Propofol Mitigates Sepsis-Induced Brain Injury by Inhibiting Ferroptosis Via Activation of the Nrf2/HO-1axis.

BACKGROUND: Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis. METHODS: An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis. RESULTS: Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment. CONCLUSION: Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Background: Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods: A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion: The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.

Edaravone alleviated propofol-induced neural injury in developing rats by BDNF/TrkB pathway.

As a variety of free radical scavenger, edaravone has shown its potential in producing antioxidant, anti-inflammatory and neuroprotective effects in various disease models. However, the underlying mechanism behind the neuroprotective effects of edaravone remained unclear. This study is aimed at determining the effects of edaravone on neuroprotection and anti-inflammatory through a propofol-induced neural injury rat model. Firstly, an observation was made of apoptosis and neuroinflammation in the hippocampus of developing under the influence of propofol. It was found out that propofol could produce inflammatory effects in the hippocampus by enhancing the astrogliosis (GFAP) activation and elevating the level of neuronal nitric oxide synthase (nNOS), pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Meanwhile, the increase of apoptosis cells and the decrease of neurons (NeuN) were speculated to aggravate neural injury. Furthermore, it was demonstrated that edaravone intervention can reverse the neural apoptosis and inflammation. Additionally, the intraperitoneal injection of edaravone, the intraperitoneal injection of the brain-derived neurotrophic factor (BDNF)-mimicking small compound (7,8 dihydroxyflavone) and the intracranial injection of the exogenous BDNF were all respectively effective in alleviating the propofol-induced neural apoptosis and inflammation in the hippocampus. It was also found out that edaravone-activated downstream signalling through tyrosine kinase receptor B (TrkB) receptors in astrocyte, microglia and neuron. However, the neural injury of propofol had no impact on long-term learning and memory, except causing a short-term neurotoxicity. In conclusion, edaravone could alleviate the propofol-induced neural injury in developing rats through BDNF/TrkB pathway.

Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway.

BACKGROUND: To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells. METHODS: Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR). RESULTS: In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats. CONCLUSION: Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway.

Effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery: A randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a complication of central nervous system in patients after surgery. Edaravone as a brain-protective agent may have protective effect on postoperative cognitive function. The study was designed to explore the effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery and potential mechanism. PATIENTS AND METHODS: Patients undergoing hip joint replacement surgery were randomly allocated into 2 groups: the edaravone group (group E) and the control group (group C). Group E received intravenous edaravone at a dose of 0.5 mg/kg after induction of anesthesia, while group C received normal saline. The cognitive function was evaluated with the Mini-Mental State Examination (MMSE) 1day before surgery,3 days and the 7 days after surgery. Patients' plasma samples were collected to detect the levels of S100ß protein (S100ß), interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), superoxide dismutase (SOD) and malondialdehyde (MDA) before the induction of anesthesia, at the end of surgery and on postoperative day 3. RESULTS: The MMSE scores in group E were higher than those of group C 3 days after surgery (25.98 ± 1.99 vs 24.86 ± 1.86, p = 0.003). There were remarkable rises (p < 0.05) in plasma IL-6, S100ßand MMP-9 levels at the end of surgery and on postoperative day 3 in the two groups, however, edaravone pretreatment could reduce these levels to a certain extent compared with group C (p < 0.05).In group E, the SOD concentration was higher at the end of surgery (16.03 ± 2.46U/ml vs. 13.65 ± 2.53U/ml, p = 0.0001), while the MDA level was lower on postoperative day 3 than those in group C (7.01 ± 2.37 nmol/ml vs. 11.34 ± 3.18 nmol/ml, p = 0.0001). CONCLUSION: The results indicated that preoperative intervention with edaravone may improve the postoperative cognitive function in elderly patients undergoing hip joint replacement surgery.