Fluids Barriers CNS. 2025 Jul 16. 22(1): 76
BACKGROUND: After a spinal cord injury (SCI), disruption of the blood-spinal cord barrier (BSCB) leads to secondary injuries, including inflammatory responses and apoptotic cell death, ultimately causing permanent neurological deficits. Imatinib, a tyrosine kinase inhibitor, has been reported to enhance BSCB integrity and improve functional recovery after SCI. However, the mechanism by which imatinib regulates BSCB integrity remains unclear. Recent studies have identified the histone H3K27me3 demethylase JMJD3 as a key mediator of BSCB disruption, with high expression observed in blood vessels after SCI. In this study, we investigated whether imatinib regulates JMJD3 expression and activation through PDGFR signaling, thereby mitigating BSCB disruption following SCI.
METHODS: Imatinib (100 mg/kg) was administered intraperitoneally to rats subjected to a contusion injury at the T9 level of the spinal cord and was continued daily for 14 days.
RESULTS: Our results indicate that imatinib inhibited the phosphorylation of PDGFRα and PDGFRβ, both tyrosine kinase receptors, without affecting their expression levels. Additionally, imatinib reduced JMJD3 and MMP-9 expression and activation in blood vessels, thereby decreasing macrophage infiltration after SCI. In an oxygen-glucose deprivation (OGD)-induced bEnd.3 cell model, phosphorylated PDGFRα and PDGFRβ, along with JMJD3 expression and activation, were significantly upregulated but were effectively inhibited by imatinib treatment. Furthermore, imatinib suppressed secondary damage, including cell death, blood cell infiltration (e.g., neutrophils and macrophages), inflammation, axonal and myelin loss, and lesion volume. These effects collectively resulted in significant improvements in functional recovery after SCI.
CONCLUSION: Based on these findings, we propose that imatinib exerts a neuroprotective effect, in part by inhibiting PDGFR-mediated JMJD3 expression and activation following SCI.
Keywords: Blood-spinal cord barrier; Imatinib; JMJD3; MMP; PDGFR; Spinal cord injury