From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division.

Accelerated neuronal death brings about cognitive as well as motor and other dysfunctions. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective. However, VIP-based drug design is hampered by the instability of the peptide and its limited bioavailability. Two independent approaches were thus taken to exploit VIP as a lead drug candidate: (1) Potent neuroprotective lipophilic analogs of VIP were synthesized, e.g. [stearyl-norleucine-17] VIP (SNV); and (2) potent neuroprotective peptide derivatives were identified that mimic the activity of VIP-responsive neuroprotective glial proteins. VIP provides neuronal defense by inducing the synthesis and secretion of neuroprotective proteins from astrocytes; activity-dependent neuroprotective protein (ADNP) was discovered as such glial cell mediator of VIP- and SNV-induced neuroprotection. In subsequent studies, an eight-amino-acid peptide, NAP, was identified as the smallest active element of ADNP exhibiting potent neuroprotective activities. This paper summarizes the biological effects of SNV and NAP and further reports advances in NAP studies toward clinical development. An original finding described here shows that NAP, while protecting neurons, demonstrated no apparent effect on cell division in a multiplicity of cell lines, strengthening the notion that NAP is a specific neuroprotective drug candidate.