Abstract

Objective Although the pathological mechanisms underlying intracerebral hemorrhage (ICH) have been widely explored, the contribution of kininogen-1 (Kng1) to inflammation-associated neuronal damage has not been fully elucidated. This study was designed to investigate the functional involvement of Kng1 and the cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling cascade in inflammation-driven neuronal injury following cerebral hemorrhage. Methods Bioinformatics analyses based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were employed to identify Kng1 and the cGMP-PKG pathway as key candidates. An in vivo ICH model was generated by intracerebral injection of autologous blood, while an in vitro hemorrhagic injury model was established by treating neuronal cells with hemoglobin chloride. Levels of inflammatory mediators and gene expression were determined using enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and reverse transcription-quantitative polymerase chain reaction. Neurological impairment and cerebral edema were evaluated through behavioral deficit scoring and brain water content analysis, respectively. Results Kng1 protein levels were markedly increased in the serum of patients with ICH as well as in experimental hemorrhage models, and this elevation was closely associated with enhanced neuroinflammatory responses. Suppression of Kng1 expression significantly alleviated neurological dysfunction, reduced cerebral edema, mitigated inflammatory activation, and limited neuronal apoptosis in ICH rats. Further mechanistic investigations demonstrated that Kng1 modulates the cGMP-PKG signaling axis, as pharmacological stimulation of cGMP or PKG reversed the protective effects induced by Kng1 silencing. Consistent findings from both animal and cellular rescue experiments indicated that Kng1 aggravates neuronal injury after ICH by activating cGMP-PKG-dependent inflammat