Alzheimer's disease–related systems (β-amyloid toxicity [7], presenilin 1 mutation [8], apolipoprotein E deficiencies [9] – genes that have been associated with the onset and progression of Alzheimer's disease (AD)). Other studies have indicated protection against oxidative stress via the maintenance of mitochondrial function and a reduction in the accumulation of intracellular reactive oxygen species [10]. In the target neurons, ADNF-9 regulates transcriptional activation associated with neuroprotection (nuclear factor-κB [11]), promotes axonal elongation through transcriptionally regulated cAMP-dependent mechanisms [12] and increases chaperonin 60 (Cpn60/Hsp60) expression, thereby providing cellular protection against the β-amyloid peptide [13].

Longer peptides that include the ADNF-9 sequence (e.g., ADNF-14) activate protein kinase C and mitogen-associated protein kinase kinase and protect developing mouse brain against excitotoxicity [14].