Neurodegenerative diseases, in which neuronal cells disintegrate, bring about deteriorations in cognitive functions as is evidenced in millions of Alzheimer patients. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective and to play an important role in the acquisition of learning and memory. A potent lipophilic analogue to VIP now has been synthesized, [stearyl- (6)(7)(8). Cholinergic blockade, resulting in impairment of learning and memory, has been used as a model of this disease (9). Ethylcholine aziridium (AF64A) is a blocker of choline uptake and it is well established that intracerebroventricular (i.c.v.) administration of this drug can induce loss in cholinergic neurons at the basal forebrain (9-11). Despite this apparent progress, successful treatment of neurodegeneration associated with Alzheimer dementia remains elusive (1,2,12,13).In the present study, we have explored the possibility that a neurotrophic peptide, vasoactive intestinal peptide (VIP) (14-16), might provide neuroprotection in models of degeneration/cognitive impairment related to Alzheimer disease. This strategy is based on the demonstrated ability of VIP to protect neurons in the central nervous system from a variety of neurotoxic substances including tetrodotoxin (17)

Stearyl‐Nle‐17‐VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100‐fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE‐deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide‐treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase‐activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 329–342, 1997

The understanding of the molecular mechanisms leading to peptide action entails the identification of a core active site. The major 28-aa neuropeptide, vasoactive intestinal peptide (VIP), provides neuroprotection. A lipophilic derivative with a stearyl moiety at the N-terminal and norleucine residue replacing the Met-17 was 100-fold more potent than VIP in promoting neuronal survival, acting at femtomolar-picomolar concentration. To identify the active site in VIP, over 50 related fragments containing an N-terminal stearic acid attachment and an amidated C terminus were designed, synthesized, and tested for neuroprotective properties. Stearyl-Lys-Lys-Tyr-Leu-NH2 (derived from the C terminus of VIP and the related peptide, pituitary adenylate cyclase activating peptide) captured the neurotrophic effects offered by the entire 28-aa parent lipophilic derivative and protected against beta-amyloid toxicity in vitro. Furthermore, the 4-aa lipophilic peptide recognized VIP-binding sites and enhanced choline acetyltransferase activity as well as cognitive functions in Alzheimer's disease-related in vivo models. Biodistribution studies following intranasal administration of radiolabeled peptide demonstrated intact peptide in the brain 30 min after administration. Thus, lipophilic peptide fragments offer bioavailability and stability, providing lead compounds for drug design against neurodegenerative diseases.

The present report relates to pharmaceutical composition for the treatment of male impotence. The transdermal application of a potent derivative of vasoactive intestinal peptide (VIP) coupled to a suitable hydrophobic moiety (e.g. stearyl-VIP) in a suitable ointment composition (e.g. Sefsol) enhances sexual activity and erection formation in a variety of impotence models in rats (sterile rats, diabetic rats, and animals with high blood pressure). Furthermore, exchange of the methionine in position 17 with norleucine enhances biological activity. Thus, stearyl-Nle17-VIP may be considered useful for the treatment of impotence.