Abstract
BackgroundElderly patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia. Except for declined organ function, the particular pathogenesis of POCD in elderly patients remains unknown. This study is carried out to determine the critical role of the NOD-like receptor protein 3 (NLRP3)-caspase-1 pathway in isoflurane-induced cognitive impairment.MethodsYoung (6–8 months old) and aged (14 months old) healthy male C57BL/6 mice were exposed to 1.5% isoflurane for 2 h. Some mice received intraperitoneal injection of Ac-YVAD-cmk (8 mg/kg), a specific inhibitor of caspase-1, 30 min before the isoflurane exposure. Morris water maze test was carried out 1 week after the isoflurane anesthesia. Brain tissues were harvested 24 h after the isoflurane anesthesia. Western blotting was carried out to detect the expression of NLRP3, interleukin (IL)-1β, and IL-18 in the hippocampus. Mouse microglial cell line BV-2 and primary microglial cultures were primed by lipopolysaccharide for 30 min before being exposed to isoflurane. NLRP3 was downregulated by RNA interference.ResultsCompared to young mice, aged mice had an increased expression of NLRP3 in the hippocampus. Isoflurane induced cognitive impairment and hippocampal inflammation in aged mice but not in young mice. These effects were attenuated by Ac-YVAD-cmk pretreatment (P < 0.05). Isoflurane activated NLRP3-caspase-1 pathway and increased the secretion of IL-18 and IL-1β in cells pretreated with lipopolysaccharide but not in cells without pretreatment. Downregulation of NLRP3 attenuated the activation of NLRP3 inflammasome by isoflurane.ConclusionsNLRP3 priming status in aged mouse brain may be involved in isoflurane-induced hippocampal inflammation and cognitive impairment.
Highlights
Patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia
Young animals develop little neuroinflammation or cognitive impairment after isoflurane exposure [16]. These results suggest the critical role of neuroinflammation in isoflurane-induced cognitive impairment in aged animals
Fourteen-month old male C57BL/6 mice were randomly assigned to four groups: (1) group AC, (2) group Aged mice exposed to isoflurane (A-ISO), (3) group A-ISO-cmk (Ac-YVADcmk administered before aged mice were exposed to isoflurane), or (4) group A-ISO-phosphate-buffered saline (PBS)
Summary
Patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia. Patients are more likely to suffer from postoperative cognitive dysfunction (POCD), which includes memory, concentration, or attention impairment, and is associated with increased. Wang et al Journal of Neuroinflammation (2018) 15:109 inflammatory status, which impairs cognitive function [7, 10,11,12] Volatile anesthetics, such as isoflurane, have been shown to induce inflammatory response and increase caspase-3 activation in the aged rat brain [13, 14]. Young animals develop little neuroinflammation or cognitive impairment after isoflurane exposure [16] These results suggest the critical role of neuroinflammation in isoflurane-induced cognitive impairment in aged animals
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