The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases

Wright, John W.; Kawas, Leen H.; Harding, Joseph W.

doi:10.1016/j.pneurobio.2014.11.004

Cited by 47 publications

(27 citation statements)

References 362 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mechanisms involved in interactions of PRR and other RAS receptors to regulate microglial polarization remain to be investigated. The peptide Ang IV and its receptor have been involved in a number of functions in the CNS (Wright et al, 2015). There are a few data on possible involvement of Ang IV in inflammatory responses in peripheral tissues (Esteban et al, 2005; Kong et al, 2015).…”

Section: The Role Of Other Angiotensin Receptors In Regulation Of Micmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

191

182

View full text Add to dashboard Cite

Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

show abstract

Section: The Role Of Other Angiotensin Receptors In Regulation Of Micmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

191

182

View full text Add to dashboard Cite

show abstract

“…The latter hexapeptide, formed after actions of aminopeptidase A (APA) and aminopeptidase N (APN), blocks insulin‐regulated aminopeptidase (IRAP), an inhibition that has been proposed to be responsible for the observed positive outcome by Ang IV on learning and memory in animal models . Recently, drug‐like compounds that mimic Ang IV and inhibitors of IRAP have attracted a considerable interest as a potential new class of cognitive enhancers, and a series of both cyclic pseudopeptides derived from the linear Ang IV and more drug‐like inhibitors have been reported . Regarding Ang III, the heptapeptide is essentially equipotent to Ang II at the AT2R, but is a poorer AT1R ligand, demonstrating that the N‐terminal Arg of Ang II is not crucial for its AT2R affinity .…”

Section: Introductionmentioning

confidence: 99%

Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

show abstract

“…Груп-па зарубежных ученых синтезировала серию мо-лекул ангиотензина IV на основе соединений, которые являются метаболически стабильными, проникают через гематоýнцефалический барьер и предназначены для взаимодействия с IRAP, что в свою очередь дает возможность предотвратить негативные последствия развития нейродегене-ративных заболеваний, в частности БА [31]. По-казано, что у мышей, получавших холестерол-со-держащую диету, обнаруживалась дисрегуляция ренин-ангиотензиновой системы в головном мозге [32] и снижался уровень цитоскелет-ас-социированного белка (Arc) -ключевого белка, участвующего в процессах консолидации памяти [33]. Данный патологический процесс регистри-ровали также в головном мозге при БА [32].…”

Section: Discussionunclassified

The effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s disease

Горина¹,

Комлева²,

Lopatina³

et al. 2017

Bûll. sib. med.

View full text Add to dashboard Cite

The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases

Cited by 47 publications

References 362 publications

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Small‐molecule AT2 receptor agonists

The effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s disease

Contact Info

Product

Resources

About