A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction.

TitleA Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction.
Publication TypeJournal Article
Year of Publication2019
AuthorsHay M, Polt R, Heien ML, Vanderah TW, Largent-Milnes TM, Rodgers K, Falk T, Bartlett MJ, Doyle KP, Konhilas JP
JournalJ Pharmacol Exp Ther
Date Published2019 04
KeywordsAngiotensin I, Animals, Behavior, Animal, Biomarkers, Brain, Cognitive Dysfunction, Dementia, Vascular, Electrocardiography, Glycosylation, Half-Life, Heart Failure, Human Umbilical Vein Endothelial Cells, Humans, Inflammation, Male, Maze Learning, Memory, Mice, Peptide Fragments, Proto-Oncogene Proteins, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Receptors, G-Protein-Coupled, Spatial Memory, Ventricular Remodeling

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 , interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.

Alternate JournalJ Pharmacol Exp Ther
PubMed ID30709867
PubMed Central IDPMC6413771
Grant ListR01 HL098256 / HL / NHLBI NIH HHS / United States
R01 NS091238 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD
Kathleen Rodgers, Ph.D.
Todd Vanderah, PhD