Comparison of Cognitive Deterioration Between Propofol and Remimazolam Anesthesia in ApoE4 Knock-In Mouse Model

Abstract

Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer's disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg/kg) or remimazolam (85 mg/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (Aβ) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater Aβ accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (p < 0.05). Propofol was associated with more pronounced neuropathologic changes in the hippocampus compared to remimazolam. These findings suggest remimazolam may be a safer anesthetic for patients at risk for neurodegenerative disorders, as it is associated with less severe hippocampal pathology, which is characteristic of AD.

Keywords: anesthesia; cognitive impairments; general; propofol; remimazolam.

Figure 1

Results of Morris water maze tests in ApoE4 knock-in mice under Propofol and Remimazolam anesthesia. (A) No significant differences were observed between the two groups in absolute escape latency. (B) No significant differences were observed between the two groups in relative escape latency. (C) During the training trials, there were no significant differences in escape latency between the two groups. Each value represents the mean ± SD. Group P: propofol group, Group R: remimazolam group.

Figure 2

Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity in the hippocampal CA3 and dentate gyrus (DG) regions of ApoE4-KI mice under propofol and remimazolam anesthesia. (A) TUNEL staining (green) shows apoptotic cells in the CA3 and DG regions at preoperative, 2, 4, and 7 days postoperatively (scale bar = 100 µm). (B) Quantification of TUNEL-positive areas in the CA3 region showed no significant difference between Group P and Group R at preoperative and 2 days after surgery. However, significant differences were found at 4 and 7 days after surgery (*** p < 0.001). In addition, significant differences were found between preoperative and postoperative days 2, 4, and 7 (^⁋ p < 0.001). (C) Quantification of TUNEL-positive areas in the DG region showed no significant difference at the preoperative stage. However, significant differences were observed between Group P and Group R on days 2, 4, and 7 after surgery (*** p < 0.001). Significant differences were also observed between preoperative and postoperative days 2, 4, and 7 (^⁋ p < 0.001). Each value represents the mean ± SD. Group P: propofol group, Group R: remimazolam group.

Figure 3

Amyloid-beta (Aβ) expression levels in the hippocampal CA3 and dentate gyrus (DG) regions of ApoE4-KI mice under propofol and remimazolam anesthesia. (A) Aβ deposits (brown) are visible in the CA3 and DG regions at preoperative, 2, 4, and 7 days after surgery (scale bar = 100 µm). (B) Quantification of Aβ deposits in the CA3 region showed no significant differences between Group P and Group R at 2 and 4 days after surgery, with higher levels in Group P. However, no significant difference was observed between the two groups at 7 days after surgery (** p < 0.01, *** p < 0.001). In addition, significant differences were observed between the preoperative and 2 and 4 days after surgery (^⁋ p < 0.001). (C) Aβ deposition in the DG region showed no significant differences preoperatively, but significant increases were observed in Group P compared to Group R at 2 and 7 days postoperatively (*** p < 0.001). Significant differences were observed between the preoperative and postoperative days 4, and 7 (^⁋ p < 0.001). Each value represents the mean ± SD. Group P: propofol group, Group R: remimazolam group.

Figure 4

Experimental timeline and group allocation. All mice underwent 5 days of pre-training with twice-daily Morris water maze (MWM) sessions. On the preoperative day, Y-maze and MWM tests were conducted, after which mice were sacrificed (n = 5 per group) for histological analysis. The remaining mice underwent surgery, under either propofol (Group P) or remimazolam (Group R) anesthesia. Postoperatively, behavioral tests and sacrifice were conducted on days 2, 4, and 7 (n = 5 per group at each time point).

Figure 5

Experimental animals, anesthesia, and surgical procedures. (A) Animals were housed at the Hallym Clinical Translational Research Center with ad libitum access to food and water. (B) General anesthesia was induced with 170 mg/kg propofol or 85 mg/kg remimazolam administered by tail vein injection; the total duration of anesthesia was up to 2 h. (C) Surgery commenced with the creation of a median abdominal incision of approximately 1.5 cm in length into the peritoneal cavity. The viscera were then gently manipulated. (D) After surgery, mice were placed on heated pads and returned to their cages after recovery.