PARP inhibition attenuates neuroinflammation and demyelination in a rat model of multiple sclerosis: A longitudinal [11C]PBR28 TSPO PET imaging study.

Poly(ADP-ribose) polymerase (PARP) plays important role in DNA repair, but is also involved in other cellular processes. PARP inhibition was suggested to suppress inflammatory signaling and has been proposed as potential treatment for neuroinflammatory disorders like multiple sclerosis. Yet, its effects on lesion-associated neuroinflammation in vivo remain insufficiently understood. We therefore evaluated whether the PARP inhibitor PJ34 can attenuate neuroinflammation and demyelination, and whether treatment response can be monitored longitudinally, using positron emission tomography (PET) with [11C]PBR28, a tracer for glial activation. In vitro, PJ34 was found to reduce [11C]PBR28 uptake and ionized calcium-binding adapter molecule 1 (IBA1) immunoreactivity in lipopolysaccharide-stimulated RAW264.7 macrophages. In vivo, focal demyelination was induced in male Sprague-Dawley rats by unilateral lysolecithin injection into the corpus callosum and striatum, followed by PJ34 or vehicle treatment and serial [11C]PBR28 PET imaging on days 3 and 7. PET revealed significantly lower tracer uptake in lesions of PJ34-treated animals compared to vehicle controls on day 3 (SUVmean 1.21 vs. 1.75; p < 0.001) and day 7 (1.00 vs. 1.29; p < 0.001). Histological analysis confirmed reduced IBA1 immunoreactivity, smaller microglial somata, and preserved process complexity in PJ34-treated animals. Furthermore, Luxol Fast Blue staining revealed significantly greater preserved myelinated area in the PJ34-treated group at day 7 (90.9% vs. 64.8%; p < 0.001). This study demonstrates that PJ34 attenuates lesion-associated neuroinflammation and demyelination in focal white matter injury and supports longitudinal [11C]PBR28 PET imaging as a sensitive noninvasive biomarker of treatment response.