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.
Highlights
Traumatic brain injury (TBI) induces activation of microglia
Time course of brain inflammation after TBI The controlled cortical impact produced a necrotic lesion in the dorsal cortex that extended from the cortical surface to the deeper cortical layers, but not to the underlying corpus callosum (Figure 1A)
We first evaluated the time course of microglia and astrocyte activation in the peri-lesion cortex and ipsilateral hippocampus after this injury to identify the period of peak inflammation
Summary
Traumatic 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, providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). We evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. (ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in both DNA repair and transcriptional regulation [9,10]. PARP-1 genetic deficiency or enzymatic inhibition suppresses NF-kBdependent gene transcription in microglia [18] and prevents their morphological transformation, proliferation and migration to injury sites [4,13,19,20]. Minocycline and related tetracycline derivatives are highly potent PARP inhibitors [21], and these drugs are potent suppressers of microglial activation [22,23,24]
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