Febuxostat attenuates secondary brain injury caused by cerebral hemorrhage through inhibiting inflammatory pathways

• Published in: Iranian journal of basic medical sciences Vol. 27; no. 6; pp. 740 - 746
• Main Authors: Bai, Yang, Shi, Hongxia, Zhang, Ying, Zhang, Chenyu, Wu, Bin, Wu, Xinghan, Fang, Zhenwei, Wang, Qi, Sima, Xiutian, Zhang, Tiejun
• Format: Journal Article
• Language: English
• Published: Iran Mashhad University of Medical Sciences 01.01.2024
• Subjects: Bioinformatics; bioinformatics analysis; febuxostat; Hemorrhage; inflammation; intracerebral hemorrhage nlrp3 inflammasome; Original; second brain injury; Traumatic brain injury; trend analysis; Bioinformatics analysis; Febuxostat; Second brain injury; Trend analysis; Inflammation; NLRP3 inflammasome; Intracerebral hemorrhage
• ISSN: 2008-3866; 2008-3874
• DOI: 10.22038/IJBMS.2024.74655.16212

Neuroinflammation is considered an important step in the progression of secondary brain injury (SBI) induced by cerebral hemorrhage (ICH). The nucleotide-binding and oligomerization structural domain-like receptor family of pyridine structural domain-containing 3 (NLRP3) inflammasomes play an important role in the immune pathophysiology of SBI. Febuxostat (Feb) is a xanthine oxidase inhibitor that is approved for the treatment of gout and has been found to have potent anti-inflammatory effects. However, it has been less studied after ICH and we aimed to explore its protective role in ICH. We established an autologous blood-brain hemorrhage model in C57BL/6 mice. Functions of co-expressed genes were analyzed by trend analysis and bioinformatics analysis. Enzyme-linked immunosorbent assay were used to assess the inflammatory factor levels. Fluoro-Jade B histochemistry and TUNEL staining were used to detect neuronal apoptosis. Immunofluorescence staining and western blotting were used to detect the expression of NLRP3 inflammasomes. Pretreatment with Feb reduced neuronal cell death and degeneration and alleviated neurobehavioral disorders . Feb was found to modulate inflammation-related pathways by trend analysis and bioinformatics analysis. In addition, Feb inhibited microglia activation and elevated cytokine levels after ICH. Furthermore, double immunofluorescence staining showed that co-localization of NLRP3 with Iba1 positive cells was reduced after treatment with Feb. Finally, we found that Feb inhibited the activation of the NLRP3/ASC/caspase-1 pathway after ICH. By inhibiting the NLRP3 inflammasome, preconditioning Feb attenuates inflammatory injury after ICH. Our findings may provide new insights into the role of Feb in neuroprotection.