Abstract
BackgroundPostoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice.MethodsSIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity.ResultsOverexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase [SOD] and malondialdehyde [MDA]) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 [Iba1]) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner.ConclusionThe results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.
Highlights
Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery
We found that the total distance traveled by the mice was not significantly changed between the control (C) and anesthesia/surgery (A/S) groups at baseline (1 day before anesthesia/surgery) (p > 0.05, Fig. 2a) or postoperation (1, 3, and 7 days after anesthesia/surgery) (p > 0.05, Fig. 2b–d)
In the fear conditioning test (FCT) tone test, the freezing time of the anesthesia/surgery group (A/S) group did not obviously differ from that of the C group after the operation (p > 0.05, Fig. 2i–k). These results indicated that anesthesia/surgery induced hippocampus-dependent cognitive decline but did not induce hippocampus-independent cognitive decline or locomotor activity impairment in aged mice
Summary
Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. The aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice. Postoperative cognitive dysfunction (POCD) is one of the most common postoperative complications in aged patients [1]. Mitochondrial damage, neuroinflammation, and synaptic plasticity dysfunction have been demonstrated to be involved in the mechanism of POCD [3,4,5,6,7,8,9]. Anesthesia/surgery may induce microglial activation, resulting in the release of inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 [11, 12]. The hippocampal CA1 region is critical for cognition [13], and overactivated microglia and neuroinflammation create a neurotoxic response and cause synaptic dysfunction, resulting in cognitive dysfunction [14]
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