A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction.
Angiotensin I
/ chemistry
Animals
Behavior, Animal
/ drug effects
Biomarkers
/ metabolism
Brain
/ drug effects
Cognitive Dysfunction
/ complications
Dementia, Vascular
/ complications
Electrocardiography
Glycosylation
Half-Life
Heart Failure
/ complications
Human Umbilical Vein Endothelial Cells
/ drug effects
Humans
Inflammation
/ physiopathology
Male
Maze Learning
/ drug effects
Memory
/ drug effects
Mice
Peptide Fragments
/ chemistry
Proto-Oncogene Mas
Proto-Oncogene Proteins
/ agonists
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
/ metabolism
Receptors, G-Protein-Coupled
/ agonists
Spatial Memory
/ drug effects
Ventricular Remodeling
/ drug effects
Journal
The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
07
11
2018
accepted:
29
01
2019
pubmed:
3
2
2019
medline:
27
12
2019
entrez:
3
2
2019
Statut:
ppublish
Résumé
Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor
Identifiants
pubmed: 30709867
pii: jpet.118.254854
doi: 10.1124/jpet.118.254854
pmc: PMC6413771
doi:
Substances chimiques
Biomarkers
0
Peptide Fragments
0
Proto-Oncogene Mas
0
Proto-Oncogene Proteins
0
Reactive Oxygen Species
0
Receptors, G-Protein-Coupled
0
Angiotensin I
9041-90-1
angiotensin I (1-7)
IJ3FUK8MOF
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
9-25Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL098256
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS091238
Pays : United States
Informations de copyright
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
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