Ang II and Ang IV: Unraveling the Mechanism of Action on Synaptic Plasticity, Memory, and Epilepsy

Abstract

The central angiotensin system plays a crucial role in cardiovascular regulation. More recently, angiotensin peptides have been implicated in stress, anxiety, depression, cognition, and epilepsy. Angiotensin II (Ang II) exerts its actions through AT(1) and AT(2) receptors, while most actions of its metabolite Ang IV were believed to be independent of AT(1) or AT(2) receptor activation. A specific binding site with high affinity for Ang IV was discovered and denominated "AT(4) receptor". The beneficiary effects of AT(4) ligands in animal models for cognitive impairment and epileptic seizures initiated the search for their mechanism of action. This proved to be a challenging task, and after 20 years of research, the nature of the "AT(4) receptor" remains controversial. Insulin-regulated aminopeptidase (IRAP) was first identified as the high-affinity binding site for AT(4) ligands. Recently, the hepatocyte growth factor receptor c-MET was also proposed as a receptor for AT(4) ligands. The present review focuses on the effects of Ang II and Ang IV on synaptic transmission and plasticity, learning, memory, and epileptic seizure activity. Possible interactions of Ang IV with the classical AT(1) and AT(2) receptor subtypes are evaluated, and other potential mechanisms by which AT(4) ligands may exert their effects are discussed. Identification of these mechanisms may provide a valuable target in the development in novel drugs for the treatment of cognitive disorders and epilepsy.

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…Initial studies of a research group suggested anti-convulsant actions of Ang peptides against pentylenetetrazol-induced seizures [244] reviewed recently [245]. Emerging new data, however, suggest a more complex effect of angotensins on seizure activity [246]. The anti-convulsant action of AngIV has been confirmed in the pilocarpine model of epilepsy [247].…”

Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents

“…These observations have long encouraged the notion that AngIV-based pharmaceuticals may have potential as antidementia therapeutics (Mustafa et al, 2001;von Bohlen und Halbach, 2003;Gard, 2004Gard, , 2008De Bundel et al, 2008;Wright and Harding, 2010). The transformation of AngIV and earlier described analogs into clinically useful agents has been impeded by their lack of metabolic stability and inability to penetrate the blood-brain barrier (BBB).…”

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

“…Not surprisingly, AngIV-based pharmaceutical agents have been suggested as antidementia therapeutic agents (Mustafa et al, 2001;von Bohlen und Halbach, 2003;Gard, 2004Gard, , 2008De Bundel et al, 2008;Wright and Harding, 2008). Despite promising behavioral effects in animal models of dementia, two critical physiochemical properties, namely lack of metabolic stability and inability to penetrate the blood-brain barrier (BBB), have precluded drug development.…”