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.
"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 "
[Show abstract][Hide abstract] 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.
Journal of Pharmacology and Experimental Therapeutics 09/2014; 351(2). DOI:10.1124/jpet.114.218735 · 3.97 Impact Factor
"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]. "
[Show abstract][Hide abstract] 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.
Current Neuropharmacology 03/2014; 12(2):140-7. DOI:10.2174/1570159X11666131120230309 · 3.05 Impact Factor
"More significantly, the acute application of AngIV or one of its analogs, Nle-Tyr-Ile-His-Pro-Phe (Nle 1 -AngIV), reverses deficits in dementia models induced by 1) treatment with the cholinergic muscarinic receptor antagonist scopolamine (Pederson et al., 2001), 2) kainic acid injections into the hippocampus (Stubley-Weatherly et al., 1996), 3) perforant path cuts (Wright et al., 1999), and 4) ischemia resulting from transient four-vessel occlusion (Wright et al., 1996). 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, 2004, 2008; De 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). "
[Show abstract][Hide abstract] ABSTRACT: Angiotensin IV (AngIV: VYIHPF) related peptides have long been recognized as pro-cognitive agents with potential as anti-dementia therapeutics. Their development as useful therapeutics, however, has been limited by susceptibility to metabolic degradation and physiochemical properties that make them impermeable to gut and blood-brain barriers. A previous study has demonstrated that the core structural information required to impart the pro-cognitive activity of the AngIV analog, Norleucine(1)-angiotensin IV (Nle(1)-AngIV), resides in its three N-terminal amino acids, Nle-Tyr-Ile. The goal of this project was to chemically modify this tripeptide in such a way as to enhance its metabolic stability and membrane permeability to produce a drug candidate with potential clinical utility. Initial results demonstrated that several N- and C-terminal modifications lead to dramatically improved stability while maintaining the capability to reverse scopolamine-induced deficits in Morris water maze performance and augment hippocampal synaptogenesis. Subsequent chemical modifications, which were designed to increase hydrophobicity and decrease hydrogen bonding, yielded an orally active, blood-brain barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr, Ile-(6) aminohexanoic amide ( Dihexa) that exhibits excellent anti-dementia activity in the scopolamine and aged rat models and marked synaptogenic activity. These data suggest that Dihexa may have therapeutic potential as a treatment for disorders, like Alzheimer's disease, where augmented synaptic connectivity may be beneficial.
Journal of Pharmacology and Experimental Therapeutics 10/2012; 344(1). DOI:10.1124/jpet.112.199497 · 3.97 Impact Factor
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