vasoactive-intestinal-peptide and Amnesia

A novel peptide VIP-TAT with a cell penetrating peptide TAT at the C-terminus of VIP was constructed and prepared using intein mediated purification with an affinity chitin-binding tag (IMPACT) system to enhance the brain uptake efficiency for the medical application in central nervous system. It was found by labeling VIP-TAT and VIP with fluorescein isothiocyanate (FITC) that the extension with TAT increased the brain uptake efficiency of VIP-TAT significantly. Then short-term and long-term treatment with scopolamine (Scop) was used to evaluate the effect of VIP-TAT or VIP on Scop induced amnesia. Both short-term and long-term administration of VIP-TAT inhibited the latent time reduction in step-through test induced by Scop significantly, but long-term administration of VIP aggravated the Scop induced amnesia. Long-term i.p. injection of VIP-TAT was shown to have positive effect by inhibiting the oxidative damage, apoptosis and the cholinergic system activity reduction that induced by Scop, while VIP exerted negative effect in brain opposite to that in periphery system. The in vitro data showed that VIP-TAT had not only protective but also proliferative effect on Neuro2a cells which was inhibited by PAC1 antagonist PACAP(6-38). Competition binding assay and cAMP assay confirmed that VIP-TAT had higher affinity and activation for PAC1 than VIP. So it was concluded that the significantly stronger protective effect of VIP-TAT against Scop induced amnesia than VIP was due to (1) the enhanced brain uptake efficiency of VIP-TAT and (2) the increased affinity and activation of VIP-TAT for receptor PAC1.

Topics: Amnesia; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Vasoactive Intestinal Peptide, Type II; Recombinant Fusion Proteins; Scopolamine; Structure-Activity Relationship; tat Gene Products, Human Immunodeficiency Virus; Vasoactive Intestinal Peptide

The effects of vasoactive intestinal peptide (VIP) on spatial cognitive deficits induced in the rat by injections of scopolamine were examined in a radial arm maze. A single intraperitoneal (i.p.), subcutaneous (s.c.) or intracerebroventricular (i.c.v.) injection of VIP inhibited the reduction in the number of initial correct responses in rats with scopolamine-induced amnesia. The inhibition was associated with a bell-shaped dose-response curve. Thus, VIP appears to have an ameliorating effect on spatial cognitive deficits induced by scopolamine in the rat.

Topics: Amnesia; Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Learning; Male; Memory; Rats; Rats, Sprague-Dawley; Scopolamine; Space Perception; Vasoactive Intestinal Peptide