LPS Pretreatment Attenuates Cerebral Ischaemia/Reperfusion Injury by Inhibiting Inflammation and Apoptosis

Abstract

Background/Aims: Lipopolysaccharide (LPS) pretreatment has a strong neuroprotective effect on cerebral ischaemia/reperfusion injury (IRI), but the mechanism has not been fully elucidated to date. This study investigated the effect of LPS pretreatment on the pathway mediated by endoplasmic reticulum (ER) stress–CCAAT/enhancer-binding protein- homologous protein (CHOP) and the role of this pathway on cerebral ischaemia/reperfusion (I/R)-induced inflammation and apoptosis. Methods: Healthy male BALB/c mice were randomised into four groups as follows: sham operation group (sham group, n=30); LPS group (BALB/c mice treated with LPS, n=30); ischaemia/reperfusion group (I/R group, n=30) and I/R+LPS group (BALB/c mice treated with LPS before ischaemia, n=30). The mice were pre-treated with LPS (0.2 mg/kg) intra-peritoneally for three days prior to cerebral ischaemia. After 24 hours, the neurological deficit score, TTC staining and TUNEL assay were used to assess the neuroprotective effect of the LPS pretreatment against cerebral IRI. To assess whether the ER stress-CHOP pathway participated in the LPS-pretreatment neuroprotective mechanism, the expression levels of related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the ischaemic cortical penumbra were detected via a western blot analysis. An immunohistochemical study was used to detect the expression and location of CHOP in the cortical penumbra. To further assess the protective effect of the LPS pretreatment, the concentrations of inflammatory factors (TNF-α, IL-6, IL-1β and IL-10) in the cortical penumbra were measured by ELISA, and ER stress-CHOP pathway inflammation-related caspase-11 was analysed through western blot analysis. Results: As demonstrated by the experiments, the pretreatment with LPS significantly reduced the neurological deficit score and the infarct size of cerebral IRI. The expression levels of ER stress-CHOP pathway related proteins (GRP78, CHOP, caspase-12 and caspase-3) from the cortical penumbra were significantly decreased by LPS, as well as the level of apoptosis in the cells in the brain. Immunohistochemistry showed that the expression of CHOP significantly decreased after the LPS pretreatment. Furthermore, the concentrations of inflammatory factors (TNF-α, IL-1β, IL-6) were reduced after the LPS pretreatment, whereas the anti-inflammatory cytokine IL-10 was upregulated. In addition, ER stress-CHOP pathway inflammation-related caspase-11 expression was significantly suppressed after the pretreatment with LPS. Conclusions: LPS pretreatment significantly ameliorates the effects of cerebral IRI by inhibiting inflammation and apoptosis, and the potential mechanism of the neuroprotective effect may be associated with the ER stress-CHOP mediated signalling pathway.

Erythropoietin Derived Peptide Improved Endoplasmic Reticulum Stress and Ischemia-Reperfusion Related Cellular and Renal Injury

“…The UPR is attributed to the activation of one ER transmembrane protein, named protein kinase RNA-like ER kinase (PERK) (15)(16)(17). Growing evidence has shown that ERS associated with apoptosis and inflammation plays important roles in IR injury (18,19). UPR could gradually develop into apoptosis and further induces inflammation, if ERS is too severe to overcome.…”

SC79, the AKT Activator Protects Cerebral Ischemia in a Rat Model of Ischemia/Reperfusion Injury

“…Many I/R animal models showed neuronal apoptosis [ 4 ], which is also evident in patients suffering from ischemic stroke [ 5 ]. Cerebral I/R induces the activation of a series of pro-apoptotic genes or inactivation of anti-apoptotic genes, leading to neuronal cell damage [ 6 , 7 ]. Therefore, searching for protective agents directed at apoptotic pathways may provide an attractive therapeutic approach for the therapy of cerebral I/R injury.…”

CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress‑associated apoptotic pathways during ischemia/reperfusion

“…Previous studies have demonstrated that caSR-induced ca 2+ release from internal stores is a PLc-mediated/IP3-dependent process. The enhancement of [ca 2+ ]i may be related to the release of ca 2+ by the ER (6,26). To examine the occurrence of ER stress, the protein levels of GRP78 were detected.…”