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

J Pharmacol Exp Ther. 2019 Apr;369(1):9-25. doi: 10.1124/jpet.118.254854. Epub 2019 Feb 1.

Abstract

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 α, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin I / chemistry*
  • Angiotensin I / pharmacokinetics
  • Angiotensin I / pharmacology*
  • Angiotensin I / therapeutic use
  • Animals
  • Behavior, Animal / drug effects
  • Biomarkers / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cognitive Dysfunction / complications*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / physiopathology
  • Dementia, Vascular / complications*
  • Electrocardiography
  • Glycosylation
  • Half-Life
  • Heart Failure / complications
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation / physiopathology
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects*
  • Mice
  • Peptide Fragments / chemistry*
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / pharmacology*
  • Peptide Fragments / therapeutic use
  • 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

Substances

  • Biomarkers
  • Peptide Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • Angiotensin I
  • angiotensin I (1-7)