Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle<sup>1</sup>-Angiotensin IV Analogs

Benoist, Caroline C.; Wright, John W.; Zhu, Mingyan; Appleyard, Suzanne M.; Wayman, Gary A.; Harding, Joseph W.

doi:10.1124/jpet.111.182220

Cited by 37 publications

(61 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have observed a correlation between the procognitive effects of Ang IV-derived peptides in rodents and their capacities to increase spine number and alter morphology (Benoist et al, 2011;McCoy et al, 2013). These data suggest that the positive impact of these peptides and peptidomimetics on cognition and dendritic spines might be attributed to a possible capacity to suppress the catalytic activity of the aminopeptidase IRAP.…”

Section: Introductionmentioning

confidence: 69%

“…In contrast, HA09 did not alter total spine density or morphology compared with the vehicle control. Given that previous studies have shown that the procognitive activity of a molecule in vivo correlates well with its in vitro ability to alter dendritic spine structure (Benoist et al, 2011;McCoy et al, 2013), these results suggest that HA08 may have cognitive enhancing effects.…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced cognitive performance has been linked to the augmentation of synaptic connectivity, which includes changes in the number and morphology of dendritic spines ( Leuner et al, 2003;McCoy, 2010;Benoist et al, 2011). To investigate the effect of HA08 and HA09 on spine development and their potential cognitive-enhancing effect, we used immunofluorescence to analyze spine formation in hippocampal cultures.…”

Section: Effect Of Ha08 and Ha09 On Spine Morphology And Densitymentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Effect Of Ha08 and Ha09 On Spine Morphology And Densitymentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Their effects in animal models of epilepsy suggest the necessity of careful analysis for their anti-convulsive actions in human. As for AT4, the identification of small but critically important peptide fragments [258] and their N-and C-terminal modifications led to the development of the selective AT4 agonist N-hexanoic-Tyr-Ile-(6) aminohexanoic amide. This molecule was sufficiently bloodbrain barrier permeable to have precognitive effects in Morris water maze performance [259].…”

Section: Angiotensinsmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

View full text Add to dashboard Cite

Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

show abstract

“…Nle 1 -AngIV, an often-employed AT 4 receptor agonist with demonstrated procognitive activity (Benoist et al, 2011), along with its metabolically stabilized and orally active derivative, N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa) (McCoy et al, 2013), were utilized to probe this question. Both agonists were found to potentiate the cellular actions of HGF.…”

Section: Introductionmentioning

confidence: 99%

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

Benoist

Kawas

Zhu

et al. 2014

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle¹-Angiotensin IV Analogs

Cited by 37 publications

References 41 publications

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

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

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

Contact Info

Product

Resources

About

Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle1-Angiotensin IV Analogs

Cited by 37 publications

References 41 publications

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

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

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

Contact Info

Product

Resources

About

Facilitation of Hippocampal Synaptogenesis and Spatial Memory by C-Terminal Truncated Nle¹-Angiotensin IV Analogs