Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

IMPORTANCE: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium. OBJECTIVE: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting. DESIGN, SETTING, and PARTICIPANTS: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery. INTERVENTIONS: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed. MAIN OUTCOMES AND MEASURES: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation. RESULTS: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly. CONCLUSIONS AND RELEVANCE: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Salidroside ameliorates orthopedic surgery-induced cognitive dysfunction by activating adenosine 5'-monophosphate-activated protein kinase signaling in mice.

Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Salidroside, a plant-derived compound, has gained increased attention as a treatment for various neurological diseases and particularly as a modifier of microglia-mediated neuroinflammation. However, the effect of salidroside on orthopedic surgery-induced cognitive dysfunction and the underlying mechanisms are largely unknown. Here, we found that salidroside greatly attenuated cognitive impairment in mice after orthopedic surgery. Neuroinflammation in the mouse hippocampus was also attenuated by salidroside. Meanwhile, salidroside treatment induced a switch in microglial polarization to the anti-inflammatory phenotype. In vitro, salidroside suppressed the expression of proinflammatory cytokines and induced a switch in microglial phenotype to the anti-inflammatory phenotype. Mechanistically, molecular docking studies revealed the potential AMPK activation activity of salidroside. And salidroside did up-regulated the AMPK pathway proteins. Moreover, AMPK antagonist abolished the effects of salidroside in vivo and in vitro. Taken together, our results demonstrated that salidroside effectively suppressed PND by suppressing microglia-mediated neuroinflammation through activating AMPK pathway, and it might be a novel therapeutic approach for PND.

Combination therapy with ropivacaine-loaded liposomes and nutrient deprivation for simultaneous cancer therapy and cancer pain relief.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

TFEB Probably Involved in Midazolam-Disturbed Lysosomal Homeostasis and Its Induced ß-Amyloid Accumulation.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and ß-amyloid (Aß) plays a leading role in the pathogenesis of AD. The transcription factor EB (TFEB), a main regulating factor of autophagy and lysosome biosynthesis, is involved in the pathogenesis of AD by regulating autophagy-lysosomal pathways. To date, the choice of anesthetics during surgery in patients with neurodegenerative diseases and evaluation of the effects and underlying mechanisms in these patients have rarely been reported. In this study, the HEK293-APP cells overexpressing APP and Hela cells were used. The cells were treated with midazolam at different concentrations and at different times, then lysosomes were stained by lysotracker and their morphology was observed under a fluorescence microscope. The number and size of lysosomes were analyzed using the ImageJ software. The levels of TFEB in the nucleus and APP-cleaved intracellular proteins were detected by nuclear separation and Western Blot. Finally, ELISA was used to detect the levels of Aß40 and Aß42 in the cells after drug treatment. We found that 30 µM midazolam decreased the number of lysosomes and increased its size in HEK293 and HeLa cells. However, 15 µM midazolam transiently disturbed lysosomal homeostasis at 24 h and recovered it at 36 h. Notably, there was no significant difference in the extent to which lysosomal homeostasis was disturbed between treatments of different concentrations of midazolam at 24 h. In addition, 30 µM midazolam prevents the transport of TFEB to the nucleus in either normal or starved cells. Finally, the intracellular C-terminal fragment ß (CTFß), CTFα, Aß40 and Aß42 levels were all significantly elevated in 30 µM midazolam-treated HKE293-APP cells. Collectively, the inhibition of TFEB transport to the nucleus may be involved in midazolam-disturbed lysosomal homeostasis and its induced Aß accumulation in vitro. The results indicated the risk of accelerating the pathogenesis of AD by midazolam and suggested that TFEB might be a candidate target for reduction of midazolam-dependent neurotoxicity.

The Changes of Intrinsic Excitability of Pyramidal Neurons in Anterior Cingulate Cortex in Neuropathic Pain.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

Autophagic Degradation Deficit Involved in Sevoflurane-Induced Amyloid Pathology and Spatial Learning Impairment in APP/PS1 Transgenic Mice.

The adverse effects of anesthetics on elderly people, especially those with brain diseases are very concerning. Whether inhaled anesthetics have adverse effects on Alzheimer's disease (AD), which is the most common form of dementia with brain degenerative changes, remains controversial. Autophagy, a crucial biological degradation process, is extremely important for the pathogenesis of AD. In this study, the inhaled anesthetic sevoflurane elicited many enlarged autolysosomes and impaired the overall autophagic degradation in the hippocampus of an AD mouse model, which is involved in the accumulation of amyloid-ß (Aß) and spatial learning deficits. However, rapamycin treatment counteracted all these effects. The results suggested that inhaled anesthetics may accelerate the pathological process of AD, and enlarged autolysosomes may be a new marker for prediction and diagnosis of the neurotoxicity of anesthetics in AD.

Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro.

BACKGROUND/AIMS: Autophagy is a well-known pathway to "clean" the misfolded mutant huntingtin protein (mHtt), which plays a considerable role in polyglutamine diseases. To date, there have been few studies of the choice of anesthetic during surgery in patients with polyglutamine diseases and evaluation of the effects and underlying mechanisms of anesthetics in these patients. METHODS: GFP-Htt (Q74)-PC12 cells, which stably express green fluorescent protein-tagged Htt protein containing 74 glutamine repeating units, were used throughout this study. Cells were treated with 15 µM midazolam and 100 mM trehalose (positive control), and the induction of autophagy and autophagic degradation were assessed by detecting changes in autophagy-related proteins and substrates, and cell viability was assessed using the MTT assay. Overexpression of cathepsin D by plasmid transfection was used to restore midazolam-impaired autophagic degradation. RESULTS: Midazolam increased intracellular mHtt levels in a time- and dose-dependent manner. Additionally, enhancing or blocking autophagic flux by trehalose or chloroquine could decrease or increase midazolam-induced mHtt elevation, respectively. Midazolam induced autophagy in the mTOR-dependent signaling pathway, but autophagic degradation was impaired, with a continuous rise in p62 and LC3 II levels and decrease in cathepsin D. However, overexpression of cathepsin D reversed the effects of midazolam. Midazolam led to a 20% decrease in GFP-Htt (Q74)-PC12 cell viability, which could be abrogated by overexpression of cathepsin D. CONCLUSIONS: Midazolam increased mHtt levels and decreased Htt (Q74)-PC12 cell viability via impairment of autophagic degradation, which could be restored by overexpression of cathepsin D.