The Non-peptide Angiotensin-(1–7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats

Abstract

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.

Cholecystokinin octapeptide improves hippocampal glutamatergic synaptogenesis and postoperative cognition by inhibiting induction of A1 reactive astrocytes in aged mice

“…The dNCR mouse model was established in accordance with previous studies. 27 , 28 , 29 Briefly, mice were anesthetized with 5% sevoflurane for 3 min and maintained with 2.0%–2.5% sevoflurane in 40% oxygen. After the surgical site was shaved and sterilized, a 1.5 cm vertical incision was made 0.5 cm below the right costal margin through the skin and muscle wall.…”

“…The dNCR mouse model was established in accordance with previous studies. [27][28][29] Briefly, mice were anesthetized with 5% sevoflurane for 3 min and maintained with 2.0%-2.5% sevoflurane in 40% oxygen.…”

Glibenclamide Attenuates Neuroinflammation and Promotes Neurological Recovery After Intracerebral Hemorrhage in Aged Rats

“…Our previous study determined that inhibition of Sur1 alleviated ICH-induced metalloproteinase (MMPs) expression. Many previous studies showed that MMPs play an important role in neuroinflammation (Vandooren et al, 2014;Hannocks et al, 2017;Mi et al, 2021). The increased activity of MMPs can affect the secretion of many types of inflammatory cytokines and the activation of inflammatory cells (Florczak-Rzepka et al, 2012).…”

Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions

“…There are several limitations to the current study. First, we used the established dNCR model with endotracheal intubation anesthesia according to our previous study (Li et al, 2016 ; Mi et al, 2021 ). Compared with other dNCR models, this model is more clinically relevant.…”