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

Benoist, Caroline C.; Kawas, Leen H.; Zhu, Mingyan; Tyson, Katherine; Stillmaker, Lori; Appleyard, Suzanne M.; Wright, John W.; Wayman, Gary A.; Harding, Joseph W.

doi:10.1124/jpet.114.218735

Cited by 32 publications

(24 citation statements)

References 48 publications

(82 reference statements)

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“…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;. Nevertheless, the hypothesis that Ang IV and its analogs improve cognitive function through IRAP inhibition by altering levels of neuropeptides in the brain and/or exerting their actions by facilitating glucose uptake in neurons have attracted the most attention (Vauquelin et al, 2002;Albiston et al, 2003;Chai et al, 2004).…”

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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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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“…We reported that Dihexa binds with high affinity to HGF and induces c-Met phosphorylation in the presence of subthreshold levels of HGF [140]. Dihexa also stimulated Hip spinogenesis and synaptogenesis equivalent with HGF.…”

Section: The Development Of Angiotensin Iv-based Small Moleculesmentioning

confidence: 84%

“…Further, Dihexa or an active metabolite penetrated the BBB in sufficient quantity to facilitate memory consolidation and retrieval in the scopolamine-induced amnesic rat model of Alzheimer's disease as well as in aged rats employing the Morris water maze task of spatial memory [81]. These findings have recently been extended to show that by day 8 of testing those animals given Hinge by intracerebroventricular (icv) injection and saline (by gavage) performed equivalently to the control group (icv aCSF followed by saline) [140]. Members of both groups located the hidden platform significantly faster than those animals given scopolamine (icv) followed by saline.…”

Section: The Development Of Angiotensin Iv-based Small Moleculesmentioning

confidence: 94%

The Development of Small Molecule Angiotensin IV-Based Analogs to Treat Depression

Wright

Harding

2015

AJPN

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Major depression is a common form of mental disorder affecting approximately 15% of the population at least once during lifetime. The etiology of depression is complex with potential contributions from central and peripheral systemic factors, and several CNS impacting diseases. Presently employed antidepressant medications are poorly responded to by upwards of 50% of patients and typically require weeks of treatment to be effective. Recent post-mortem brain scans indicate significant volume reductions in two limbic brain structures, the hippocampus and prefrontal cortex of depressed patients. These findings focus attention on hippocampal plasticity in the neuropathology of depression and the possible dysfunction of several important processes including neurogenesis, synaptogenesis, and contributions by neurotrophic growth factors. The hepatocyte growth factor (HGF)/c-Met receptor system is a powerful mediator of synaptogenesis and neurogenesis, and if adequately activated may serve to counter the neuropathology of depression. The brain renin-angiotensin system (RAS) interacts with the HGF/c-Met system and plays a major role in responding to stress and the pathophysiology of depression. We have developed an angiotensin IV-based small molecule designed to activate the HGF/c-Met receptor system in order to provide neuroprotection, synaptogenesis, and neurogenesis in the hippocampus and prefrontal cortex. This analog may be efficacious in treating the neuropathology of depression.

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“…HGF, the target protein of HGFAC, is a strong neurotrophic factor in certain brain regions and its activation has been shown to have neuroprotective and neurorestorative effects in studies on ALS, MS, Parkinson disease and spinal cord trauma [41][42][43][44][45][46]. HGF has also been shown to stimulate neurogenesis [47][48][49].…”

Section: Hgf Activator (Hgfac)mentioning

confidence: 97%

Cortical gene expression correlates of temporal lobe epileptogenicity

et al. 2016

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

Cited by 32 publications

References 48 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

The Development of Small Molecule Angiotensin IV-Based Analogs to Treat Depression

Cortical gene expression correlates of temporal lobe epileptogenicity

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