yang bai - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Hongxia Shi - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Ying Zhang - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Chenyu Zhang - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Bin Wu - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Xinghan Wu - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Zhenwei Fang - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Qi Wang - Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Xiutian Sima - Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Tiejun Zhang - Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Objective(s): 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 ۳ (NLRP۳) 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.Materials and Methods: We established an autologous blood-brain hemorrhage model in C۵۷BL/۶ 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 NLRP۳ inflammasomes.Results: Pretreatment with Feb reduced neuronal cell death and degeneration and alleviated neurobehavioral disorders in vivo. 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 NLRP۳ with Iba۱ positive cells was reduced after treatment with Feb. Finally, we found that Feb inhibited the activation of the NLRP۳/ASC/caspase-۱ pathway after ICH. Conclusion: By inhibiting the NLRP۳ inflammasome, preconditioning Feb attenuates inflammatory injury after ICH. Our findings may provide new insights into the role of Feb in neuroprotection.

Bioinformatics analysis, Febuxostat, Inflammation, Intracerebral hemorrhage NLRP۳ inflammasome, Second brain injury, Trend analysis