Pharmacodynamic assessment of orally available Mas agonists

Abstract

AbstractBackgroundOxidative stress (OS) plays a crucial role in driving Alzheimer’s disease (AD) pathogenesis. Angiotensin II (A‐II), the ligand for AT1R (pathological axis of the renin angiotensin system [RAS]), promotes the development of AD in part by increasing OS. Mas receptor and its ligand angiotensin (1‐7) (A(1‐7); protective axis of RAS) inhibits A‐II's pathological actions. Two orally available small molecule Mas agonists, RASRx1902 and RASRx1911, were developed to overcome shortcomings of A(1‐7). Both RASRx1902 and RASRx1911 reduce brain OS 90 days after transaortic constriction surgery (TAC), suggesting that both drugs might reduce neurodegeneration. To understand their pharmacodynamics, RASRx1902 and RASRx1911 were tested in the TAC model to determine their optimal dose and dosing regimen, and biological activity.MethodC57BL/6J mice underwent TAC or sham surgery. After echocardiography performed, mice were randomized based on their TAC gradient. Mice received one dose of saline, RASRx1902, or RASRx1911 at a range of subcutaneous or oral doses and euthanized at 0.5, 1, 2, 4 and 6 hours post‐treatment. After dose and route of delivery optimization, mice were treated 1x/day, 2x/day, 2x/week or 3x/week for 2 weeks. Brain tissues were isolated and analyzed for pharmacokinetics, functional markers for OS, and Akt/ERK activation.ResultsOne to three weeks after TAC surgery, the levels of mitochondrial superoxide were increased in microglia, but not in neurons, oligodendrocytes, and astrocytes compared with sham surgery. Treatment with RASRx1902 and RASRx1911, administered either subcutaneously or orally, reduced microglial superoxide levels compared to saline‐treated TAC mice. RASRx1902 showed a stronger inhibitory activity on TAC‐mediated superoxide production than RASRx1911. RASRx1902 and RASRx1911 treatment reduced the TAC‐mediated decreased Akt/Erk activity in brain compared to saline treatment.ConclusionsMicroglial mitochondrial superoxide is the main contributor to promote OS, a contributor to AD neurodegeneration. Our data clearly show that our metabolically stable small molecule Mas agonists have the capacity to decrease ROS levels in microglia and might mediate neuronal survival through Akt/Erk signaling pathway. Therefore, RASRx1902 and RASRx1911 are promising novel drug for the treatment of AD.