Roles of Polymorphonuclear Neutrophils in Ischemic Brain Injury and Post-Ischemic Brain Remodeling

Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized.

Relationship Between Injured Cingulum and Impaired Consciousness in Patients with Hypoxic-Ischemic Brain Injury

Objectives We investigated the relationship between cingulum injury and impaired consciousness in patients with hypoxic-ischemic brain injury (HI-BI) by using diffusion tensor tractography (DTT). Methods We recruited 29 patients with HI-BI and 25 normal control subjects. The patients were classified as intact consciousness (group A, 13 patients) or impaired consciousness (group B, 16 patients). The DTT parameters of fractional anisotropy (FA) and tract volume (TV) were estimated for both cinguli. Glasgow Coma Scale (GCS) and Coma Recovery Scale-Revised (CRS-R) scores were also evaluated. Results The FA and TV values of the cinguli in groups A and B were lower than those of the control group (p < 0.05), and the FA and TV values of group B were lower than those of group A (p < 0.05). The FA and TV values of the cinguli in group A were not significantly correlated with GCS and CRS-R scores (p > 0.05); however, regarding the group B, the FA correlations with GCS (r = 0.457, p < 0.05) and CRS-R (r = 0.494, p < 0.05) and those of TV with GCS (r = 0.500, p < 0.05) and CRS-R (r = 0.491, p < 0.05) were moderately positive. Conclusions We found a significant relationship between injury of the cingulum and impaired consciousness in patients with HI-BI. Our results suggest that an injured cingulum could be an appropriate target for neurointervention or neurorehabilitation in patients with impaired consciousness following HI-BI.

C3a Receptor Signaling Inhibits Neurodegeneration Induced by Neonatal Hypoxic-Ischemic Brain Injury

Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis.

NogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates

Astrocytes play critical roles after brain injury, but their precise function is poorly defined. Utilizing single-nuclei transcriptomics to characterize astrocytes after ischemic stroke in the visual cortex of the marmoset monkey, we observed nearly complete segregation between stroke and control astrocyte clusters. Screening for the top 30 differentially expressed genes that might limit stroke recovery, we discovered that a majority of astrocytes expressed RTN4A/ NogoA, a neurite-outgrowth inhibitory protein previously only associated with oligodendrocytes. NogoA upregulation on reactive astrocytes post-stroke was significant in both the marmoset and human brain, whereas only a marginal change was observed in mice. We determined that NogoA mediated an anti-inflammatory response which likely contributes to limiting the infiltration of peripheral macrophages into the surviving parenchyma.