vasoactive-intestinal-peptide and Memory-Disorders

The aim of this work was to study the nasal route for the delivery of vasoactive intestinal peptide (VIP) to the brain and to evaluate the toxicity of VIP nasal spray. Mice were injected intracerebroventricularly with the aggregated Abeta25-35 to mimic Alzheimer's disease. Following administration, different groups of mice were treated over one week, and their spatial learning and memory capacities were evaluated by the Morris water maze test. The toxicity of VIP nasal spray was evaluated by examining the morphology of individual rat nasal mucosa cilia and the pathology of rat nasal mucosa. Rats receiving intranasal VIP (40 microg/ml) showed good spatial memory relative to the Abeta25-35 model group, but the escape latency did not show any statistically significant difference. Intranasal administration of VIP nasal spray (200 microg/ml) improved deficits in spatial memory to the point that test animals receiving intranasal VIP showed no statistically significant differences from the normal control group in escape latency. This indicated that the nasal spray method could increase the quantity of VIP entering the brain and protect the central nervous systems of mice. Toxicity evaluation showed that the preparation could cause minor irritation, which resolved spontaneously within a week at the end of treatment. In conclusion, VIP can be delivered successfully to the brain using the intranasal route.

Topics: Administration, Intranasal; Aerosols; Amyloid beta-Peptides; Animals; Cilia; Injections, Intraventricular; Irritants; Maze Learning; Memory Disorders; Mice; Microscopy, Electron, Scanning; Nasal Mucosa; Peptide Fragments; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

Stearyl-Nle17-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.

Topics: Alzheimer Disease; Animals; Apolipoproteins E; Brain; Brain Diseases; Choline O-Acetyltransferase; Cholinergic Fibers; Learning; Memory Disorders; Mice; Mice, Knockout; Neuropeptides; Neuroprotective Agents; RNA, Messenger; Vasoactive Intestinal Peptide