Abstract
Angiotensin IV (AngIV; Val1-Tyr2-Ile3-His4-Pro5-Phe6)-related peptides have emerged as potential antidementia agents. However, their development as practical therapeutic agents 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 procognitive 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 procognitive 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 procognitive activity and its capacity to increase spine numbers and enlarge spine head size. These data suggest that the procognitive activity of these molecules is attributable to their ability to augment synaptic connectivity.
Footnotes
This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH086032]; the Edward E. and Lucille I. Lainge Endowment for Alzheimer's Research, State of Washington Initiative [Measure 171] (to J.W.W.); and the Hope for Depression Research Foundation (to G.A.W.).
J.W.W. and J.W.H. are the cofounders of Pacific Northwest Biotechnology, LLC and hold stock in this company, which is involved in the development of antidementia drugs.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.182220.
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ABBREVIATIONS:
- AngIV
- angiotensin IV
- Nle
- norleucine
- BBB
- blood-brain barrier
- aCSF
- artificial cerebrospinal fluid
- mRFP
- monomeric red fluorescent protein
- DIV
- days in vitro
- PBS
- phosphate-buffered saline
- α-VGLUT1
- vesicular glutamate transporter
- EPSC
- excitatory postsynaptic current
- mEPSC
- mini-excitatory postsynaptic current
- ANOVA
- analysis of variance
- BDNF
- brain-derived neurotrophic factor
- LTP
- long-term potentiation.
- Received April 7, 2011.
- Accepted June 29, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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