Involving synthesis, folding, and posttranslational modification of secretory and membrane proteins. ER stress under any harmful conditions could lead to decrease protein synthesis and increase the expression of molecular chaperones that promote proper folding and cellular recovery. However, prolonged activation of ER stress ultimately initiates the apoptotic pathway. Several proteins have been implicated in this apoptotic pathway, including a transcription factor, C/EBP homologous protein, and the ER-resident caspase, caspase-12. Increasing evidences demonstrated that ER stress may play a critical role in the pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer��s disease, Parkinson��s disease and amyotrophic lateral sclerosis. Volatile anesthetics could induce neuronal degeneration and apoptosis, then lead to memory impairment. Evidences from animal models suggested volatile anesthetics interaction with neurodegenerative mechanisms, such as the onset and progression of Alzheimer��s disease. Sevoflurane is one of the most commonly used volatile anesthetics and it had been shown to impair long-term emotional memory consolidation in human research, and especially in old mice. But the underlying molecular mechanisms are still unknown. Therefore, we hypothesized that ER stress mediated hippocampal neurons apoptosis then induced neurons lost in the aging brain under long time sevoflurane exposure. It might play a role in the sevofluraneinduced memory impairment in aging rats. Previous studies have shown that volatile anesthetics, such as sevoflurane and isoflurane, are very helpful for reduction of perioperative mortality. But volatile anesthetics may also contribute to memory impairment by neurons lost in hippocampus through cells apoptosis. The Morris water maze test of the present study showed that the sevoflurane group rats showed significantly longer latency to locate the hidden platform than the control group on the training days. it suggested that sevoflurane anesthesia had a significant effect on spatial orientation in the navigation task because it impaired the performance of the sevoflurane group. Meanwhile the number of times that crossing over the previous platform site and the percentage of time swimming in the rats of the sevoflurane group are also decreased that indicating the impairment in memory. The present data also demonstrated that 2% sevoflurane concentration for 5 h exposure would cause neurons apoptosis as the clumped chromatin with fragmentation of the nuclear membrane, verifying apoptotic degeneration under TEM observation. TUNEL staining revealed the same trend that the number of TUNEL positive cells was significantly higher in the sevoflurane group in the hippocampal CA1 and DG region. However, the upstream mechanism of volatile anesthetics induced apoptosis remains unknown. The two most well studied pathways are the cell surface death receptor pathway and the mitochondria-initiated pathway. The study showed that isoflurane might induce caspase activation and apoptosis through the mitochondrial pathway. ER stressinduced apoptosis became an important pathological event in some neurological disease processes and neuronal cell death. It has been reported that CHOP and caspase-12 are both key mediators of ER stress-induced apoptosis. CHOP is expressed at very low levels under physiological conditions, but strongly induced in response to ER stress.
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