scholarly journals Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Hanna Andersson ◽  
Mathias Hallberg
Keyword(s):  
Intracerebroventricular Injection ◽  
Binding Affinities ◽  
Ang Ii ◽  
Angiotensin Iv ◽  
Positive Effects ◽  
Main Target ◽  
The Status ◽  
Ang Iv ◽  
The Relationship ◽  
The Brain

The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

Central ventilatory and cardiovascular actions of angiotensin peptides in trout

2012 ◽  
Vol 303 (3) ◽  
pp. R311-R320 ◽  
Author(s):  
Frédéric Lancien ◽  
Marty Wong ◽  
Ali Al Arab ◽  
Nagi Mimassi ◽  
Yoshio Takei ◽  
...  
Keyword(s):  
Brain Tissue ◽  
High Performance ◽  
Third Ventricle ◽  
Renin Angiotensin System ◽  
Intracerebroventricular Injection ◽  
Ang Ii ◽  
Stimulatory Action ◽  
Cardiovascular Actions ◽  
Ang Iv ◽  
The Brain

In the brains of teleosts, angiotensin II (ANG II), one of the main effector peptides of the renin-angiotensin system, is implicated in various physiological functions notably body fluid and electrolyte homeostasis and cardiovascular regulation, but nothing is known regarding the potential action of ANG II and other angiotensin derivatives on ventilation. Consequently, the goal of the present study was to determine possible ventilatory and cardiovascular effects of intracerebroventricular injection of picomole doses (5–100 pmol) of trout [Asn1]-ANG II, [Asp1]-ANG II, ANG III, ANG IV, and ANG 1–7 into the third ventricle of unanesthetized trout. The central actions of these peptides were also compared with their ventilatory and cardiovascular actions when injected peripherally. Finally, we examined the presence of [Asn1]-ANG II, [Asp1]-ANG II, ANG III, and ANG IV in the brain and plasma using radioimmunoassay coupled with high-performance liquid chromatography. After intracerebroventricular injection, [Asn1]-ANG II and [Asp1]-ANG II two ANG IIs, elevated the total ventilation through a selective stimulatory action on the ventilation amplitude. However, the hyperventilatory effect of [Asn1]-ANG II was threefold higher than the effect of [Asp1]-ANG II at the 50-pmol dose. ANG III, ANG IV, and ANG 1–7 were without effect. In addition, ANG IIs and ANG III increased dorsal aortic blood pressure (PDA) and heart rate (HR). After intra-arterial injections, none of the ANG II peptides affected the ventilation but [Asn1]-ANG II, [Asp1]-ANG II, and ANG III elevated PDA (50 pmol: +80%, +58% and +48%, respectively) without significant decrease in HR. In brain tissue, comparable amounts of [Asn1]-ANG II and [Asp1]-ANG II were detected (ca. 40 fmol/mg brain tissue), but ANG III was not detected, and the amount of ANG IV was about eightfold lower than the content of the ANG IIs. In plasma, ANG IIs were also the major angiotensins (ca. 110 fmol/ml plasma), while significant but lower amounts of ANG III and ANG IV were present in plasma. In conclusion, our study suggests that the two ANG II isoforms produced within the brain may act as a neurotransmitter and/or neuromodulator to regulate the cardioventilatory functions in trout. In the periphery, two ANG IIs and their COOH-terminal peptides may act as a circulating hormone preferentially involved in cardiovascular regulations.

The optimism-pessimism ratio as predictor of employee creativity: the promise of duality

2018 ◽  
Vol 21 (3) ◽  
pp. 423-442 ◽  
Author(s):  
Arménio Rego ◽  
Miguel Pina e Cunha ◽  
Dálcio Reis Júnior ◽  
Cátia Anastácio ◽  
Moriel Savagnago
Keyword(s):  
Cross Sectional ◽  
Content Type ◽  
Future Studies ◽  
Positive Effects ◽  
The Status ◽  
Single Moment ◽  
Quasi Experimental ◽  
Creativity And Innovation ◽  
The Relationship ◽  
Practical Implications

Purpose The purpose of this paper is to study if the employees’ optimism-pessimism ratio predicts their creativity. Design/methodology/approach In total, 134 employees reported their optimism and pessimism, and the respective supervisors described the employees’ creativity. Findings The relationship between the optimism-pessimism ratio and creativity is curvilinear (inverted U-shaped); beyond a certain level of the optimism-pessimism ratio, the positive relationship between the ratio and creativity weakens, suggesting that the possible positive effects of (high) optimism may be weakened by a very low level of pessimism. Research limitations/implications Being cross-sectional, the study examines neither the causal links between the optimism-pessimism ratio and creativity nor other plausible causal links. The study was carried out at a single moment and did not capture the dynamics that occur over the course of time involving changes in optimism/pessimism and creativity. Future studies may adopt longitudinal or quasi-experimental designs. Practical implications Managers and organizations must consider that, even though positivity promotes creativity, some level of negativity may help positivity to produce creativity. Originality/value This study suggests that scholars who want to study the antecedents of creativity (and innovation) must be cautious in focusing only on the positive or the negative sides of individuals’ characteristics, and rather they must explore the interplay between both poles. Individuals may experience both positive and negative states/traits (Smith et al., 2016), and this both/and approach may impel them to think divergently, to challenge the status quo and to propose “out the box” and useful ideas.

A Memória de Longo Prazo e a Análise Sobre sua Função no Processo de Aprendizagem

2018 ◽  
Vol 19 (1) ◽  
pp. 66
Author(s):  
Lia Almeida Mapurunga ◽  
Elcyana Bezerra Elcyana Bezerra Carvalho
Keyword(s):  
Cognitive Psychology ◽  
Learning Strategies ◽  
Long Term Memory ◽  
Term Memory ◽  
Positive Effects ◽  
Bibliographical Survey ◽  
And Function ◽  
The Relationship ◽  
The Brain

A neurociência é uma ciência natural que estuda a função e a estrutura, que compõem o cérebro. A educação, embora tenha outra natureza, tem tido muitos benefícios com as contribuições que a neurociência tem para oferecer. Como o cérebro aprende e por que aprende traz para o ensino o objetivo e a função de criar condições (entre estratégias, recursos e adequação do meio), para que ocorra a aprendizagem. E, para que essa ocorra, é necessário que as funções mentais superiores, como a memória, estejam envolvidas. O objetivo deste estudo consiste em fazer uma revisão de literatura para conhecer a função da memória de longo prazo na aprendizagem, analisar os mecanismos neurobiológicos, que ocorrem durante esse processo e algumas estratégias de aprendizagem, que se utilizam da memória como recurso. Para isso, foi realizado no período de agosto a outubro de 2016, um levantamento bibliográfico nas bases de dados Scielo, Capes, Bireme e Google Acadêmico, buscando artigos científicos, que poderiam trazer alguma contribuição na construção dessa pesquisa. Foram selecionados, preferencialmente, os que continham enfoque na relação entre aprendizagem e memória, tanto na perspectiva da neurociência, quanto da psicologia cognitiva, trazendo argumentos que pudessem  comprovar o entendimento das estratégias de aprendizagem, a partir da memória de longo prazo. Também foram selecionados livros que apresentavam apoio às temáticas discorridas para esse trabalho, possibilitando essa relação. Os resultados apontam que estratégias de aprendizagens, que utilizam a memória, produzem efeitos positivos para a retenção de longo prazo.Palavras-chave: Aprendizagem. Neurociências. Estratégias de Aprendizagem.AbstractNeuroscience is a natural science that studies the function and structure that forms the brain. Although education has another nature, it has had many benefits from the contributions that neuroscience has to offer. How the brain learns and why it learns brings to teaching the intent and function to create conditions (among strategies, resources and suitability to the environment) so that learning can happen. And, for it to occur, it is  necessary that higher mental functions, such as memory, beinvolved. The purpose of this study is to do a literature review to get to know the function of long-term memory on the learning process, to analyze the neurobiological mechanisms that happen during that process, and some learning strategies that use memory as a resource. Therefore a bibliographical survey was conducted at the databases Scielo, Capes, Bireme and Academic Google, from August to October 2016, searching for scientific articles that could contribute somehow on the construction of this research. The articles that used the neuroscience perspective or the cognitive psychology to focus on the relationship  between learning and memory were chosen, preferentially those whose arguments could prove the  learning strategies understanding about he long-term memory. Books supporting the themes discussed for this work were also selected, creating, therefore, a relationship. The results show that learning strategies that use memory have positive effects for long-term retention.Keywords: Learning. Neuroscience. Learning Strategies.

A Present Folded Back on the Past (Bergson)

2005 ◽  
Vol 35 (1) ◽  
pp. 55-76 ◽  
Author(s):  
Rudolf Bernet
Keyword(s):  
The Unconscious ◽  
The Past ◽  
The Status ◽  
Metaphysics Of Presence ◽  
The Relationship ◽  
The Brain

AbstractIn Matter and Memory, Bergson examines the relationship between perception and memory, the status of consciousness in its relation to the brain, and more generally, a possible conjunction of matter and mind. Our reading focuses in particular on his understanding of the evanescent presence of the present and of its debt vis-à-vis the "unconscious" consciousness of a "virtual" past. We wish to show that the Bergsonian version of a critique of "the metaphysics of presence" is, for all that, an offshoot of a Platonic type of metaphysics. It is true that Bergson departs from traditional standpoints on the side of a self-sufficient and original present and a form of presence to which the transparency of consciousness would confer the character of immediate evidence. All the same, it can hardly be claimed that his rehabilitation of the past and the unconscious opens up new perspectives on how forgetting and death are bound up with the work of memory.

scholarly journals Angiotensin IV suppresses inflammation in the brains of rats with chronic cerebral hypoperfusion

2018 ◽  
Vol 19 (3) ◽  
pp. 147032031879958 ◽  
Author(s):  
Qing-Guang Wang ◽  
Xiao Xue ◽  
Yang Yang ◽  
Peng-Yu Gong ◽  
Teng Jiang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Angiotensin Iv ◽  
Artificial Cerebrospinal Fluid ◽  
Ang Iv ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Introduction: This study aimed to evaluate the influence of central angiotensin IV (Ang IV) infusion on chronic cerebral hypoperfusion (CCH)-related neuropathological changes including amyloid-β (Aβ), hyperphosphorylated tau (p-tau) and the inflammatory response. Materials and methods: Rats with CCH received central infusion of Ang IV, its receptor AT4R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for six weeks. During this procedure, the systolic blood pressure (SBP) was monitored, and the levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain were detected. Results: Rats with CCH exhibited higher levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain when compared with controls. Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines in the brains of rats with CCH. Meanwhile, the reduction of pro-inflammatory cytokines levels caused by Ang IV was reversed by divalinal-Ang IV. During the treatment, the SBP in rats was not significantly altered. Conclusion: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation through AT4R in the brains of rats with CCH, which is independent from SBP. These findings suggest that Ang IV/AT4R may represent a potential therapeutic target for CCH-related neurological diseases.

scholarly journals AT1 receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats

2006 ◽  
Vol 290 (5) ◽  
pp. F1024-F1033 ◽  
Author(s):  
Xiao C. Li ◽  
Duncan J. Campbell ◽  
Mitsuru Ohishi ◽  
Shao Yuan ◽  
Jia L. Zhuo
Keyword(s):  
Blood Flow ◽  
Phospholipase C ◽  
Mitogen Activated Protein Kinase ◽  
Classical Type ◽  
Dependent Manner ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Angiotensin Iv ◽  
Ang Iv ◽  
Dose Dependent

Angiotensin IV (ANG IV), an active ANG II fragment, has been shown to induce systemic and renal cortical effects by binding to ANG IV (AT4) receptors and activating unique signaling transductions unrelated to classical type 1 (AT1) or type 2 (AT2) receptors. We tested whether ANG IV exerts systemic and renal cortical effects on blood pressure, renal microvascular smooth muscle cells (VSMCs), and glomerular mesangial cells (MC) and, if so, whether AT1 receptor-activated signaling is involved. In anesthetized rats, systemic infusion of ANG II, ANG III, or ANG IV (0.01, 0.1, and 1.0 nmol·kg−1·min−1 iv) caused dose-dependent increases in mean arterial pressure (MAP) and decreases in renal cortical blood flow (CBF; P < 0.01). ANG II also induced dose-dependent reductions in renal medullary blood flow ( P < 0.01), whereas ANG IV did not. ANG IV-induced pressor and renal cortical vasoconstriction were completely abolished by AT1 receptor blockade with losartan (5 mg/kg iv; P < 0.05). When ANG IV (1 nmol·kg−1·min−1) was infused directly in the renal artery, CBF was reduced by >30%, and the response was also blocked by losartan ( P < 0.01). In the renal cortex, unlabeled ANG IV displaced 125I-labeled [Sar1,Ile8]ANG II binding, whereas unlabeled ANG II (10 μM) inhibited 125I-labeled Nle1-ANG IV (AT4) binding in a concentration-dependent manner ( P < 0.01). In freshly isolated renal VSMCs, ANG IV (100 nM) increased intracellular Ca2+ concentration, and the effect was blocked by losartan and U-73122, a selective inhibitor of phospholipase C/inositol trisphosphate/Ca2+ signaling (1 μM). In cultured rat MCs, ANG IV (10 nM) induced mitogen-activated protein kinase extracellular/signal-regulated kinase 1/2 phosphorylation via AT1 receptor- and phospholipase C-activated signaling. These results suggest that, at nanomolar concentrations, ANG IV can increase MAP and induce renal cortical effects by interacting with AT1 receptor-activated signaling.

Stimulation of DNA and RNA Synthesis in Cultured Rabbit Cardiac Fibroblasts by Angiotensin IV

1995 ◽  
Vol 88 (5) ◽  
pp. 557-562 ◽  
Author(s):  
L. Wang ◽  
M. Eberhard ◽  
P. Erne
Keyword(s):  
Rna Synthesis ◽  
Cardiac Fibroblasts ◽  
Leucine Incorporation ◽  
Ang Ii ◽  
Angiotensin Iv ◽  
Single Class ◽  
Dna And Rna ◽  
Dna And Rna Synthesis ◽  
Ang Iv ◽  
Stimulation Of

1. Although angiotensin II (ANG II) has been identified as a key factor in the development of cardiac hypertrophy and remodelling, the role of its degradation fragment ANG II (3–8), angiotensin IV (ANG IV), is unknown. The presence of ANG IV in the blood circulation as well as the identification of ANG IV receptors in the heart and other organs indicates that ANG IV may act as a peptide hormone. 2. ANG IV receptors were characterized by binding of 125I-ANG IV to membranes of cultured rabbit cardiac fibroblasts. Incorporation of [3H]thymidine, [3H]uridine and [3H]Ieucine into DNA, RNA and proteins, respectively, was determined to analyse the growth effects of ANG IV, ANG II and the combination of both peptides. 3. ANG IV displaces 125I-ANG IV bound to membranes of rabbit cardiac fibroblasts with high affinity, whereas ANG II receptor-specific ligands ([Sar1,Ile8]ANG II, losartan, CGP 42 112 A) do not. 125I-ANG IV binds to a single class of binding site with a dissociation constant (Kd) of 4.87 ± 0.11 nmol/l. The density of ANG IV receptors (Bmax.) is 371 ± 8.3 fmol/mg of protein. 125I-ANG IV binding is not markedly affected in the presence of the non-hydrolysable GTP analogue GTPγS, whereas binding of 125I-ANG II is reduced. 4. In quiescent cells, a 24 h exposure of ANG IV (100 nmol/l) increased rates of thymidine and uridine incorporation by 127% and 246%, respectively. A small but statistically insignificant increase in leucine incorporation was observed under these conditions. Similar effects have been observed after stimulation by ANG II (100 nmol/l, 24 h). The combination of ANG II and ANG IV has additive effects on uridine, but not on thymidine and leucine incorporation. 5. In conclusion, rabbit cardiac fibroblasts express a specific ANG IV receptor, distinct from the known ANG II receptors, which mediates the stimulation of cellular DNA and RNA synthesis.

Angiotensin IV induces tyrosine phosphorylation of focal adhesion kinase and paxillin in proximal tubule cells

2001 ◽  
Vol 280 (6) ◽  
pp. F980-F988 ◽  
Author(s):  
Jian-Kang Chen ◽  
Joe Zimpelmann ◽  
Raymond C. Harris ◽  
Kevin D. Burns
Keyword(s):  
Proximal Tubule ◽  
Focal Adhesion Kinase ◽  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Specific Binding ◽  
Ang Ii ◽  
Angiotensin Iv ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Ang Iv

Angiotensin IV (ANG IV), the COOH-terminal hexapeptide fragment of angiotensin II (ANG II), binds to specific sites in the kidney, distinct from type 1 (AT1) and type 2 (AT2) receptors and designated type 4 (AT4) receptors. We determined signaling pathways for ANG IV in a proximal tubular cell line, LLC-PK1/Cl4. In these cells, we found no specific binding of [125I]-ANG II. In contrast, ANG IV dose dependently competed for [125I]-labeled ANG IV binding, with no displacement by either ANG II, the AT1receptor antagonist losartan, or the AT2 antagonist PD-123319. Saturation binding indicated the presence of AT4receptors of high affinity [dissociation constant ( K d) = 1.4 nM]. ANG IV did not affect cAMP or cGMP production and did not increase cytosolic calcium concentration in these cells. In contrast, immunoprecipitation and immunoblotting studies revealed that ANG IV caused dose-dependent tyrosine phosphorylation of p125-focal adhesion kinase (p125-FAK) and p68-paxillin within 2 min, with maximal stimulation at 30 min. ANG IV-stimulated tyrosine phosphorylation of p125-FAK and paxillin was not affected by pretreatment with either losartan or PD-123319, and ANG II (10−7 M) did not induce protein tyrosine phosphorylation. Our results indicate that LLC-PK1/Cl4 cells express ANG IV receptors, which we demonstrate for the first time are linked to tyrosine phosphorylation of focal adhesion-associated proteins. This suggests that ANG IV, a product of ANG II metabolism, may regulate function of the focal adhesion complex in proximal tubule cells.

Influence of food intake timing on daily variations of leptin and other metabolic variables in nzw rabbits

2002 ◽  
Vol 2002 ◽  
pp. 100-100
Author(s):  
F. Rosi ◽  
D. Magistrelli ◽  
F. Vitrani
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Peptide Hormone ◽  
The Status ◽  
Influence Of Food ◽  
Metabolic Variables ◽  
Plasma Leptin ◽  
Body Energy ◽  
The Relationship ◽  
The Brain

The 16kDa peptide hormone leptin is an adipose tissue-derived regulator of food intake and energy homeostasis, and a signal of the status of body energy stores to the brain. Plasma levels of leptin reflect body fat mass in humans, rodents and ruminants (Houseknecht et al., 1998; Delavaud et al., 2000). The aim of this study was to investigate circadian rhythms of plasma leptin and other metabolic variables in rabbits, to assess the influence of the timing of food intake and to investigate the relationship between leptin and lipid metabolites.

scholarly journals The Angiotensin II Type 2 Receptor in Brain Functions: An Update

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Marie-Odile Guimond ◽  
Nicole Gallo-Payet
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Brain Functions ◽  
Physiological Relevance ◽  
Ang Iv ◽  
The Brain

Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2receptor in the brain must also consider the Ang IV/AT4receptor.

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