Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that
cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the
angiotensin 2/
angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1-7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following
laparotomy.
AVE 0991, a nonpeptide analog of Ang-(1-7), was administered intranasally immediately after
laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1-7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal
AVE 0991 treatment significantly improved hippocampus-dependent learning and
memory deficits induced by surgery. Furthermore, it attenuated hippocampal
neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the
AVE 0991 treatment also alleviated the imbalance between
matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of
occludin, and alleviated the
IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by
AVE 0991 attenuates dNCR after surgery by reducing
neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1-7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.