Microthrombosis plays an important role in secondary brain injury after experimental subarachnoid hemorrhage (SAH), but the specific mechanism of microthrombosis remains unclear. The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs) in microthrombosis after SAH. SAH was induced in male C57BL/6 mice using an endovascular perforation technique. The marker protein of NETs, citrullinated histone H3 (CitH3), was significantly elevated in the cerebral cortex after SAH, and was co-labeled with microthrombi. Both depletion of neutrophils by anti-Ly6G antibody and DNase I treatment significantly reduced the formation of NETs and microthrombi, and ameliorated neurological deficits, brain edema, BBB disruption, and neuronal injury at 24 h after SAH induction. Cerebral hypoperfusion in the first hours after SAH is a major determinant of poor neurological outcome; in this study, we found that DNase I treatment significantly improved the restoration of early cortical perfusion after SAH. In addition, DNase I treatment also significantly attenuated cerebrospinal fluid (CSF) flow after SAH, which was associated with the diffusion barrier caused by microthrombi in the paravascular space after SAH. In conclusion, NETs are associated with early microthrombosis after SAH; they may be a novel therapeutic target for early brain injury (EBI) after SAH. Supplementary Information The online version contains supplementary material available at 10.1007/s12975-022-01074-9.

Survivors suffering from acute carbon monoxide poisoning (ACMP) are apt to develop white matter injury (WMI). While, the mechanism that ACMP evokes WMI remains unclear. Given that ferroptosis plays an evident role in igniting oligodendrocyte damage to deteriorate WMI, exploring regimens to attenuate ferroptosis is a feasible approach to alleviate WMI post-ACMP. Here, the results indicated that ACMP induced WMI to evoke motor impairment resulting from the surplus iron and reactive oxygen species (ROS) accumulation after ACMP. And, the administration of ferrostatin-1 reduced iron and ROS deposition to repress ferroptosis, thereafter reducing WMI to promote motor recovery. Furthermore, the result demonstrated that the nuclear factor erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was involved in attenuating ferroptosis resulting from the application of ferrostatin-1. The present study offers a rationale that targeting ferroptosis to alleviate WMI is a feasible therapeutic strategy for ACMP.

Survivors experiencing acute carbon monoxide poisoning (ACMP) tend to develop white matter injury (WMI). The mechanism of ACMP-induced WMI remains unclear. Considering the role of ferroptosis in initiating oligodendrocyte damage to deteriorate WMI, exploring therapeutic options to attenuate ferroptosis is a feasible approach to managing WMI. Our results indicated that ACMP induced accumulation of iron and reactive oxygen species (ROS) eventually leading to WMI and motor impairment after ACMP. Further, ferrostatin-1 reduced iron and ROS deposition to alleviate ferroptosis, thereafter reducing WMI to promote the recovery of motor function. The nuclear factor erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was found to be involved in alleviating ferroptosis as seen with the administration of ferrostatin-1. The present study rationalizes that targeting ferroptosis to alleviate WMI is a feasible therapeutic strategy for managing ACMP.

Microthrombosis plays an important role in secondary brain injury after experimental subarachnoid hemorrhage (SAH), but the specific mechanism of microthrombosis remains unclear. The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs) in microthrombosis after SAH. SAH was induced in male C57BL/6 mice using an endovascular perforation technique. The marker protein of NETs, citrullinated histone H3 (CitH3), was significantly elevated in the cerebral cortex after SAH, and was co-labeled with microthrombi. Both depletion of neutrophils by anti-Ly6G antibody and DNase I treatment significantly reduced the formation of NETs and microthrombi, ameliorated neurological deficits, brain edema, BBB disruption, and neuronal injury at 24 h after SAH induction. Cerebral hypoperfusion in the first hours after SAH is a major determinant of poor neurological outcome, in this study, we found that DNase I treatment significantly improved the restoration of early cortical perfusion after SAH. In addition, DNase I treatment also significantly attenuated cerebrospinal fluid (CFS) flow and glymphatic system dysfunction after SAH, which was associated with the diffusion barrier caused by microthrombi in the paravascular space after SAH. In conclusion, NETs is associated with early microthrombosis after SAH, it may be a novel therapeutic target for early brain injury (EBI) after SAH.