BACKGROUND: Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms. METHODS: C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism. RESULTS: Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor. CONCLUSIONS: Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.

Background. Albumin has been regarded as a potent antioxidant with free radical scavenging activities. Oxidative stress and neuronal apoptosis are responsible for its highly damaging effects on brain injury after intracerebral hemorrhage (ICH). Here, the present study investigated the neuroprotective effect of albumin against early brain injury after ICH and the potential underlying mechanisms. Methods. Adult male Sprague‐Dawley rats were subjected to intrastriatal injection of autologous blood to induce ICH. Human serum albumin was given by intravenous injection 1 h after ICH. U0126, an inhibitor of extracellular signal‐regulated kinase (ERK1/2), and ML385, an inhibitor of nuclear factor‐E2‐related factor 2 (Nrf2), were intraperitoneally administered 1 h before ICH induction. Short‐ and long‐term neurobehavioral tests, western blotting, immunofluorescence staining, oxidative stress evaluations, and apoptosis measurements were performed. Results. Endogenous expression of albumin (peaked at 5 days) and heme oxygenase 1 (HO‐1, peaked at 24 h) was increased after ICH compared with the sham group. Albumin and HO‐1 were colocalized with neurons. Compared with vehicle, albumin treatment significantly improved short‐ and long‐term neurobehavioral deficits and reduced oxidative stress and neuronal death at 72 h after ICH. Moreover, albumin treatment significantly promoted the phosphorylation of ERK1/2; increased the expression of Nrf2, HO‐1, and Bcl‐2; and downregulated the expression of Romo1 and Bax. U0126 and ML385 abolished the treatment effects of albumin on behavior and protein levels after ICH. Conclusions. Albumin attenuated oxidative stress‐related neuronal death may in part via the ERK/Nrf2/HO‐1 signaling pathway after ICH in rats. Our study suggests that albumin may be a novel therapeutic method to ameliorate brain injury after ICH.

Stroke is the third most common cause of death globally and a leading cause of disability. The cellular and molecular changes following stroke and causes of neuronal death are not fully understood, and there are few effective treatments currently available. A rapid increase in the levels of reactive oxygen species (ROS) post stroke can overwhelm antioxidant defenses and trigger a series of pathophysiologic events including the inflammatory response, blood-brain barrier (BBB) disruption, apoptosis, and autophagy, ultimately leading to neuron degeneration and apoptosis. It is thought that beyond a certain age, the ROS accumulation resulting from stroke increases the risk of morbidity and mortality. In the present review, we summarize the role of oxidative stress (OS) as a link between aging and stroke pathogenesis. We also discuss how antioxidants can play a beneficial role in the prevention and treatment of stroke by eliminating harmful ROS, delaying aging, and alleviating damage to neurons.

Background: Pyroptosis is a programmed cell death mediated by inflammasomes. Previous studies have reported that inhibition of neurokinin receptor 1 (NK1R) exerted neuroprotection in several neurological diseases. Herein, we have investigated the role of NK1R receptor inhibition using Aprepitant to attenuate NLRC4-dependent neuronal pyroptosis after intracerebral hemorrhage (ICH), as well as the underlying mechanism. Methods: A total of 182 CD-1 mice were used. ICH was induced by injection of autologous blood into the right basal ganglia. Aprepitant, a selective antagonist of NK1R, was injected intraperitoneally at 1 h after ICH. To explore the underlying mechanism, NK1R agonist, GR73632, and protein kinase C delta (PKCδ) agonist, phorbol 12-myristate 13-acetate (PMA), were injected intracerebroventricularly at 1 h after ICH induction, and small interfering ribonucleic acid (siRNA) for NLRC4 was administered via intracerebroventricular injection at 48 h before ICH induction, respectively. Neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results: The expression of endogenous NK1R and NLRC 4 were gradually increased after ICH. NK1R was expressed on neurons. Aprepitant significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased neuronal pyroptosis, as well as decreased expression of NLRC4, Cleaved-caspase-1, GSDMD (gasdermin D), IL-1β, and IL-18. Activation of NK1R or PKCδ abolished these neuroprotective effects of Aprepitant after ICH. Similarly, knocking down NLRC4 using siRNA produced similar neuroprotective effects. Conclusion: Aprepitant suppressed NLRC4-dependent neuronal pyroptosis and improved neurological function, possibly mediated by inhibition of NK1R/PKCδ signaling pathways after ICH. The NK1R may be a promising therapeutic target for the treatment of ICH.

The pathological mechanisms of acute intracerebral hemorrhage (ICH) remain unknown and unverified. In the present study, we used quantitative proteomics to elucidate the pathological mechanisms and to identify novel biomarker and therapeutic target candidates via tissue proteome in a rat model of acute ICH. Rats were experimentally induced with ICH (n = 6) or Sham (n = 6), and their brain tissue was obtained by 24 h. The TMT-LC–MS/MS-based proteomics approach was used to quantify the differential proteomes across brain tissue, and the results were further analyzed by ingenuity pathway analysis to explore canonical pathways and the relationship involved in the uploaded data. Upon quantification, we found that 96 secreted proteins that were identified in the ICH 24-h group were significantly different those in the control group (P < 0.05); among these proteins, 57 increased and 39 decreased in abundance. Bioinformatic analyses of differentially expressed proteins demonstrated that the protein localization and ERK1 and ERK2 cascade were the top two biological processes with the highest concentrations of differentially proteins. The top protein-protein action network with high confidence levels of protein was the albumin and ERK signaling pathways. Albumin, ERK, and p-ERK were assessed in brain tissue by western blot analysis, and higher expression levels of albumin and p-ERK were observed in the ICH group. Our proteomic results highlight important change in the biological processes of ERK1 and ERK2 cascade, which are possible targets for future interventions of ICH. To our knowledge, this study provides in-depth analysis of ICH in brain tissue, and we propose 96 new biomarker candidates for ICH, including albumin and ERK.

Procalcitonin (PCT) is a reliable biomarker of sepsis and infection. The level of PCT associated with sepsis and infection in patients with traumatic brain injury is currently unknown. The purpose of this study was to investigate the value of PCT and C-reactive protein (CRP) as diagnostic markers of sepsis and to evaluate the prognostic value of these markers related to the severity of injury, sepsis and mortality.