Diammonium glycyrrhizinate attenuates neuroinflammation after intracerebral hemorrhage by suppressing VCAM-1 expression via the PI3K-Akt pathway

Abstract

Intracerebral hemorrhage (ICH) is a devastating stroke subtype with limited therapeutic options, and excessive neuroinflammation plays a critical role in secondary brain injury following ICH. Here, we investigated whether diammonium glycyrrhizinate (DG), a clinically approved anti-inflammatory agent, confers neuroprotection in a mouse model of ICH and explored the underlying mechanisms. Adult male C57BL/6J mice subjected to collagenase-induced ICH were treated with DG or vehicle, and we assessed neurological function, brain water content, hematoma volume, and blood–brain barrier (BBB) integrity at 3 days post-ICH. DG treatment significantly reduced brain edema, hematoma volume, and BBB leakage while improving neurological outcomes. RNA sequencing revealed that DG downregulated 94 genes, with enrichment in cell surface receptor activity pathways, and identified Vascular cell adhesion molecule-1 (VCAM-1) as a key downstream target. VCAM-1 upregulation in brain microvascular endothelial cells after ICH was markedly suppressed by DG, accompanied by reduced neutrophil infiltration, attenuated microglial M1 polarization, and decreased production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), matrix metalloproteinase-9, oxidative stress markers, and apoptotic factors. Mechanistically, DG activated the PI3K-Akt signaling pathway, and this activation was associated with suppression of VCAM-1 expression and subsequent attenuation of neuroinflammation. These findings demonstrate that DG attenuates neuroinflammation and secondary brain injury after ICH by activating the PI3K-Akt pathway to suppress VCAM-1 expression, thereby limiting peripheral immune cell infiltration and modulating microglial polarization. The PI3K-Akt/VCAM-1 axis represents a promising therapeutic target, and DG may serve as a potential candidate for ICH management.