The effect of propofol and ketamine used in repetitive anesthesia on neurocognitive functions in rats

Introduction and Objective: Postoperative cognitive dysfunction (POCD) is a common postoperative condition that seriously threatens the quality of life, particularly in elderly patients. Postoperative elevation of proinflammatory cytokines both in the central nervous system and in the systemic circulation may be related to the degree of cognitive decline. Anesthetic agents are considered a critical risk factor for POCD because they can lead to both microglial activation and neuroinflammation. It has been reported that repeated propofol administration may cause neurocognitive impairment by triggering neuroinflammation. Ketamine has been shown to decrease TNF-α, IL-6, IL-1β levels in the hippocampus and may protect neuronal loss in the hippocampus by inhibiting autophagy. The hypothesis of our study is that neurocognitive dysfunction that may occur with the use of propofol may be reduced by using it together with ketamine. The primary aim of this study was to investigate the effects of repeated doses of propofol, ketamine and ketamine+propofol on neurocognitive functions, spatial learning and memory changes in rats. The secondary aim was to evaluate the effects of these applications on markers of learning (BDNF, NF-κB) and inflammation (TNF-α, IL-1β, IL-6). Materials and Methods: In our study, 32 male Sprague Dawley rats, each 12 weeks old and weighing between 410-570 g, were divided into 4 groups of 8 rats. The groups were named as Control (K), Propofol (P), Ketamine (Ke), Ketamine+Propofol (KeP) group. Initially, to simulate repeated anesthesia, the groups received the following treatments for 5 days at 24-hour intervals: group K received 4 ml saline; group P received 150 mg/kg propofol; group Ke received 120 mg/kg ketamine; and group KeP received 60 mg/kg ketamine + 75 mg/kg propofol (i.p.). The anesthesia and recovery times of the groups, except for group K, were recorded. After resting for two days, the rats were first subjected to the passive avoidance test and then to the Morris water maze test. After the behavioral experiments, hippocampus tissues of decapitated rats were isolated and levels of inflammation markers (TNF-α, IL-1β, IL-6) and learning markers (BDNF, NF-κB) were measured by biochemical tests. Results: Among the groups that underwent repeated anesthesia, the duration of anesthesia was statistically significantly longer in group P and group KeP, and the recovery time was statistically significantly shorter in group Ke and group KeP. No significant difference was found between the groups in passive avoidance and MSL tests performed to evaluate learning and memory functions (p>0.05). When biochemical markers were analyzed, IL-6 level was significantly lower in group P (p<0.001) and group Ke (p<0.05) compared to group KeP, while BDNF level was lower in all groups compared to group K (p<0.05; p<0.01). No significant difference was observed between the groups in terms of TNF-α, IL-1β and NF-κB levels (p>0.05). Conclusion: : In this study, it was observed that learning and memory functions were negatively affected in group Ke and group KeP compared to group K, but this effect was not statistically significant. The results of the study showed that the combined use of propofol and ketamine, which are frequently used in repetitive sedation applications, may increase the development of POCD. Based on these findings, we believe that more caution should be exercised during the combined use of these drugs and the risk of POCD development should be considered in repeated anesthesia procedures. Key Words: Postoperative cognitive dysfunction, learning, memory, repeated anesthesia