Sepsis-associated encephalopathy (SAE) is linked to increased morbidity and mortality rates in patients with sepsis. Increased cytokine production and neuronal apoptosis are implicated in the pathogenesis of the SAE. Neuroinflammation plays a major role in sepsis-induced brain injury. Thioredoxin-interacting protein (TXNIP), an inhibitor of thioredoxin, is associated with oxidative stress and inflammation. However, whether the TXNIP is involved in the sepsis-induced brain injury and the underlying mechanism is yet to be elucidated. Therefore, the present study was aimed at elucidating the effects of TXNIP knockdown on sepsis-induced brain injury and cognitive decline in mice. Lipopolysaccharide (LPS) was injected intraperitoneally to induce sepsis brain injury in mice. The virus-carrying control or TXNIP shRNA was injected into the lateral ventricle of the brain 4 weeks before the LPS treatment. The histological changes in the hippocampal tissues, encephaledema, and cognitive function were detected, respectively. Also, the 7-day survival rate was recorded. Furthermore, the alterations in microglial activity, oxidative response, proinflammatory factors, apoptosis, protein levels (TXNIP and NLRP3 inflammasome), and apoptosis were examined in the hippocampal tissues. The results demonstrated that the TXNIP and NLRP3 inflammasome expression levels were increased at 6, 12, and 24 h post-LPS injection. TXNIP knockdown dramatically ameliorated the 7-day survival rate, cognitive decline, brain damage, neuronal apoptosis, and the brain water content, inhibited the activation of microglia, downregulated the NLRP3/caspase-1 signaling pathway, and reduced the oxidative stress and the neuroinflammatory cytokine levels at 24 h post-LPS injection. These results suggested a crucial effect of TXNIP knockdown on the mechanism of brain injury and cognitive decline in sepsis mice via suppressing oxidative stress and neuroinflammation. Thus, TXNIP might be a potential therapeutic target for SAE patients.
Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability in survivors of cardiac arrest (CA), where autophagy and ferroptosis are believed to play a pivotal role. Liraglutide, a synthetic, long-acting glucagon-like peptide-1 (GLP-1) analog, can exert organ-protective effects through regulating autophagy and ferroptosis. This study aimed to investigate whether liraglutide had a neuroprotective after cardiac arrest and cardiopulmonary resuscitation and explore its potential mechanisms. We used the 8-min asphyxial cardiac arrest and cardiopulmonary resuscitation model in Sprague–Dawley rats to determine the possible mechanism. The histological changes, proinflammatory factors, apoptosis, autophagy and ferroptosis in hippocampal tissues were detected. Furthermore, the neurologic deficits scores (NDS) and 7-day survival rate was observed respectively. Our results showed that autophagyand apoptosis were activated and the expressions of proteins reached significance at 24h after CA/ROSC. Moreover, rapamycin enhanced apoptosis, ferroptosis and aggravated neuro-pathological damage while 3-methyladenine reduced that. Furthermore, liraglutide treatment improved the 7-day survival rate and NDS, reduced histology injury and inhibited apoptosis, ferroptosisand inflammatory cytokines released after cardiac arrest, and these effects were offset by autophagy agonist. These results suggested that liraglutide could exert a protective role against post-cardiac arrest brain injury, which could be partially mediated by partially inhibiting autophagy and ferroptosis.
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