Angiotensin as a target for the treatment of Alzheimer?s disease, anxiety and depression
University of Brighton, School of Pharmacy and Biomolecular Sciences, UK.Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 02/2004; 8(1):7-14. DOI: 10.1517/14728220.127.116.11
The brain renin-angiotensin system (RAS), which is comprised of a variety of peptides including angiotensin II, angiotensin III and angiotensin IV acting on AT 1 , AT 2 and AT 4 receptors, is important in cognition and anxiety. Perturbation of the RAS improves basal cognition and reverses age-, scopolamine-, ethanol- and diabetes-induced deficits. In studies of dementias and Alzheimer's disease (AD), some studies have shown that antihypertensive drugs, including angiotensin-converting enzyme inhibitors, have some moderate effects on cognitive decline, but that the angiotensin receptor antagonist losartan has a significantly beneficial effect. These findings suggest that angiotensin receptor ligands may have potential in the prevention or even reversal of vascular dementias and AD. With respect to depression and anxiety, there is similar experimental evidence from animal models that drugs acting on the RAS may be antidepressant or anxiolytic, but insufficient clinical data exist. Such effects, if proven, could promote the use of such agents in the treatment of hypertension coexisting with depression or anxiety.
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- "Since the dopamine agonist L-DOPA, although not fully satisfactory, is currently one of the most efficacious treatments to relieve motor symptoms of the disease, any therapeutic approach targeting stimulation of DA release for treatment of PD could constitute a promising alternative. The interest of the brain RAS as a potential target for AD comes from the observation of its effects on learning and memory (Gard, 2004). To support these findings, it was shown that ACE inhibitors and angiotensin analogues enhance cognitive processing, being effective in delaying or reversing symptoms of AD or PD in both human and animal models (Kehoe and Wilcock, 2007;Ohrui et al., 2004;Yamada et al., 2011). "
ABSTRACT: Using a “built-in-house” bioinformatics program, we identified a nonapeptide of sequence H-Pro-Pro-Thr-Thr-Thr-Lys-Phe-Ala-Ala-OH. The goal of this work was to study its in vivo and in vitro biological activity, and to identify its target. The affinity of the peptide was characterised on both purified whole and striatum brain membranes of rodents. The peptide stimulated dopamine release both in vitro and in vivo in rats. Its effect on behaviour in rats following peptide intra-striatal injection was investigated. A photoaffinity UV cross-linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target. The peptide was able to bind with high affinity to a single class of binding sites, specifically localised in the striatum and substantia nigra of rodent brains. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine-like effects. We purified the target of the peptide, a ~151 kDa protein that was identified by MS/MS as Angiotensin Converting Enzyme I (ACE1). Therefore, we decided to name the peptide acein. Our results demonstrate that the synthetic peptide acein interacts with high affinity to brain membrane-bound ACE. This interaction occurs at a different site from the well-known active site involved in the peptidase activity, without modifying the peptidase activity. Acein significantly stimulates in vitro and in vivo dopamine release in the brain. These results suggest a more important role for brain ACE than initially suspected. This article is protected by copyright. All rights reserved.
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- "It should be noted that the AT 1 angiotensin receptor subtype may also contribute to the cognitive effects of AngIV (De Bundel et al., 2010). Not surprisingly, AngIV-based pharmaceutical agents have been suggested as antidementia therapeutic agents (Mustafa et al., 2001; von Bohlen und Halbach, 2003; Gard, 2004, 2008; De Bundel et al., 2008; Wright and Harding, 2008). Despite promising behavioral effects in animal models 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 "
ABSTRACT: A subset of angiotensin IV (AngIV)-related molecules are known to possess pro-cognitive/ anti-dementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier (BBB) penetrant analogs; and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, BBB permeable analog Dihexa (N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide) (McCoy et al., 2013). Therefore, the goal of this study was to elucidate the mechanism that underlies Dihexa's pro-cognitive activity. Here we demonstrate that Dihexa binds with high affinity to hepatocyte growth factor (HGF) and both Dihexa and its parent compound Norleucine 1-AngIV (Nle1-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, Dihexa and Nle1-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a sh-RNA directed at c-Met. Most importantly the pro-cognitive/anti-dementia capacity of orally delivered Dihexa was blocked by an HGF antagonist delivered intraventricularly as measured using the Morris water maze task of spatial learning.
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- "It is likely that multiple signaling pathways involving antioxidant [42, 44], anti-inflammatory , and/or anti-apoptotic  mechanisms may regulate anxiety-like behavior. Additional evidence supporting the hypothesis that NOX-derived ROS are involved in the pathophysiology of anxiety and bipolar disorders has also been presented [58-64]. In fact, it is proposed that anxiety and mood disorders are closely linked to NOX-mediated oxidative stress [28, 36, 37, 65, 66]. "
ABSTRACT: Oxidative stress is an imbalance between cellular production of reactive oxygen species and the counteracting antioxidant mechanisms. The brain with its high oxygen consumption and a lipid-rich environment is considered highly susceptible to oxidative stress or redox imbalances. Therefore, the fact that oxidative stress is implicated in several mental disorders including depression, anxiety disorders, schizophrenia and bipolar disorder, is not surprising. Although several elegant studies have established a link between oxidative stress and psychiatric disorders, the causal relationship between oxidative stress and psychiatric diseases is not fully determined. Another critical aspect that needs much attention and effort is our understanding of the association between cellular oxidative stress and emotional stress. This review examines some of the recent discoveries that link oxidative status with anxiety, depression, schizophrenia and bipolar disorder. A discussion of published results and questions that currently exist in the field regarding a causal relationship between oxidative and emotional stress is also provided.
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