Effects of isoflurane-induced anaesthesia on cognitive performance in a mouse model of Alzheimer's disease: A randomised trial in transgenic APP23 mice.

BACKGROUND: Results from in-vitro experiments suggest that inhalational anaesthetics may have a detrimental effect on the course and incidence of Alzheimer's disease. However, case-control studies in humans show no negative impact of anaesthetics on the course of Alzheimer's disease. OBJECTIVE: To test the hypothesis that 2 h of general anaesthesia with 1 MAC isoflurane changes learning abilities of young and old transgenic Alzheimer's mice (APP23 mice). DESIGN: Randomised controlled double-blinded study in mice. SETTING: Animal laboratory and operating theatre in the Klinik für Anästhesiologie, Technische Universität München, Germany ANIMALS: Ninety-six male mice divided in four groups: young (4 months) APP23 mice and corresponding wild-type mice; old (14 to 16 months) APP23 and corresponding wild-type mice. INTERVENTION: Mice were either anaesthetised for 2 h with 1 MAC isoflurane or sham-anaesthetised ('isoflurane' or 'control'). MAIN OUTCOME MEASURES: Learning and locomotor activity during the following 8 days using the modified Hole Board Test for mice. Results are median (interquartile range) and median difference (95% confidence interval). RESULTS: Young mice, [1.0 (1.3)] as assessed by the number of omission errors, learned better than old [1.8 (1.8); age: P = 0.004, median difference 0.5 (0.2 to 1.0)]. Anaesthetised animals [0.8 (1.5)] learned better than controls [1.6 (1.7); anaesthesia: P = 0.010, median difference 0.5 (0.1 to 0.9)]. This was accompanied by higher locomotor activity in young compared to old mice as assessed by number of line crossings per minute [10 (5) min(-1) vs. 7 (3) min(-1), P < 0.001, median difference 3 (2 to 4) min(-1)]. Anaesthesia and genotype Alzheimer's disease had no impact on locomotor activity. CONCLUSION: Isoflurane may have protective, rather than detrimental, effects on cognition in Alzheimer's disease.

Transgenic Alzheimer mice have a larger minimum alveolar anesthetic concentration of isoflurane than their nontransgenic littermates.

BACKGROUND: More than 12% of all people older than 65 yr have Alzheimer's disease. Because nothing is known about changes in demand of volatile anesthetics in this disease, we determined minimum alveolar anesthetic concentration (MAC) values of isoflurane in young and aged transgenic mice at risk of developing Alzheimer's disease (heterozygote APP23 mice with the "Swedish double mutation"). To differentiate between unspecific effects of the transgenic model and specific Alzheimer effects, we additionally evaluated MAC values in mice with the same genetic construct but without the Alzheimer's disease-causing Swedish double mutation (heterozygote APP51/16 mice). METHODS: MAC was determined in 60 mice (10 per group): heterozygote APP23 mice and their wild type littermates at the age of 4 and 18 mo, respectively, and heterozygote APP51/16 mice and their wild type littermates at the age of 18 mo. Anesthesia was induced with isoflurane in oxygen/air. The concentration of inhaled isoflurane varied between 1.0 and 2.0 Vol%, and the motor reaction to toeclamping was recorded. Means of the MAC values were compared with an unpaired t-test. RESULTS: The MAC of 18-mo-old heterozygote APP23 mice was 1.67 +/- 0.09, i.e., 9% larger than the MAC of their wild type littermates (1.53 +/- 0.14; P = 0.020). Heterozygote APP51/16 mice had a lower MAC than their wild type littermates (1.32 +/- 0.14 vs 1.48 +/- 0.13; P = 0.037). All wild type groups and young heterozygote APP23 mice had comparable MAC values. CONCLUSIONS: The increased MAC value in aged heterozygote APP23 mice seems to be attributable to changes related to Alzheimer's disease.

Isoflurane anaesthesia reversibly improves cognitive function and long-term potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression.

Postoperative cognitive dysfunction (POCD) is a decline in cognitive performance after a surgery performed under anaesthesia. The exact roles of surgery and/or anaesthesia for facilitating POCD are unclear. This study investigates the effects of isoflurane anaesthesia on cognitive performance and cellular mechanisms involved in learning and memory function. Male C57BL6/J mice (age: 4-5 months) were anaesthetized with isoflurane in oxygen/air (FiO(2)=0.5) for 2h, non-anaesthetized mice served as controls. After 24h, neurocognitive function, in vitro long-term potentiation (LTP), or protein expression were evaluated. In a visuospatial test, anaesthetized mice showed better cognitive performance as they learned faster compared to controls. In hippocampal slices of anaesthetized mice, in vitro LTP was enhanced as reflected in an increased extracellular field potential (fEPSP) slope after 1h to 210.2+/-17% (control: 156.8+/-7.2%; n=14; p<0.05). NR2B subunits of the NMDA receptors were selectively up-regulated in hippocampal neurones after anaesthesia. Blocking these receptors either with the NR2B selective antagonists ifenprodil or RO25-6981 (R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol), prevents the anaesthesia-induced improvement in cognitive function as well as enhancement of in vitro LTP. The anaesthesia-mediated effects on NR2B subunits were fully reversed to control levels seven days after anaesthesia. The present data suggests that isoflurane anaesthesia induces a hippocampus-specific elevation of NR2B subunit composition, enhances LTP in CA1 neurones, and produces hippocampal-dependent cognitive improvement.

Sevoflurane anesthesia improves cognitive performance in mice, but does not influence in vitro long-term potentation in hippocampus CA1 stratum radiatum.

BACKGROUND: Whether the occurrence of postoperative cognitive dysfunction is a result of the effects of surgery or anesthesia is under debate. In this study, we investigated the impact of sevoflurane anesthesia on cognitive performance and cellular mechanisms involved in learning and memory. METHODS: Male C57Bl6/J mice (4-5 months) were exposed to one minimum alveolar concentration sevoflurane for two hours. After 24 h, cognitive performance of mice was assessed using the modified hole board test. Additionally, we evaluated hippocampal long-term potentiation and expression levels of different receptor subunits by recording excitatory postsynaptic field potentials and using the western blot technique, respectively. Non-anesthetized mice served as controls. RESULTS: In anesthetized mice, neither cognitive performance nor long-term potentiation was impaired 24 h after anesthesia. Interestingly, sevoflurane anesthesia induced even an improvement of cognitive performance and an elevation of the expression levels of N-methyl-D-aspartate (NMDA) receptor type 1 and 2B subunits in the hippocampus. CONCLUSIONS: Since NMDA receptor type 1 and 2B subunits play a crucial role in processes related to learning and memory, we hypothesize that sevoflurane-induced changes in NMDA receptor subunit composition might cause hippocampus-dependent cognitive improvement. The data of the present study are in favor of a minor role of anesthesia in mediating postoperative cognitive dysfunction.