Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences.

AIMS: Infection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. MAIN METHODS: Male and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. KEY FINDINGS: CLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1ß in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SIGNIFICANCE: The parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.

NLRP3 inflammasome activation increases brain oxidative stress after transient global cerebral ischemia in rats.

Pupurpose of the study: Oxidative stress has been reported to be an important mechanism for brain damage following ischemic stroke. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes has been demonstrated to perpetuate oxidative stress. Herein, we report the effect of NLRP3 inhibition with MCC950 on brain oxidative stress in an animal model of transient global cerebral ischemia.Materials and methods: Male Wistar rats received an intracerebroventricularly (icv) injection of MCC950 (140 ng/kg) or saline and were subjected to sham procedure or ischemia/reperfusion (I/R). Twenty-four hours after I/R, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, lipid peroxidation, protein carbonyls formation, superoxide dismutase (SOD) and catalase (CAT) activity were determined in the prefrontal cortex, hippocampus, cortex, cerebellum and striatum. Results: After I/R, MPO activity increased in the prefrontal cortex, hippocampus, cortex and cerebellum and N/N concentration elevated in the prefrontal cortex, hippocampus and cortex, while MCC950 decreased this level except in hippocampus. After I/R, lipid peroxidation enhanced in the prefrontal cortex and cerebellum and increased the oxidative protein damage in both structures and hippocampus. MCC950 decreased lipid peroxidation in the prefrontal cortex and decreased protein oxidative damage in all brain structures except in the striatum. SOD activity decreased in the cortex after I/R and MCC950 reestablished these levels. CAT activity decreased in the prefrontal cortex, hippocampus and cerebellum after I/R and MCC950 reestablished these levels in the prefrontal cortex.Conclusion: Our data provide novel demonstration that inhibiting NLRP3 activation with MCC950 reduces brain oxidative damage after cerebral I/R in rats.