Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats

Lee, Joohyung; Albiston, Anthony L.; Allen, Andrew M.; Mendelsohn, Frederick A.O.; Ping, Sophie E.; Barrett, Graham L.; Murphy, Mark; Morris, Margaret J.; McDowall, Sharon G.; Chai, Siew Yeen

doi:10.1016/j.neuroscience.2003.12.006

Cited by 116 publications

(106 citation statements)

References 52 publications

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“…Considering the wide-ranging effects mediated by IRAP and its inhibitors, understanding the genetic basis of IRAP functions is critical. In normal and memorycompromised rodent models, enhancement of memory upon intracerebroventricular delivery of AngIV and its analog peptides is the defining pharmacological property, which is thought to be mediated solely by the IRAP/AngIV binding site (Albiston et al, 2004b;Lee et al, 2004). Biochemically, these ligands show highaffinity binding to the IRAP catalytic site.…”

Section: E Distribution Of the Of Angiv Binding Sitesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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Section: E Distribution Of the Of Angiv Binding Sitesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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“…13,17) But the most important correlation is, that like Ang IV, LVV-H7 facilitates memory in both normal and scopolamine treated rats. 18) Utilizing the Barnes circular maze, Ang IV and LVV-H7 were both demonstrated to facilitate memory as assessed by mean number of days to reach learner criterion. 18) In addition, like Ang IV, central administration of LVV-H7 attenuates the deleterious effects of scopolamine on memory performance, observed in rats in the two different behavioral paradigms, the swim water maze and the passive aviodance task (Albiston et al, in press).…”

Section: Angiotensin IVmentioning

confidence: 99%

Alzheimer's, Angiotensin IV and an Aminopeptidase

Albiston

Fernando

et al. 2004

Biological & Pharmaceutical Bulletin

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The angiotensin AT 4 receptor was originally defined as the specific, high affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT 4 receptor. Central administration of Ang IV or LVV-hemorphin 7 (LVV-H7) markedly enhances learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The high affinity binding site has a broad distribution in the brain including areas such as the hippocmapus that are involved in memory processing. The high affinity Ang IV binding site (AT 4 receptor) has been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). Insulin-regulated aminopeptidase is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and in insulin-responsive cells colocalizes with GLUT4 in specific intra-cellular vesicles. Both Ang IV and LVV-H7 are competitive inhibitors of IRAP catalytic activity and are not substrates of the enzyme.

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“…In 2001, the hexapeptide angiotensin IV (Ang IV; Val-Tyr-IleHis-Pro-Phe), which improves memory and learning in both rats and mice (Braszko et al, 1988;Wright et al, 1993Wright et al, , 1996Wright et al, , 1999Lee et al, 2004;Gard et al, 2007Gard et al, , 2012Braszko et al, 2008;De Bundel et al, 2009), was demonstrated to inhibit the membrane-bound zinc-dependent insulin-regulated aminopeptidase (EC 3.4.11.3 IRAP,oxytocinase), a member of the M1 family, which is expressed in a diversity of tissues/cells (Albiston et al, 2001;Liao et al, 2006;Saveanu and van Endert, 2012;Nikolaou et al, 2014). There has been dispute in the field as to the target that mediates the memory-enhancing effects of Ang IV, because this hexapeptide has the ability to bind to other proteins (Vanderheyden, 2009;Kawas et al, 2012;Benoist et al, 2014;.…”

Section: Introductionmentioning

confidence: 99%

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

et al. 2016

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Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09, and of Ang IV in either the extended or g-turn conformation at the C terminus to human IRAP were predicted by docking and molecular dynamics simulations. The binding free energies calculated with the linear interaction energy method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

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Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats

Cited by 116 publications

References 52 publications

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

Alzheimer's, Angiotensin IV and an Aminopeptidase

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

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