Angiotensin IV (AngIV: VYIHPF) related peptides have emerged as potential anti-dementia agents. However, their development as practical therapeutics has been impeded by a combination of metabolic instability, poor blood-brain barrier permeability, and an incomplete understanding of their mechanism of action. This study establishes the core structure contained within Norleucine1-angiotensin IV (Nle1-AngIV) that is required for its pro-cognitive activity. Results indicated that Nle1-AngIV-derived peptides as small as tetra- and tripeptides are capable of reversing scopolamine-induced deficits in Morris water maze performance. This identification of the active core structure contained within Nle1-AngIV represents an initial step in the development of AngIV-based pro-cognitive drugs. The second objective of the study was to clarify the general mechanism of action of these peptides by assessing their ability to affect changes in dendritic spines. A correlation was observed between a peptide's pro-cognitive activity and its capacity to increase spine numbers and enlarge spine head size. These data suggest that the pro-cognitive activity of these molecules is attributable to their ability to augment synaptic connectivity.
- Received April 7, 2011.
- Revision received June 28, 2011.
- Accepted June 29, 2011.
- The American Society for Pharmacology and Experimental Therapeutics