Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation

Abstract

The present study investigated the effect of dexmedetomidine on hippocampal inflammation and cognitive function in rats with postoperative cognitive dysfunction (POCD). A total of 80 healthy male Sprague Dawley rats were used, 72 of which developed POCD. The rats were randomly divided into four groups: The control, model, low‑dose and high‑dose dexmedetomidine anesthesia groups. A POCD model was established and dexmedetomidine was administered. Cognitive function tests were performed and expression levels of interleukin 1β (IL‑1β), tumor necrosis factor‑α (TNF‑α) and NF‑κB biomarkers were evaluated on the first, third and seventh day following modeling. The cognitive function of rats was measured using a Y‑maze test. The expression levels of IL‑1β and TNF‑α in the hippocampus were determined by ELISA. The protein expression levels of NF‑κB p65 in the hippocampus were determined by western blotting. It was revealed that at 1, 3 and 7 days after surgery, there were no alterations in the exercise ability of rats in the different groups, as reflected by the number of rats passing the alternative arms in the Y‑maze. On the first and third day after surgery, the cognitive dysfunction reflected by the alteration scores of the low‑dose and high‑dose dexmedetomidine anesthesia groups were significantly higher than those of the model group, and the increase in the high‑dose group was more pronounced. Additionally, on the first day after surgery, the expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampi of rats in the low‑ and high‑dose dexmedetomidine anesthesia groups were significantly lower than those in the model group, and the decrease was more pronounced in the high‑dose group. At 7 days after surgery, the differences in expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampus among groups were not identified to be statistically significantly different. Taken together, the results of the present study indicated that dexmedetomidine may inhibit hippocampal inflammation induced by surgical trauma, and that dexmedetomidine may effectively improve postoperative cognitive function in rats.

Figure 1.

Number of passes between alternative arms in the Y-maze in each group at different time points following surgery. There was no statistically significant difference observed in the number of rats passing the alternative arms in each group at 1, 3 or 7 days after surgery.

Figure 2.

Alteration scores at different time points following surgery. The alteration score of the model group was significantly lower than that of the control group. The alteration scores of the high-dose and low-dose anesthesia groups were significantly higher compared with those of the model group, particularly in the high-dose group. On day 7, there was no statistical difference in alteration score among rats in each group. *P<0.05 vs. control group; ^#P<0.05 vs. model group.

Figure 3.

Expression levels of IL-1β and TNF-α in the rat hippocampus following surgery. At 1 and 3 days after surgery, the expression levels of IL-1β and TNF-α in the model group were significantly higher compared with those in the control group. The expression levels of IL-1β and TNF-α in the high-dose and low-dose anesthesia groups were decreased significantly compared with in the model group, and the decrease in the high-dose group was more pronounced. At 7 days after surgery, the expression levels of IL-1β and TNF-α were low in all groups and there was no statistically significant difference identified among the groups. *P<0.05 vs. control group; ^#P<0.05 vs. model group. IL-1β, interleukin 1β; TNF-α, tumor necrosis factor α.

Figure 4.

Expression levels of NF-κB p65 in the hippocampus of rats following surgery. NF-κB p65 expression in the model group was significantly increased compared with the control group at 1 and 3 days after surgery (P<0.05). The expression levels of NF-κB p65 in the high-dose and low-dose groups were significantly decreased compared with those in the model group, and the decrease was more obvious in the high-dose group. At 7 days after surgery, the expression levels of NF-κB p65 remained low and there was no statistically significant difference identified among the groups. *P<0.05 vs. control group; ^#P<0.05 vs. model group. HD, high-dose; LD, low-dose.

Figure 5.

Activation of microglia in the brains of rats following surgery. (A) Immunofluorescence staining of microglia in the hippocampus at 1 day after surgery. Magnification, ×400. Arrows indicate activated microglia. (B) Microglial activation rates at 1, 3 and 7 days after surgery. At 1 day after surgery, the microglial cells in the brain tissues of rats in the control group were in an inactive state, cell bodies were small with irregular protrusions. By contrast, the microglial cells in the brain tissues of rats in the model group were large, cell bodies were round and they exhibited an activation state of deformation and phagocytosis. At day 1, the quantification of immunofluorescence staining revealed that the proportion of activated microglial cells was 79.54±5.52% in the model group, which was significantly higher than that of the control group (P<0.05). The activation of microglia in the brain tissue from the high-dose and low-dose anesthesia groups was inhibited, the activation rates were 21.84±2.03 and 39.45±3.55%, respectively, which were significantly lower than that of the model group (P<0.05). At 3 days after surgery, the activation of microglia in brain tissue was decreased to 55.16±5.23% in the model group, to 15.97±1.26% in the low-dose and to 10.65±1.12% high-dose groups. At 7 days after surgery, there was no statistically significant difference observed in the activation rates of microglial cells in the brain tissues of each group (P>0.05). These results indicated that microglia were activated by dexmedetomidine. *P<0.05 vs. control group; ^#P<0.05 vs. model group. Iba-1, ionized calcium-binding adapter molecule 1.