Effect of dexmedetomidine on mammalian target of rapamyein signaling pathway in hippocampus of mice with postoperative cognitive dysfunction

Abstract

Objective To investigate the effect of dexmedetomidine (DEX) on mammalian target of rapamyein (mTOR) signaling pathway in the hippocampus of mice with postoperative cognitive dysfunction (POCD). Methods A total of 64 specific pathogen free (SPF) adult C57BL/6J mice were randomly divided into four groups (n=16): sham-operated group, POCD group, DEX-L group (giving low dose of DEX) and DEX-H group (giving high dose of DEX). Mice only received anesthesia but not partial hepatectomy surgery in sham-operated group; mouse models of POCD in POCD group were established by partial hepatectomy surgery under anesthesia; DEX (25 μg/kg or 50 μg/kg) was given by intraperitoneal injection 30 min prior to partial hepatectomy surgery, and then, the mouse models of POCD were established in DEX-L group and DEX-H group; normal saline of the same volume was injected intraperitoneally prior to partial hepatectomy surgery in sham-operated group and POCD group. Behavioral test was performed via Fear Conditioning Test (FCS) one d before surgery and 3 d after surgery for training and behavioral testing, and the percentage of freezing time was recorded. Enzyme linked immunosorbent assay (ELISA) was used to detect the protein levels of beta amyloid protein 42 (Aβ-42) and phosphorylated(p)-tau-181 in cerebrospinal fluid of mice 3 d after surgery. The hippocampus tissues of mice were collected 3 d after surgery, and the mRNA expressions of mTOR, Tau, nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) in hippocampal tissues were tested by reverse transcription-polymerase chain reaction (RT-PCR). The protein expressions of mTOR, p-tau (pS396 Tau protein), NF-κB and TNF-α in hippocampal tissues were tested by Western blotting. Results (1) As compared with that in sham-operated group, the percentage of freezing time in conditioning FCS in POCD group was statistically lower (P<0.05); as compared with that in POCD group, the percentage of freezing time in conditioning FCS in DEX-L group and DEX-H group was significantly higher (P<0.05). (2) The protein levels of Aβ-42 and p-tau-181 in cerebrospinal fluid of POCD group, DEX-L group and DEX-H group were significantly higher than those in sham-operated group (P<0.05); the protein levels of Aβ-42 and p-tau-181 in cerebrospinal fluid of DEX-L group and DEX-H group were significantly lower as compared with those in POCD group (P<0.05); DEX-H group had significantly lower protein levels of Aβ-42 and p-tau-181 in cerebrospinal fluid as compared with DEX-L group (P<0.05). (3) The mRNA and protein expressions of mTOR, NF-κB p65 and TNF-α, Tau mRNA expression, and pS396 Tau protein expression in the hippocampus of the POCD group were significantly higher as compared with those in the sham-operated group (P<0.05); the mRNA and protein expressions of mTOR, NF-κB p65 and TNF-α, Tau mRNA expression, and pS396 tau protein expression in the hippocampus of the DEX-L group and DEX-H group were significantly lower as compared with those in the POCD group (P<0.05); those in the DEX-H group were significantly lower than those in the DEX-L group (P<0.05). Conclusion DEX can improve early POCD in mice, and the mechanism may be related to down-regulation of mTOR signaling pathway. Key words: Dexmedetomidine; Postoperative cognitive dysfunction; Mammalian target of rapamyein; Fear conditioning test