Tanshinone IIA Alleviates Postintracerebral Hemorrhage Infection-Induced NETosis and Neuroinflammation via Downregulating the NLRP3/Caspase-1 Pathway

Intracerebral hemorrhage (ICH) is a cerebrovascular event associated with a high fatality rate, leading to a considerable health and economic burden. Tanshinone IIA (Tan IIA), a promising compound used to treat coronary artery disease, has recently been shown to exert significant neuroprotective effects. Therefore, whether Tan IIA can alleviate NETosis induced by LPS after ICH remains unclear. For this purpose, we explored the effects of Tan IIA on collagenase-induced ICH with peripheral inflammation and its potential mechanisms using an after-ICH infection animal model (male C57BL/6J mice) treated with Tan IIA for 5 days, starting at 2 months of age. Further analysis demonstrated that Tan IIA-treated ICH mice with peripheral inflammation exhibited improved motor and sensory dysfunction compared with untreated groups. Administration of Tan IIA in ICH mice with peripheral inflammation alleviated neuropathological alterations of the corpus striatum, including NETosis inhibition, glial inactivation, and inflammasome activity attenuation, and significantly decreased levels of PAD4 and H3 Cit in the corpus striatum of ICH mice with peripheral inflammation. In vitro investigations showed that Tan IIA suppressed neuroinflammation in LPS-stimulated glial cells by inhibiting the NLRP3/caspase-1 signaling pathway. Further molecular docking predicted that Tan IIA directly interacted with the NLRP3 protein. Collectively, these findings strongly indicate that Tan IIA is an effective compound for mitigating hemiplegia symptoms, NETosis, and neuroinflammation in the collagenase-induced ICH model with peripheral inflammation, primarily through the dual actions of inhibiting NET formation and suppressing the NLRP3/caspase-1 pathway.