Neuroglobin (Ngb) is proposed to be a neuron-specific, hypoxia-responsive, neuroprotective protein. However, results are conflicting concerning both Ngb's physiological and pathological significance. This study was designed to investigate the in vivo localization and regulation of Ngb in different neuropathological models representing traumatic injury, infectious, autoimmune, and excitotoxic pathogeneses. We profiled Ngb immunohistochemistry in murine models of traumatic brain injury, cerebral malaria, experimental autoimmune encephalitis, and kainic acid (KA)-mediated epileptic seizures that, to our knowledge, have not been studied in the context of Ngb. In control mice Ngb was expressed exclusively in neurons. In all pathological models except KA, in addition to neurons Ngb was present in reactive astrocytes. Ngb positive astrocytes were found within regions associated with most severe pathology and the astroglial scar. This is the first report of Ngb present in reactive astroglia and in scar-forming astrocytes in response to different pathological conditions relevant to human disease. In light of previously reported cyto-protective properties of Ngb, further insight may result in therapeutic ramifications.

ObjectivesIn this study, we address a gap in knowledge regarding the therapeutic potential of acute treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist after severe brain trauma. Moreover, it remains still unknown whether GLP-1 treatment activates the protective, anti-neurodegenerative cAMP response element binding protein (CREB) pathway in the brain in vivo, and whether activation leads to observable increases in protective, anti-neurodegenerative proteins. Finally, we report the first use of a highly sensitive in vivo imaging agent to assess reactive species generation after brain trauma.MethodsSevere trauma was induced with a stereotactic cryo-lesion in mice and thereafter treated with vehicle, liraglutide, or liraglutide + GLP-1 receptor antagonist. A therapeutic window was established and lesion size post-trauma was determined. Reactive oxygen species were visualized in vivo and quantified directly ex vivo. Hematological analysis was performed over time. Necrotic and apoptotic tone and neuroinflammation was assessed over time. CREB activation and CREB-regulated cytoprotective proteins were assessed over time.ResultsLira treatment reduced lesion size by ∼50% through the GLP-1 receptor. Reactive species generation was reduced by ∼40–60%. Necrotic and apoptotic tone maintained similar to sham in diseased animals with Lira treatment. Phosphorylation of CREB was markedly increased by Lira in a GLP-1 receptor-dependent manner. CREB-regulated cytoprotective and anti-neurodegenerative proteins increased with Lira-driven CREB activation.InterpretationThese results show that Lira has potent effects after experimental trauma in mice and thus should be considered a candidate for critical care intervention post-injury. Moreover, activation of CREB in the brain by Lira – described for the first time to be dependent on pathology – should be investigated further as a potential mechanism of action in neurodegenerative disorders.

Background and Purpose— The GLX (glycocalyx) is a protein/polysaccharide meshwork at the cellular surface. Consisting largely of glycosaminoglycans and proteoglycans, the GLX can shed in response to stress. In this study, we assay 11 components of the GLX in plasma from patients with ischemic stroke from a longitudinal cohort. Methods— Plasma samples from healthy individuals (N=8), and patients with ischemic stroke day ≥3, day 7, and day 90 (N=9–14) were immunoassayed for diverse components of the GLX. Results— Median stroke severity was mild (National Institutes of Health Stroke Scale 2.0 (range, 0–6) at day ≤3). Three (keratan-chondroitin-heparan-sulfate) of 4 glycosaminoglycans and CD44 (proteoglycan) were increased at day 7 and returned to baseline at day 90. Proteoglycan syndecan (Syn)-3 increased and Syn-2 levels decreased, significantly. Conclusions— Individual GLX components are often assayed as stand-alone biomarkers for endothelial health. This study suggests a full assessment of GLX components is more indicative of the endothelial health of an individual and represents a complex GLX signature that may be valuable as a composite biomarker of disease.