A non-peptidic MAS1 agonist AVE0991 alleviates hippocampal synaptic degeneration in rats with chronic cerebral hypoperfusion.

Background Chronic cerebral hypoperfusion (CCH) is a contributing factor for neurodegenerative diseases. As a recently identified heptapeptide of the brain renin-angiotensin system, angiotensin-(1-7) was revealed to activate its receptor MAS1 and thus ameliorated cognitive impairments in rats with CCH. Since hippocampal synaptic degeneration represents an important pathological basis of cognitive deficits, we hypothesize that activation of MAS1-mediated signaling may alleviate CCH-induced synaptic degeneration in the hippocampus. Methods In this study, we tested this hypothesis and uncovered the underlying mechanisms in a rat model of CCH induced by bilateral common carotid artery ligation surgery. At 1 week after the surgery, rats received a daily intraperitoneal injection of vehicle or a non-peptidic MAS1 agonist AVE0991 for 8 weeks. During this procedure, cerebral blood flow (CBF) was recorded. The levels of MAS1, amyloid-β (Aβ), neuroinflammatory cytokines, glial cell markers and synaptophysin in the hippocampus were assessed at the end of the treatment period. Results We showed that AVE0991 significantly alleviated hippocampal synaptic degeneration in rats with CCH. This protection might be achieved by facilitating CBF recovery, reducing hippocampal Aβ levels and suppressing neuroinflammatory responses. Conclusions These findings indicate that MAS1-mediated signaling may represent a novel therapeutic target for CCH-related neurodegenerative diseases.