Spatiotemporal PET imaging of P2X7R-driven neuroinflammation using [F]GSK1482160 after experimental acute spinal cord injury in mice.

Abstract

BACKGROUND: The severe inflammatory cascade after spinal cord injury (SCI) is a major driver of secondary injury. Precise monitoring and effective intervention in neuroinflammation are critical for functional recovery. After SCI, microglia accumulate at the lesion site and the P2X7 receptor (P2X7R) on their surface becomes markedly hyperactivated. However, the spatiotemporal activation profile and role of P2X7R in SCI remain unclear. In this study, with [F]FDG as a reference tracer, we evaluated the feasibility of the P2X7R-specific PET tracer [F]GSK1482160 for dynamic tracking the spatiotemporal progression of neuroinflammation after SCI. METHODS: An acute mouse model of SCI was established. PET/CT imaging with [F]GSK1482160 and, for comparison, [F]FDG was performed in SCI (n = 60) and control (n = 48) mice. Basso Mouse Scale (BMS) scoring, histological staining, and Western blotting (WB) were conducted at 1, 3, 7, 14, and 28 days post injury (dpi). To evaluate therapeutic potential, a selective P2X7R antagonist was administered to SCI mice and efficacy was assessed. RESULTS: At 1 dpi, [F]GSK1482160 uptake in SCI mice was lower than in time-matched controls (0.54 ± 0.10 vs. 1.00 ± 0.10). Uptake then increased significantly from 3 dpi (1.14 ± 0.13 vs. 0.96 ± 0.14) to 28 dpi (3.16 ± 0.20 vs. 1.00 ± 0.13) and was significantly associated with BMS scores. In contrast, [F]FDG uptake remained consistently high throughout the observation period and showed no correlation with BMS scores. Treatment with a P2X7R antagonist significantly reduced [F]GSK1482160 uptake at 7 dpi compared with the time-matched vehicle-treated SCI group (1.51 ± 0.17 vs. 1.94 ± 0.21) and improved BMS scores. Histological findings and WB results were consistent with the imaging results. Unless otherwise stated, n = 6 per group at each time point and data are presented as mean ± standard deviation. CONCLUSIONS: P2X7R-targeted PET/CT molecular imaging enables monitoring of the spatiotemporal evolution of neuroinflammation after SCI. These findings support the therapeutic potential of P2X7R-targeted interventions and underscore the importance of P2X7R in advancing SCI management and individualized precision therapy.