Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor
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RESEARCH
JOURNAL OF NEUROINFLAMMATION
Open Access
Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor Joana C d’Avila1,3, Tina I Lam1, Deborah Bingham2, Jian Shi1, Seok Joon Won1, Tiina M Kauppinen1, Stephen Massa1, Jialing Liu2 and Raymond A Swanson1*
Abstract Background: 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, 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. Methods: Rats 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. Results: Peak 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. Conclusions: Treatment 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. Keywords: Astrocyte, Behavioral, Forelimb, Inflammation, Microglia, Minocycline, Poly(ADP-ribose) polymerase, traumatic brain injury
Background Microglia are the resident macrophages of the CNS [1]. Traumatic brain injury (TBI) leads to tissue disruption and release of molecules from injured and dead cells that elicit microglial and astrocyte activation [2,3]. Activated microglia change morphology, migrate to injury sites, and release reactive oxygen species, nitric oxide, cytokines, metalloproteinases, and other factors with * Correspondence: [email protected] 1 Depts. of Neurology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA Full list of author information is available at the end of the article
cytotoxic effects. Astrocytes
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