Background: It is widely accepted that mitochondria have a direct impact on neuronal function and survival. Oxidative stress caused by mitochondrial abnormalities play an important role in the pathophysiology of lipopolysaccharide (LPS)-induced memory impairment. Elamipretide (SS-31) is a novel mitochondrion-targeted antioxidant. However, the impact of elamipretide on the cognitive sequelae of inflammatory and oxidative stress is unknown. Methods: We utilized MWM and contextual fear conditioning test to assess hippocampus-related learning and memory performance. Molecular biology techniques and ELISA were used to examine mitochondrial function, oxidative stress, and the inflammatory response. TUNEL and Golgi-staining was used to detect neural cell apoptosis and the density of dendritic spines in the mouse hippocampus. Results: Mice treated with LPS exhibited mitochondrial dysfunction, oxidative stress, an inflammatory response, neural cell apoptosis, and loss of dendritic spines in the hippocampus, leading to impaired hippocampus-related learning and memory performance in the MWM and contextual fear conditioning test. Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests. Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity. Conclusion: These findings indicate that LPS-induced memory impairment can be attenuated by the mitochondrion-targeted antioxidant elamipretide. Consequently, elamipretide may have a therapeutic potential in preventing damage from the oxidative stress and neuroinflammation that contribute to perioperative neurocognitive disorders (PND), which makes mitochondria a potential target for treatment strategies for PND.

Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown. A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO. Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus. Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.

Considerable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. Increasing evidence suggests that acetaminophen (APAP) has unappreciated antioxidant and anti-inflammatory properties. However, the impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. The objective of this study is to explore whether APAP could have neuroprotective effects on lipopolysaccharide (LPS)-induced cognitive impairment in mice. A mouse model of LPS-induced cognitive impairment was established to evaluate the neuroprotective effects of APAP against LPS-induced cognitive impairment. Adult C57BL/6 mice were treated with APAP half an hour prior to intracerebroventricular microinjection of LPS and every day thereafter, until the end of the study period. The Morris water maze was used to assess cognitive function from postinjection days 1 to 3. Animal behavioural tests as well as pathological and biochemical assays were performed to evaluate LPS-induced hippocampal damage and the neuroprotective effect of APAP. Mice treated with LPS exhibited impaired performance in the Morris water maze without changing spontaneous locomotor activity, which was ameliorated by treatment with APAP. APAP suppressed the accumulation of pro-inflammatory cytokines and microglial activation induced by LPS in the hippocampus. In addition, APAP increased SOD activity, reduced MDA levels, modulated glycogen synthase kinase 3β (GSK3β) activity and elevated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, APAP significantly decreased the Bax/Bcl-2 ratio and neuron apoptosis in the hippocampus of LPS-treated mice. Our results suggest that APAP may possess a neuroprotective effect against LPS-induced cognitive impairment and inflammatory and oxidative stress via mechanisms involving its antioxidant and anti-inflammatory properties, as well as its ability to inhibit the mitochondrial permeability transition (MPT) pore and the subsequent apoptotic pathway.

Postoperative delirium (POD) is a common and severe complication in elderly patients with hip fractures. Identifying high-risk patients with POD can help improve the outcome of patients with hip fractures. We conducted a retrospective study on elderly patients (≥65 years of age) who underwent orthopedic surgery with hip fracture between January 2014 and August 2019. Conventional logistic regression and five machine-learning algorithms were used to construct prediction models of POD. A nomogram for POD prediction was built with the logistic regression method. The area under the receiver operating characteristic curve (AUC-ROC), accuracy, sensitivity, and precision were calculated to evaluate different models. Feature importance of individuals was interpreted using Shapley Additive Explanations (SHAP). About 797 patients were enrolled in the study, with the incidence of POD at 9.28% (74/797). The age, renal insufficiency, chronic obstructive pulmonary disease (COPD), use of antipsychotics, lactate dehydrogenase (LDH), and C-reactive protein are used to build a nomogram for POD with an AUC of 0.71. The AUCs of five machine-learning models are 0.81 (Random Forest), 0.80 (GBM), 0.68 (AdaBoost), 0.77 (XGBoost), and 0.70 (SVM). The sensitivities of the six models range from 68.8% (logistic regression and SVM) to 91.9% (Random Forest). The precisions of the six machine-learning models range from 18.3% (logistic regression) to 67.8% (SVM). Six prediction models of POD in patients with hip fractures were constructed using logistic regression and five machine-learning algorithms. The application of machine-learning algorithms could provide convenient POD risk stratification to benefit elderly hip fracture patients.

Aims: To compare the performance of logistic regression and machine learning methods in predicting postoperative delirium (POD) in elderly patients.Method: This was a retrospective study of perioperative medical data from patients undergoing non‐cardiac and non‐neurology surgery over 65 years old from January 2014 to August 2019. Forty‐six perioperative variables were used to predict POD. A traditional logistic regression and five machine learning models (Random Forest, GBM, AdaBoost, XGBoost, and a stacking ensemble model) were compared by the area under the receiver operating characteristic curve (AUC‐ROC), sensitivity, specificity, and precision.Results: In total, 29,756 patients were enrolled, and the incidence of POD was 3.22% after variable screening. AUCs were 0.783 (0.765–0.8) for the logistic regression method, 0.78 for random forest, 0.76 for GBM, 0.74 for AdaBoost, 0.73 for XGBoost, and 0.77 for the stacking ensemble model. The respective sensitivities for the 6 aforementioned models were 74.2%, 72.2%, 76.8%, 63.6%, 71.6%, and 67.4%. The respective specificities for the 6 aforementioned models were 70.7%, 99.8%, 96.5%, 98.8%, 96.5%, and 96.1%. The respective precision values for the 6 aforementioned models were 7.8%, 52.3%, 55.6%, 57%, 54.5%, and 56.4%.Conclusions: The optimal application of the logistic regression model could provide quick and convenient POD risk identification to help improve the perioperative management of surgical patients because of its better sensitivity, fewer variables, and easier interpretability than the machine learning model.

CNS inflammation is known to be an important pathogenetic mechanism of perioperative neurocognitive disorder (PND), and iron overload was reported to participate in this process accompanied by oxidative stress. Ferroptosis is an iron-dependent form of cell death, and occurs in multiple neurodegenerative diseases with cognitive disorder. However, the effect of ferroptosis in inflammation-related PND is unknown. In this study, we found that the ferroptosis inhibitor liproxstatin-1 ameliorated memory deficits in the mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Moreover, liproxstatin-1 decreased the activation of microglia and the release of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF)-α, attenuated oxidative stress and lipid peroxidation, and further weakened mitochondrial injury and neuronal damage after LPS exposure. Additionally, the protective effect of liproxstatin-1 was related to the alleviation of iron deposition and the regulation of the ferroptosis-related protein family TF, xCT, Fth, Gpx4, and FtMt. These findings enhance our understanding of inflammation-involved cognitive dysfunction and shed light on future preclinical studies.