Neuroinflammation is closely associated with functional outcome in subarachnoid hemorrhage (SAH) patients. Our recent study demonstrated that fluoxetine inhibited NLRP3 inflammasome activation and attenuated necrotic cell death in early brain injury after SAH, while the effects and potential mechanisms of fluoxetine on neuroinflammation after SAH have not been well-studied yet. One hundred and fifty-three male SD rats were subjected to the endovascular perforation model of SAH. Fluoxetine (10 mg/kg) was administered intravenously at 6 h after SAH induction. TAK-242 (1.5 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h after SAH. SAH grade, neurological scores, brain water content, Evans blue extravasation, immunofluorescence/TUNEL staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were performed. Fluoxetine administration attenuated BBB disruption, brain edema, and improved neurological function after SAH. In addition, fluoxetine alleviated the number of Iba-1-positive microglia/macrophages, neutrophil infiltration, and cell death. Moreover, fluoxetine reduced the levels of pro-inflammatory cytokines, downregulated the expression of TLR4 and MyD88, and promoted the nuclear translocation of NF-κB p65, which were also found in rats with TAK-242 administration. Combined administration of fluoxetine and TAK-242 did not enhance the neuroprotective effects of fluoxetine. Fluoxetine attenuated neuroinflammation and improved neurological function in SAH rats. The potential mechanisms involved, at least in part, TLR4/MyD88/NF-κB signaling pathway.

The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO‐1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1‐like activation and promoted the activation of the M2‐like microglial phenotype. Omav inhibited OxyHb‐induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.

Isocitrate dehydrogenase (IDH)–wild-type (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMC) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAM) in tumors with the highest protumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased chimeric antigen receptor (CAR) T-cell exhaustion and improved CAR T-cell antitumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand–receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.

Aim: The complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined.Methods: There were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined.Results: There were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1.Conclusions: The complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.

Background: In recent years, there have been an increasing number of studies on trigeminal neuralgia (TN). However, a scientific and comprehensive study of the current situation and trends in the field of TN research is lacking. The purpose of this study is to summarize and visualize the development, research hotspots, and future trends in TN based on a bibliometric approach.Methods: Studies on TN published from 2001 to 2021 were obtained from the Web of Science Core Collection (WoSCC). Bibliometrics, CiteSpace, and VOSviewer tools were used for bibliometric analysis and visualization.Results: In total, 4,112 documents were searched. The number of research articles in the field is generally on an upward trend, with the fastest growth in the number of articles from 2017 to 2020. Shanghai Jiao Tong University, Pittsburgh University, and Mayo Clinic are the three institutions with the most publications. Shiting Li and Zakrzewska JM are the most prolific author and top co-cited authors, respectively. The Journal of Neurosurgery is the most influential journal. The top 5 keywords in that time frame are TN, microvascular decompression, facial pain, stereotactic radiosurgery, and neuropathic pain.Conclusion: This is the first comprehensive scientific bibliometric analysis of the global research field on TN over the past 21 years, providing a meaningful reference for further exploration of topical issues and research trends in the field.

Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.