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4,4′-Dimethoxychalcone Mitigates Neuroinflammation Following Traumatic Brain Injury Through Modulation of the TREM2/PI3K/AKT/NF-κB Signaling Pathway

Year: 2025

Type: article

Abstract: Research on 4,4'-dimethoxychalcone (DMC) in the context of traumatic brain injury (TBI) is extremely limited, and no effective clinical treatments are available to improve outcomes for individuals with TBI. Our study aims to investigate the underlying mechanisms by which DMC may alleviate neuroinflammation and neuronal damage following TBI. This study seeks to provide a theoretical foundation for the development of future pharmacological therapies for TBI. A moderate TBI model was established using the fluid percussion injury (FPI) method. The recovery of neuromotor function following TBI was evaluated using the modified neurological severity score (mNSS), the Morris water maze test, and analysis of cerebral edema. Gene and protein expression levels were quantified using cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and immunofluorescence. Network pharmacology was employed to predict potential targets of DMC, and gene ontology (GO) analysis along with KEGG pathway enrichment was conducted to predict signaling pathways affected by DMC.DMC treatment significantly improved neuromotor deficits in mice after TBI. In both in vivo and in vitro experiments, DMC suppressed microglial activation and decreased the production and release of inflammatory factors. Additionally, DMC reduced neuronal lesions after TBI. DMC notably decreased the elevated expression of triggering receptor expressed on myeloid cells 2 (TREM2) following TBI. Network pharmacological analysis indicated that DMC's therapeutic effects may be mediated through the PI3K/AKT signaling cascade. These findings indicate that DMC has therapeutic potential for TBI, with significant anti-inflammatory and neuroprotective properties likely mediated by the TREM2/PI3K/AKT/NF-κB signaling cascade.

Source: Inflammation

DOI: 10.1007/s10753-025-02279-4