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

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.

Keywords:

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