Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation

Abstract

Background Postoperative 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. Methods SIRT3 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. Results Overexpression 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. Conclusion The 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.

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

“…Neuroinflammation is primarily involved in the pathological mechanism of PND ( Liu et al, 2021 ). In the present study, we measured the expression levels of TNF-α and IL-1β in the hippocampus of aged mice.…”

“…Various mechanisms are involved in the pathogenesis of PND, such as neuroinflammation, oxidative stress and neurodegeneration. The pathophysiological changes caused by neuroinflammation of the central nervous system are the main mechanism of PND ( Granger and Barnett, 2021 ; Liu et al, 2021 ). In the present study, we found that the expression of TNF-α and IL-1β in the hippocampus increased significantly in the PND group compared with the CON group.…”

Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

“…Recently, it was also reported that Sirt3 protects against anesthesia/surgery-induced cognitive decline by suppressing hippocampal neuroinflammation. In aged mice with postoperative cognitive dysfunction, microglial activation and elevated proinflammatory cytokine levels were found to be associated with decreased SOD and Sirt3 expression in the hippocampus ( Liu et al, 2021 ). In addition, Sirt3 promoted microglial migration to the site of the lesion by upregulating the fractalkine receptor CX3CR1 in mice with ischemic stroke ( Cao et al, 2019 ).…”

The Expression of Interleukin-1β Is Regulated by DNA Methylation in Microglia of Hippocampus to Participate Postoperative Cognitive Dysfunction in Aged Mice

“…Golgi-Cox impregnation was one of the effective methods to study the morphology of neurons and visualize synaptic structural plasticity [31]. The FD Rapid GolgiStain™ Kit (FD Neurotechnologies, PK401, Columbia) was employed according to the manufacturer's instructions.…”