It was reported three decades ago that intracerebroventricular injection of angiotensin IV (Ang IV, Val-Tyr-Ile-His-Pro-Phe) improved memory and learning in the rat. There are several explanations for these positive effects of the hexapeptide and related analogues on cognition available in the literature. In 2001, it was proposed that the insulin-regulated aminopeptidase (IRAP) is a main target for Ang IV and that Ang IV serves as an inhibitor of the enzyme. The focus of this review is the efforts to stepwise transform the hexapeptide into more drug-like Ang IV peptidemimetics serving as IRAP inhibitors. Moreover, the discovery of IRAP inhibitors by virtual and substance library screening and direct design applying knowledge of the structure of IRAP and of related enzymes is briefly presented.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593869 | PMC |
| http://dx.doi.org/10.3389/fphar.2020.590855 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition.
Biomedicines
December 2024
Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary.
Background: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning the modulation of its glutamatergic neurotransmission as a promising therapeutic target. Our recently published findings indicate that AT receptor activation enhances NMDAR activity in layer V pyramidal neurons of the rat PFC.
View Article and Find Full Text PDFIRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.
Adv Sci (Weinh)
January 2025
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
Platelets play crucial roles in multiple pathophysiological processes after energy-dependent activation. It is puzzling how such a small cellular debris has abundant energy supply. In this study, it is shown that insulin-regulated aminopeptidase (IRAP), a type II transmembrane protein, is a key regulator for platelet activation by promoting energy regeneration during septic thrombosis.
View Article and Find Full Text PDFSexual and Metabolic Differences in Hippocampal Evolution: Alzheimer's Disease Implications.
Life (Basel)
November 2024
Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaen, Las Lagunillas University Campus, 23009 Jaen, Spain.
Sex differences in brain metabolism and their relationship to neurodegenerative diseases like Alzheimer's are an important emerging topic in neuroscience. Intrinsic anatomic and metabolic differences related to male and female physiology have been described, underscoring the importance of considering biological sex in studying brain metabolism and associated pathologies. The hippocampus is a key structure exhibiting sex differences in volume and connectivity.
View Article and Find Full Text PDFInhibition of IRAP Enhances the Expression of Pro-Cognitive Markers Drebrin and MAP2 in Rat Primary Neuronal Cells.
Int J Mol Sci
November 2024
The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, Biomedical Centre, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden.
The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 aminopeptidase family and is highly expressed in many tissues, including the neocortex and hippocampus of the brain. IRAP is involved in various physiological functions and has been identified as a receptor for the endogenous hexapeptide Angiotensin IV (Ang IV). The binding of Ang IV inhibits the enzymatic activity of IRAP and has been proven to enhance learning and memory in animal models.
View Article and Find Full Text PDFSex- and time-dependent role of insulin regulated aminopeptidase in lipopolysaccharide-induced inflammation.
Front Immunol
October 2024
Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
Article Synopsis
- IRAP is an enzyme found in various immune cells, and it helps regulate the body's immune response; its genetic variants are linked to survival rates in septic shock patients.
- In a study modeling systemic inflammation from gram-negative sepsis using LPS, immune responses were compared between IRAP knockout and wildtype mice.
- Results showed that IRAP deficiency led to increased activation and pro-inflammatory response in dendritic cells and macrophages, highlighting the enzyme's role in inflammation, which varies by time and sex.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!