Mitigation of cognitive decline and brain pathology after transaortic constriction by Mas agonists

Abstract

AbstractBackgroundMas and A(1‐7), the endogenous ligand of Mas, were first characterized for their ability to counter regulate the pathological actions of A‐II and AT1R. A(1‐7) has been shown to decrease inflammation and OS and increase cerebral blood flow reactivity. Plasma A(1‐7) levels were decreased in AD patients as compared to age and gender matched controls. Intra‐cerebroventricular (ICV) infusion of A(1‐7) improved cognitive and cerebrovascular function in mice receiving ICV infusion of A‐II. In SAMP8 and in P301S mice, low brain levels of A(1‐7) were correlated with increased tau hyperphosphorylation. However, the short half‐life and lack of oral bioavailability of A(1‐7) make it challenging to develop as a therapeutic modality. In order to overcome this shortcoming, our lab has developed equipotent small molecule analogs of A(1‐7), RASRx1902 and RASRx1911.MethodC57/Bl6 mice underwent transaortic constriction (TAC). One week later, echocardiography was performed and the animals randomized based on their TAC gradient and treatment (vehicle or 2 mg/kg RASx1902 or RASRx 1911 subcutaneously, once daily for 12 weeks. After 10 weeks of treatment, the mice underwent novel object recognition. At necropsy, brain tissue was analyzed by flow cytometry and levels of inflammatory cytokines by MSD.ResultTAC surgery alone resulted in reduced cognitive function measured by NOR. This cognitive decline was reversed by RASRx1902 and RASRx1911 treatment. Treatment with RASRx1902 and RASRx1911 also reduced the levels of microglial and neuronal mitochondrial dysfunction, oxidative stress (OS) and inflammation seen in saline treated mice to levels comparable to sham controls.ConclusionIn conclusion, RASRx1902 and RASRx1911 resulted in improved cognition and reduced OS and inflammation in the brain of mice that had undergone TAC surgery.