Receptor for advanced glycation end products mediates sepsis-triggered amyloid-ß accumulation, Tau phosphorylation, and cognitive impairment.

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-ß peptide (Aß) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1ß, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aß and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aß and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

Effects of S100B neutralization on the long-term cognitive impairment and neuroinflammatory response in an animal model of sepsis.

The nervous system is one of the first systems to be affected during sepsis. Sepsis not only has a high risk of mortality, but could also lead to cerebral dysfunction and cognitive impairment in long-term survival patients. The receptor for advanced glycation end products (RAGE) can interact with several ligands, and its activation triggers a series of cell signaling events, resulting in the hyperinflammatory condition related to sepsis. Recent studies show that elevated levels of S100B (RAGE ligand) are associated with the pathophysiology of neurodegenerative disorders. They also participate in inflammatory brain diseases and may lead to an increased activation of microglia and astrocytes, leading to neuronal death. This study aimed to determine the effect of S100B inhibition on the neuroinflammatory response in sepsis. Sepsis was induced in Wistar rats by cecal ligation and perforation (CLP). There were three groups: Sham, CLP, and CLP +10 µg/kg of monoclonal antibody (Anti-S100B) administered intracerebroventricularly. The animals were killed 30 days after sepsis following behavioral evaluation by open field, novel object recognition, and splash test. The hippocampus, prefrontal cortex, and amydgala were used for the determination of S100B and RAGE proteins by western blotting and for the evaluation of cytokine levels and verification of the number of microglial cells by immunohistochemistry. On day 30, both the Sham and CLP + anti-S100B groups were capable of recovering the habitual memory in the open field task. Regarding novel object recognition, Sham and CLP + anti-S100B groups increased the recognition index during the test session in comparison to the training session. There was a significant increase in the time of grooming in CLP + anti-S100B in comparison to the CLP group. There was a modulation of cytokine levels and immunohistochemistry showed that the CLP + anti-S100B group had a decrease in the number of microglial cells only in the hippocampus. These results helped to understand the role of S100B protein in the pathophysiology of sepsis-associated encephalopathy and could be helpful to further experimental studies regarding this subject.

Evaluation of an alternative technique for preserving crustaceans in dry conditions with joint mobility: a proposal for didactic purposes

Although crustaceans are traditionally preserved in liquids (formaldehyde and/or ethyl alcohol), those substances tend to alter their morphological aspects. Glycerin, used in human anatomy, is considered a good substitute for formaldehyde, as it preserves animals in states similar to in vivo conditions. There are no records in the literature, however, concerning the use of glycerin for conserving invertebrates. The objective of this work was to elaborate and evaluate alternative techniques for conserving the crustacean Ucides cordatus (Linnaeus, 1763). Six fixatives (1, 3, 4 and 5% formaldehyde, 70% alcohol, and dietrich solution) and two controls (positive and negative) were tested, as well as the effects of freezing before fixation on the integrity of U. cordatus specimens. Our results were evaluated with respect to nine variables. The treatments that demonstrated the best aesthetic results were 4% formaldehyde and 70% ethyl alcohol. The freezing of the animals resulted in brittle organs in all treatments tested. The technique discussed here is extremely promising for the conservation of animals for educational purposes, as it produces preserved specimens that are aesthetically similar to their in vivo conditions.