Intranasal Insulin Prevents Anesthesia-Induced Cognitive Impairment and Chronic Neurobehavioral Changes

Abstract

General anesthesia increases the risk for cognitive impairment post operation, especially in the elderly and vulnerable individuals. Recent animal studies on the impact of anesthesia on postoperative cognitive impairment have provided some valuable insights, but much remains to be understood. Here, by using mice of various ages and conditions, we found that anesthesia with propofol and sevoflurane caused significant deficits in spatial learning and memory, as tested using Morris Water Maze (MWM) 2-6 days after anesthesia exposure, in aged (17-18 months old) wild-type (WT) mice and in adult (7-8 months old) 3xTg-AD mice (a triple transgenic mouse model of Alzheimer's disease (AD)), but not in adult WT mice. Anesthesia resulted in long-term neurobehavioral changes in the fear conditioning task carried out 65 days after exposure to anesthesia in 3xTg-AD mice. Importantly, daily intranasal administration of insulin (1.75 U/mouse/day) for only 3 days prior to anesthesia completely prevented the anesthesia-induced deficits in spatial learning and memory and the long-term neurobehavioral changes tested 65 days after exposure to anesthesia in 3xTg-AD mice. These results indicate that aging and AD-like brain pathology increase the vulnerability to cognitive impairment after anesthesia and that intranasal treatment with insulin can prevent anesthesia-induced cognitive impairment.

Keywords: Alzheimer’s disease; cognitive impairment; general anesthesia; insulin; intranasal administration; postoperative cognitive dysfunction; propofol; sevoflurane.

Figures

Figure 1

Effect of anesthesia on spatial learning and memory. Wild-type (WT) mice of the indicated ages and 7–8-month-old 3xTg-AD mice were trained in Morris Water Maze (MWM) starting 24 h after general anesthesia with propofol and sevoflurane. Control group did not receive anesthesia. (A,G,M) Training curves show the latencies to locate the platform during training sessions for four consecutive days (4 trials/day). (B–F, H–L, N–R) Probe trial was performed 24 h after the last training trial. The first latency to reach the platform location (B,H,N), the number of the platform location crossings (C,I,O), the percent time the mice stayed in the target quadrant (D,J,P), the distance the mice swam in the target quadrant (E,K,Q) and the swim speed (F,L,R) of mice during the 60 s probe tests are shown. Reversal MWM test was performed for the 3xTg-AD mice starting on the next day following the probe trial. The training curves (S), as well as the first latency to reach the platform location (T), the number of the platform location crossings (U), the percent time the mice swam in the target quadrant (V), the distance the mice swam in the target quadrant (W) and the swim speed (X) of the mice during the 60 s probe tests are shown. Data are presented as mean ± SEM (n = 10–15 mice per group).

Figure 2

Effect of intranasal insulin on anesthesia-induced impairment of spatial learning and memory. The 3xTg-AD mice (7–8 months old, female) received daily intranasal insulin or saline for 3 days, followed by anesthesia with propofol/sevoflurane for 3 h. The mice were then trained in the MWM starting on the following day. (A) Training curves show the latency to locate the platform during training sessions for four consecutive days (4 trials/day). (B–D) Probe trial was performed 24 h after the last training session. The number of the platform location crossing (B), the percent time the mice swam in the target quadrant (C) and the distance the mice swam in the target quadrant (D) are shown. Reversal MWM test was performed on the next day following the probe trial. The training curves (E), the number of the platform location crossing (F), the percent time the mice swam in the target quadrant (G), the distance the mice swam in the target quadrant (H) and the swim speed (I) of the mice during the 60 s probe tests are shown. Data are presented as mean ± SEM (n = 12–15 mice per group).

Figure 3

Effect of anesthesia and intranasal insulin on long-term behavior of 3xTg-AD mice. (A) Experimental design. The 3xTg-AD mice (7–8 months old, female) received daily intranasal insulin or saline for 3 days, followed, on the next day, by anesthesia with propofol/sevoflurane for 3 h. The mice were then tested using various behavioral tests at various time periods indicated in the diagram. MWM, Morris water maze; rMWM, reversal MWM; OF, open field; NOR, novel object recognition; FC, fear conditioning; EPM, elevated plus maze. (B) FC test schedule, which was carried out over three consecutive days. (C) Percentage of time the mice froze during the conditioning phase on day 1 of the FC test. (D) Percentage of time the mice froze in different time periods (data with 7 s bout) during the 5-min context test on day 2 of the FC test. (E) Percentage of time the mice froze during the first 3 min (data 7 s bout) in the context test. (F) Percentage of time the mice froze in different time periods (data with 7 s bout) during the cued tone test on day 3 of the FC test. (G) Percentage of time the mice froze (data with 7 s bout) during the first 3 min in the cued tone test results. Data are presented as mean ± SEM (n = 11–13 mice per group).