Nrf2 attenuates neuroinflammatory injury in intracerebral hemorrhage via an ASK1/JNK-related signaling pathway.

Intracerebral hemorrhage (ICH) is a clinically prevalent cerebrovascular disorder in which neuroinflammation is a major contributor to secondary brain injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of intracellular redox homeostasis, whereas apoptosis signal-regulating kinase 1 (ASK1) is involved in stress-associated inflammatory and apoptotic signaling. However, the relationship between Nrf2 signaling and ASK1/JNK pathway activity in ICH-related inflammatory injury remains incompletely understood. In this study, we established a rat ICH model and used molecular, histological, and behavioral approaches to examine the association between Nrf2 signaling and ASK1/JNK-related neuroinflammatory changes. We found that ICH was accompanied by increased Nrf2 and phosphorylated ASK1 expression. siRNA-mediated modulation of Nrf2 or ASK1 was associated with reciprocal changes in ASK1/JNK pathway activation. In parallel, changes in CD80/CD206 expression and inflammatory cytokine levels suggested that Nrf2 signaling was associated with altered inflammation-related responses, potentially involving ASK1/JNK pathway activity. Histological analyses, including TUNEL staining, Nissl staining, and brain water content measurement, further showed that preservation of Nrf2 signaling was associated with reduced neuronal injury and cerebral edema after ICH. Behavioral assessments showed corresponding changes in locomotor and anxiety-related performance. Overall, these findings support an association between Nrf2 signaling and ASK1/JNK-related neuroinflammatory responses following ICH and provide a basis for further mechanistic investigation of this pathway in hemorrhagic brain injury.