Background: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust antiinflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.

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Ischemic stroke (IS) is a serious cerebrovascular disease with high morbidity and disability worldwide. Despite the great efforts that have been made, the prognosis of patients with IS remains unsatisfactory. Notably, recent studies indicated that mesenchymal stem cell (MSCs) therapy is becoming a novel research hotspot with large potential in treating multiple human diseases including IS. The current article is aimed at reviewing the progress of MSC treatment on IS. The mechanism of MSCs in the treatment of IS involved with immune regulation, neuroprotection, angiogenesis, and neural circuit reconstruction. In addition, nutritional cytokines, mitochondria, and extracellular vesicles (EVs) may be the main mediators of the therapeutic effect of MSCs. Transplantation of MSCs-derived EVs (MSCs-EVs) affords a better neuroprotective against IS when compared with transplantation of MSCs alone. MSC therapy can prolong the treatment time window of ischemic stroke, and early administration within 7 days after stroke may be the best treatment opportunity. The deliver routine consists of intraventricular, intravascular, intranasal, and intraperitoneal. Furthermore, several methods such as hypoxic preconditioning and gene technology could increase the homing and survival ability of MSCs after transplantation. In addition, MSCs combined with some drugs or physical therapy measures also show better neurological improvement. These data supported the notion that MSC therapy might be a promising therapeutic strategy for IS. And the application of new technology will promote MSC therapy of IS.

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH.

Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, which is associated with high morbidity and mortality. However, at present, the cellular and molecular mechanisms of SAE have remained elusive. The pathogenesis of SAE is complex and multifactorial, in which activated inflammation is recognized as a major factor. Pathological characteristics of SAE include blood- brain barrier (BBB) disruption, reduction of cerebral blood fluid (CBF) and glucose uptake, inflammatory response and activation of microglia and astrocytes. The BBB disruption induces the leakage of immune cells and inflammatory mediators, which trigger an inflammatory response in the brain. Inflammatory mediators released by activated microglia and astrocytes cause neuronal loss and brain function defect. In the review we describe the most recent findings in the pathogenesis of SAE and focus on summarizing the major mechanisms related to SAE pathogenesis.

Neutrophil extracellular traps (NETs) are complexes of decondensed DNA fibers and antimicrobial peptides that are released by neutrophils and play important roles in many noninfectious diseases, such as cystic fibrosis, systemic lupus erythematosus, diabetes, and cancer. Recently, the formation of NETs has been detected in many central nervous system diseases and is thought to play different roles in the occurrence and development of these diseases. Researchers have detected NETs in acute ischemic stroke thrombi, and these NETs are thought to promote coagulation and thrombosis. NETs in ischemic brain parenchyma were identified as the cause of secondary nerve damage. High levels of NETs were also detected in grade IV glioma tissues, where NETs were involved in the proliferation and invasion of glioma cells by activating a signaling pathway. Extracellular web-like structures have also recently been observed in mice with traumatic brain injury (TBI), and it was hypothesized that NETs contribute to the development of edema after TBI. This article reviews the effect of NETs on multiple diseases that affect the CNS and explores their clinical application prospects.