ABSTRACT

Hundreds of peptide transmitters are produced in the central nervous system (CNS) and wide range of brain functions, including analgesia, reward, food intake, metabolism, reproduction, social behaviours, learning and memory. These peptides influence cell behaviour and brain function in a variety of contexts, but their short serum half-lives have prevented the use of peptides neurotransmitters as CNS drugs. Peptide-based drugs offer significant advantages in that they bind with exquisite specificity to in vivo targets, resulting in exceptionally high potencies and relatively few off-target side effects as they mimic the endogenous ligand. However, they often possess poor metabolic stability, membrane permeability, pharmacokinetics and pharmacodynamics (PK/PD). One peptide of particular interest is Angiotensin 1-7 (Ang 1-7).

A growing body of evidence indicates that decreased brain blood flow, increased ROS and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as vascular dementia and Alzheimer’s disease (AD). Our comprehensive ProNeurogen and University of Arizona team has developed a novel approach to take advantage of the antinflammatory and neuroprotective nature of the G-protein linked Mas receptor and its agonist Ang-(1-7). Within the brain, the Mas receptor is expressed on neurons, microglia and vascular endothelial cells and activation of Mas decreases ROS and brain inflammation, increases cerebral circulation via increases in endothelial NO release and inhibits hypoxia-inducing factor. Because the Mas receptor is found in high quantities within the hippocampus and perirhinal cortex as well as in vascular endothelial cells, Ang-(1-7) will be particularly effective in targeting memory impairments associated with hypoxia and inflammation-related neurodegenerative disease and patients at risk for AD.
We have synthesized a series of glycosylated Ang 1-7 derivatives which have improved serum stability and improved brain penetration. We have identified 2 lead compounds that selectively activate the MasR, inhibit reactive oxygen species production and increase endothelial nitric oxide release. To assess the ability of our glycosylated Ang 1-7 to affect brain function, we employed our novel mouse model of systemic inflammation induced cognitive impairment in mice with heart failure (HF). Mice with 12 weeks of HF were given 28-day subcutaneous daily injections of Ang 1-6-Ser-OGlc-NH2. We then measured spatial memory performance and object recognition as determined by the Morris Water Maze test (MWM) and novel object recognition test (NOR), respectively. The NOR test was conducted 3 days after the last injection and the MWM memory task was conducted 5 days after the last injection. Treatment with Ang 1-6-Ser-OGlc-NH2 reversed HF induced memory impairment. Treated animals (n=11) showed significantly (p= 3.6×10-5 , ANOVA, Bonferroni post hoc test ) improved corrected integrated path length (CIPL) score between day 1 and day 4 of the task as compared to HF-saline (n=11) treated animals (HF-saline Day 1 M = 36.0, SD 16.6, Day 4 M = 27.8, SD 19.8; HF- Ang 1-6-Ser-OGlc-NH2 Day 1 M = 37.1, SD 16.5, Day 4 M = 21.6, SD 15.5; Control-saline Day 1 M = 29.2, SD 18.8, Day 4 M = 13.9, SD 15.0). These results demonstrate that systemic treatment with Ang 1-6-Ser-OGlc-NH2 Ang-(1-7) rescues cognitive function in models of inflammation induced cognitive impairment such as heart failure and may be a novel therapeutic strategy to treat vascular dementia.

BIO

Dr. Hay is the Founder of a new Tucson biotechnology company, ProNeurogen, Inc. (http://www.proneurogen.com/). ProNeurogen is a preclinical and clinical stage biopharmaceutical company developing novel peptide-based therapeutics to treat cognitive impairment in patients at risk for Alzheimer’s disease and brain injury caused by cardiovascular disease and trauma. Dr. Hay and ProNeurogen are collaborating with physicians and scientists at the University of Arizona’s Sarver Heart Center, the Evelyn F. McKnight Brain Institute, BIO5 Institute and Banner Alzheimer’s Institute to advance these peptides through FDA Phase II clinical trials. The goal of these studies is to reduce or prevent memory loss related to decreased brain blood flow and inflammation. Future studies are underway for treatment of traumatic brain injury.
Dr. Hay is the former Executive Vice President and Provost of The University of Arizona. She was the University of Arizona’s chief operating officer with responsibilities for the entire $2.1B university budget including the Arizona Health Sciences Center. Prior to coming to Arizona, Dr. Hay served as Vice President for Research at the University of Iowa.