Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

Abstract

BackgroundTraumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat.MethodsRats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone) beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression), astrocyte activation (GFAP), and neuronal survival (NeuN). Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test.ResultsPeak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI.ConclusionsTreatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

“…Consistent with these findings, our present in vitro and in vivo experiments showed that nuclear DNA oxidation in microglia is associated with PARP activation, which was reversed by MUTYH deficiency. Previous studies showed that PARP is essential for microglial activation in experimental models of neuronal damage (43)(44)(45). The results of the present and previous studies suggest that oxidative nuclear DNA damage and MUTYH are critical upstream regulators of microglial PARP activity during neurodegeneration.…”

Tibial Fracture Exacerbates Traumatic Brain Injury Outcomes and Neuroinflammation in a Novel Mouse Model of Multitrauma

“…For example, here we found no evidence of changes in microglia/macrophage levels in brain tissue at 24 hours and 35 days after injury using Western blotting, which may be related to previous findings indicating that peak microglia activation occurs 5 to 7 days after TBI. 34 However, histologic analysis may have been sensitive to more subtle changes in There were no differences in the distance traveled (C). There were no significant differences on the measure of duration on rotarod during training (D).…”

“…microglia phenotype, 34 and should be applied in future studies. Overall, further research is required to better understand the role and nature of the elevated inflammatory factors in brain tissue and circulation after multitrauma.…”

A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

“…Using Image Pro Plus software the color threshold was adjusted to detect immunostained inflammatory cells, and the number of colored objects was counted within a 0.2-mm 2 area of interest centered on the lesion epicenter at a depth that included the area of greatest immunoreactivity. Neurons immunoreactive for neuronal nuclear antigen (NeuN) were counted in the hippocampus at 4 weeks post-injury as an indication of neuronal survival levels (D'Avila et al, 2012). For this analysis, a 20× field of view (0.33 mm 2 in area) was sampled using the hippocampal shape as the landmark.…”