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

Abstract

Aims: Delayed neurocognitive recovery (dNCR) is a common postoperative complication in geriatric surgical patients for which there is no efficacious therapy. Cholecystokinin octapeptide (CCK-8), an immunomodulatory peptide, regulates memory and learning. Here, we explored the effects and mechanism of action of CCK-8 on dNCR. Methods: We applied laparotomy to establish a model of dNCR in aged mice. Morris water maze and fear conditioning tests were used to evaluate cognition. Immunofluorescence was used to detect the density of CCK-8, A1 reactive astrocytes, glutamatergic synapses, and activation of microglia in the hippocampus. Quantitative PCR was performed to determine mRNA levels of synapse-associated factors. A1 reactive astrocytes, activated microglia, and glutamatergic synapse-associated protein levels in the hippocampus were assessed by western blotting. Results: Administration of CCK-8 suppressed the activation of microglia, the induction of A1 reactive astrocytes, and the expression of tumor necrosis factor alpha, complement 1q, and interleukin 1 alpha in the hippocampus. Furthermore, it promoted glutamatergic synaptogenesis and neurocognitive recovery in aged dNCR model mice. Conclusion: Our findings indicated that CCK-8 alleviated cognitive impairment and promoted glutamatergic synaptogenesis by inhibiting the induction of A1 reactive astrocytes and the activation of microglia. CCK-8 is, therefore, a potential therapeutic target for dNCR.