title: Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor.
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.
authors.affiliation: Dept. of Neurology, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
authors.forename: Joana C
authors.initials: JC
authors.lastname: d'Avila
authors.forename: Tina I
authors.initials: TI
authors.lastname: Lam
authors.forename: Deborah
authors.initials: D
authors.lastname: Bingham
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kauppinen
authors.forename: Stephen
authors.initials: S
authors.lastname: Massa
authors.forename: Jialing
authors.initials: J
authors.lastname: Liu
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology; D005552:Forelimb / Q000503:physiopathology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal / Q000379:methods; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases