| Objective Several studies about cognitive dysfunctions of isoflurane on rodents reported contrary results, and its mechanism is not clear. This study was designed to reveal the possible relationship of isoflurane to the subsequent occurrence of cognitive dysfunction, and to explore whether isoflurane affects the expression of neuron-specific ubiquitin C-terminal hydrolase L1 (UCH-L1) in hippocampus, and may cause the degradation of ubiquitin-dependent proteins disorder through the ubiquitin-proteasom system (UPS), finally leading to functional impairment of neurons.Methods To evaluate the effect of isoflurane on subsequent performances of spatial memory tasks in aged rats, we acquired 22-mo-old male Sprague Dawley rats. After a 1-wk acclimation period in the laboratory and screening, rats were randomly assigned to receive 2L/min oxygen (control group, n=10) and 2%ISO+2L/min oxygen (ISO group). Anesthesia was induced by placing rats in a chamber flushed with 3%ISO+2L/min oxygen, and the trachea was intubated with a 14-gauge catheter. Rats then kept spontaneous ventilation with the appropriate anesthetic for 2h. Arterial pulse oxygen saturation (SPO2), heart rates (HR), and mean arterial blood pressure (MAP) were measured noninvasively using a pulse oximeter and a rat tail cuff during anesthesia. PetCO2, respiratory frequency and rectal temperature were monitored. After 2h, the anesthetics were discontinued and 100% oxygen delivered. The trachea was extubated when the rat was responsive and then placed in their home cage. Then,24 hours (24-h group) and 72 hours (72-h group) later, the rats of the ISO group were randomly selected (n=10 per group) to do cognitive function tests, including open-field test and the Y-maze test. And the scores of all the three groups were compared. Then we randomly selected five rats respectively from the three groups to make frozen sections of brains and to process UCH-L1 immunohistochemistry staining. The expressions of UCH-L1 in hippocampus were observed under the optical microscope, including positive cell count and image analysis.Results In both groups of anesthetized rats, MAP, HR, RF, SpO2, PetCO2 and rectal temperature remained within the physiologically acceptable ranges. There were no statistically significant differences in open-field test scores among the three groups (respectively P>0.05). But aged previously anesthetized rats lagged behind age-matched nonanesthetized controls in their ability to perform the Y maze task 24h later (70.50±16.25 versus 49.20±8.56, P<0.01), but not 72h later (61.8±23.49 versus 49.20±8.56, P>0.05). Immunohistochemical experiments demonstrate that UCH-L1 was localized throughout neurons in hippocampus of all the three groups. In contrast, the UCH-L1-positive cell numbers in CA1 and CA3 areas of hippocampus and the iOD value decreased (P<0.01) in the 24-h group, while the 72-h group had no significant differences with others (P>0.05).Conclusion There were spatial learning and memory impairments of aging rats even 24h after isoflurane anesthesia, but not 72h. Isoflurane affected the expression of UCH-L1 in hippocampus, and was consistent with the cognitive dysfunction. Isoflurane may induce cognitive dysfunction by affecting the ubiquitination and subsequent degradation of proteins, owing to UCH-L1 expression reduction.
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