Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

Neuroinflammation is implicated in the onset of postoperative cognitive dysfunction (POCD), with CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) playing crucial roles in immune response modulation and neuroinflammatory processes. A total of 96 aged male C57/BL6 mice (9-12 months) were randomly assigned to one of four groups, each receiving an siRNA injection into the lateral ventricle. Subsequently, the mice underwent partial hepatectomy under general anesthesia. To assess cognitive function, the Morris water maze tests were conducted both pre- and post-surgery. Following behavioral assessments, hippocampal tissues were swiftly harvested. The regulation of CD33 and TREM2 expression was achieved through siRNA in the BV2 microglia cell line. Expression levels of CD33 and TREM2 were evaluated both in vitro and in vivo using quantitative RT-PCR and western blot analyses. This study explored the impact of CD33 and TREM2 on POCD in aged mice and revealed that surgery and anesthesia increased CD33 expression, leading to spatial learning and memory impairments. Inhibiting CD33 expression via siRNA administration ameliorated cognitive deficits and mitigated the neuroinflammatory response triggered by surgery. Additionally, CD33 inhibition reversed the surgery-induced decrease in synaptic-related proteins, highlighting its role in preserving synaptic integrity. Moreover, our experiments suggest that CD33 may influence neuroinflammation and cognitive function through mechanisms involving TREM2. This is evidenced by the suppression of pro-inflammatory cytokines following CD33 knockdown in microglia and the reversal of these effects when both CD33 and TREM2 are concurrently knocked down. These findings imply that CD33 might promote neuroinflammation by inhibiting TREM2. This study highlights the potential of targeting CD33 as a promising therapeutic strategy for preventing and treating POCD. It provides valuable insights into the intricate mechanisms underlying cognitive dysfunction following surgical procedures.

UNASSIGNED: To review how anecdote and narrative medicine, primary cohort studies, epidemiological studies, and the dementia literature can be bridged to understand long-term postoperative cognitive decline.
UNASSIGNED: Primary cohort studies have measured recoverable declines in memory and executive function after major surgery, but less-appreciated sources also offer critical insights. Anecdote reveals that functionally-impactful cognitive decline may persist after physical recovery in some patients despite modern medications and monitoring, and that physicians are unprepared to address patients\' cognitive concerns. However, epidemiological studies reproducibly demonstrate that elective surgery has no, or a negligible, average impact on cognition in older patients. Cognitively provocative factors - like medical hospital admissions or health factors like diabetes and smoking - are common in late life, and surgery likely contributes minimally to long-term cognitive change for most patients.
UNASSIGNED: Patients should be reassured that, while anecdotes of durable cognitive change after surgery are easily accessible, most patients experience cognitive recovery after major surgery. However, those who do not recover deserve characterization of their symptoms and investigation of modifiable causes to facilitate cognitive recovery.

Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients\' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients\' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

BACKGROUND: Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism.
METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist.
RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31.
CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients. Liraglutide (LRG) has high homology (97%) with natural glucagon like peptide-1, and it has been proved to be effective in some nervous system diseases. Whether LRG could regulate POCD has not been reported.
Sevoflurane (Sev) was used to simulate postoperative cognitive dysfunction (POCD) model. Morris water maze test was performed to evaluate the memory ability and neurological function of rats. Escape latency, swim distance, crossing platform times, average velocity, and targeting quadrant time were analyzed. The cell apoptosis, mRNA and protein expression were measured through flow cytometry, PCR, and western blotting, respectively.
LRG significantly improved the memory ability and neurological function of Sev-treated rats, but 3-MA reversed the effects of LRG. LRG remarkably inhibited apoptosis but up-regulated autophagy related proteins both in vivo and in vitro levels. However, knocking down AMPK could markedly reverse the influence of LRG on apoptosis, autophagy, and cell apoptosis.
LRG induced autophagy activation can maintain cell homeostasis and promote cell survival by blocking the apoptotic pathway. LRG could improve Sev-induced POCD via activating autophagy, inhibiting apoptosis, and regulating AMPK/mTOR signaling pathway. This study provides a novel therapeutic strategy for the prevention and treatment of POCD.

Postoperative cognitive dysfunction (POCD) commonly occurs after surgery, particularly in elderly individuals. It is characterized by a notable decline in cognitive performance, encompassing memory, attention, coordination, orientation, verbal fluency, and executive function. This reduction in cognitive abilities contributes to extended hospital stays and heightened mortality. The prevalence of POCD can reach 40% within 1 week following cardiovascular surgery and remains as high as 17% 3 months post-surgery. Furthermore, POCD exacerbates the long-term risk of Alzheimer\'s disease (AD). As a result, numerous studies have been conducted to investigate the molecular mechanisms underlying POCD and potential preventive strategies. This article provides a review of the research progress on POCD.

BACKGROUND: Neuroinflammation following peripheral surgery plays a key role in postoperative cognitive dysfunction (POCD) development and there is no effective therapy to inflammation-mediated cognitive impairment. Recent studies showed that rutin, a natural flavonoid compound, conferred neuroprotection. However, the effects and mechanisms of rutin on cognition of surgical and aged mice and LPS-induced BV2 need deeper exploration.
METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells.
RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1.
CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.