Uates Memory ImpairmentSeveral studies have shown that the ultimate effects of isoflurane critically depend on both the concentration and duration of exposure. Pan [14] demonstrated that treatment with 0.5 isoflurane for 8 hours attenuated the hypoxia-induced activation of caspase-3 and the levels of the aspartyl protease Homatropine (methylbromide) biological activity b-site amyloid precursor protein-cleaving enzyme in H4 human neuroglioma cells; treatment with 2 isoflurane for 8 hours enhanced this response. Wei [15] reported that pre-conditioning with isoflurane for one hour dose-dependently inhibited the neurotoxicity induced by a 24-h exposure to 2.4 isoflurane in both primary cortical neurons and PC12 cells. Lee [16] showed that 2 isoflurane postconditioning for 20 or 30 minutes after oxygen-glucose deprivation ameliorated the cell injury induced thereof. However, exposure to 2 isoflurane for 60 minutes or 2.5 isoflurane for 20?0 minutes had no post-conditioning effects. These results suggest that the effects of isoflurane may be concentration- and duration-dependent. In the present study, the concentration of isoflurane was relatively low, and the duration was relatively short. Although no study has used isoflurane for 2 hours for 5 days as preconditioning, many studies have demonstrated that chronic ischemia or pharmacological pre-conditioning is associated with a reduction in myocardial infarct size [17,18]. Many other studies demonstrated the neuroprotective effects of isoflurane preconditioning against ischemia [19,20] or hypoxia [21,22]. Therefore, pre-conditioning effects may be involved. In cell culture models, isoflurane alters APP processing and increases the production of Abeta [3,23]; however, in the present study, we found that isoflurane exposure decreased the Abeta plaque in the hippocampus. However, the Abeat plaques is poorly correlated with the synaptic loss or cognitive impairment in AD subjects [24]. At the same time, accumulating evidences demonstrated that there are a strong correlation between the Abeta oligomer and the synaptic loss and cognitive impairment[24?7]. In present study, we found that the Abeta oligomers reduced significantly after isoflurane exposure. However, further studies are required to elucidate the detailed mechanism by which this occurs. Our study has many limitations. The MWM and Y-maze studies were 4EGI-1 cost performed at different time points. The MWM primarily measures hippocampal function, whereas the Y-maze measures a mixture of hippocampal and amygdala function. We did not use both tests at both time points. Although we assumed the protective effects of isoflurane found in the present study were due to pre-conditioning, we did not confirm this. Therefore, more studies are warranted. In conclusion, isoflurane exposure during mid-adulthood improved not only the spatial memory of both the APP/PS1 transgenic and wild-type mice but also the impaired learning and memory in aged transgenic mice and attenuated the Abeta plaque and oligomers in the hippocampus.This mouse strain is a double transgenic hemizygote that expresses a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and mutant human presenilin 1 (PS1-dE9). Abeta deposits in the brain can be detected by 6 to 7 months of age. All animals were bred in the animal facilities at the School of Medicine, Shanghai Jiaotong University. The initial pairs of mice were a gift from Prof. Shumin Duan, Shanghai Institutes for Biological Science, Chinese Academy of Sciences. Genetic.Uates Memory ImpairmentSeveral studies have shown that the ultimate effects of isoflurane critically depend on both the concentration and duration of exposure. Pan [14] demonstrated that treatment with 0.5 isoflurane for 8 hours attenuated the hypoxia-induced activation of caspase-3 and the levels of the aspartyl protease b-site amyloid precursor protein-cleaving enzyme in H4 human neuroglioma cells; treatment with 2 isoflurane for 8 hours enhanced this response. Wei [15] reported that pre-conditioning with isoflurane for one hour dose-dependently inhibited the neurotoxicity induced by a 24-h exposure to 2.4 isoflurane in both primary cortical neurons and PC12 cells. Lee [16] showed that 2 isoflurane postconditioning for 20 or 30 minutes after oxygen-glucose deprivation ameliorated the cell injury induced thereof. However, exposure to 2 isoflurane for 60 minutes or 2.5 isoflurane for 20?0 minutes had no post-conditioning effects. These results suggest that the effects of isoflurane may be concentration- and duration-dependent. In the present study, the concentration of isoflurane was relatively low, and the duration was relatively short. Although no study has used isoflurane for 2 hours for 5 days as preconditioning, many studies have demonstrated that chronic ischemia or pharmacological pre-conditioning is associated with a reduction in myocardial infarct size [17,18]. Many other studies demonstrated the neuroprotective effects of isoflurane preconditioning against ischemia [19,20] or hypoxia [21,22]. Therefore, pre-conditioning effects may be involved. In cell culture models, isoflurane alters APP processing and increases the production of Abeta [3,23]; however, in the present study, we found that isoflurane exposure decreased the Abeta plaque in the hippocampus. However, the Abeat plaques is poorly correlated with the synaptic loss or cognitive impairment in AD subjects [24]. At the same time, accumulating evidences demonstrated that there are a strong correlation between the Abeta oligomer and the synaptic loss and cognitive impairment[24?7]. In present study, we found that the Abeta oligomers reduced significantly after isoflurane exposure. However, further studies are required to elucidate the detailed mechanism by which this occurs. Our study has many limitations. The MWM and Y-maze studies were performed at different time points. The MWM primarily measures hippocampal function, whereas the Y-maze measures a mixture of hippocampal and amygdala function. We did not use both tests at both time points. Although we assumed the protective effects of isoflurane found in the present study were due to pre-conditioning, we did not confirm this. Therefore, more studies are warranted. In conclusion, isoflurane exposure during mid-adulthood improved not only the spatial memory of both the APP/PS1 transgenic and wild-type mice but also the impaired learning and memory in aged transgenic mice and attenuated the Abeta plaque and oligomers in the hippocampus.This mouse strain is a double transgenic hemizygote that expresses a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and mutant human presenilin 1 (PS1-dE9). Abeta deposits in the brain can be detected by 6 to 7 months of age. All animals were bred in the animal facilities at the School of Medicine, Shanghai Jiaotong University. The initial pairs of mice were a gift from Prof. Shumin Duan, Shanghai Institutes for Biological Science, Chinese Academy of Sciences. Genetic.
