Activating ryanodine receptor improves isoflurane-induced cognitive dysfunction

Abstract

Background: Postoperative cognitive dysfunction (POCD) is characterized by impaired learning and memory. 6 h duration isoflurane anesthesia is an important factor to induce POCD, and the dysfunction of ryanodine receptor (RyR) in the hippocampus may be involved in this process. We investigated the expression of RyR3 in the hippocampus of mice after 6-h duration isoflurane anesthesia, as well as the improvement of RyR receptor agonist caffeine on POCD mice, while attempting to identify the underlying molecular mechanism.

Materials: We constructed a POCD model using 8-week-old male C57BL/6J mice that were exposed to 6-h duration isoflurane. Prior to the three-day cognitive behavioral experiment, RyR agonist caffeine were injected. Fear conditioning and location memory tests were used in behavioral studies. We also exposed the mouse neuroblastoma cell line Neuro-2a (N2A) to 6-h duration isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. We administered ryanodine receptor agonist (caffeine) and inhibitor (ryanodine) to N2a cells. Following that, we performed a series of bioinformatics analysis to discover proteins that are involved in the development of cognitive dysfunction. Rt-PCR and Western blot were used to assess mRNA level and protein expression.

Results: 6-h duration isoflurane anesthesia induced cognitive dysfunction and increased RyR3 mRNA levels in hippocampus. The mRNA levels of RyR3 in cultured N2a cells after anesthesia were comparable to those in vivo, and the RyR agonist caffeine corrected the expression of some cognitive-related phenotypic proteins that were disturbed after anesthesia. Intraperitoneal injection of RyR agonist caffeine can improve cognitive function after isoflurane anesthesia in mice, and bioinformatics analyses suggest that CaMKⅣ may be involved in the molecular mechanism.

Conclusion: Ryanodine receptor agonist caffeine may improve cognitive dysfunction in mice after isoflurane anesthesia.

Keywords: Isoflurane anesthesia; Postoperative cognitive decline; Ryanodine receptor.