Related Experiment Video
Updated: May 24, 2026
Acute Brain Trauma in Mice Followed By Longitudinal Two-photon Imaging
Published on: April 6, 2014
Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor
Joana C d'Avila1, Tina I Lam, Deborah Bingham
1Dept. of Neurology, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
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.
Insights
A poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, INO-1001, reduced inflammation and improved outcomes after traumatic brain injury (TBI) in rats. This therapeutic approach shows promise for TBI recovery.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Traumatic brain injury (TBI) triggers microglial activation, contributing to secondary injury and hindering recovery.
- Microglial activation, an innate immune response, presents a therapeutic window for intervention.
- Poly(ADP-ribose) polymerase-1 (PARP-1) regulates microglial activation; its inhibition may mitigate TBI-induced inflammation.
Purpose of the Study:
- To evaluate the efficacy of the PARP inhibitor INO-1001 in suppressing microglial activation post-TBI.
- To assess the impact of INO-1001 on neuronal survival and functional recovery following cortical impact injury.
Main Methods:
- Rats received controlled cortical impact and were treated with INO-1001 or vehicle 20-24 hours post-TBI.
- Histological analysis examined microglial (CD11b) and astrocyte (GFAP) activation, and neuronal survival (NeuN).
- Forelimb dexterity was assessed 8 weeks post-TBI using sticky tape, cylinder, and vermicelli tests.
Main Results:
- INO-1001 significantly reduced microglial and astrocyte activation in the peri-lesion cortex and hippocampus.
- Reduced inflammation correlated with enhanced neuronal survival and improved forelimb dexterity.
- No rebound inflammation was observed after a 12-day treatment followed by a 4-day drug holiday.
Conclusions:
- Administering a PARP inhibitor up to 20 hours after TBI can effectively reduce neuroinflammation.
- Delayed PARP inhibition improves histological outcomes and promotes functional recovery after TBI.
- This study supports the potential of PARP inhibitors as a therapeutic strategy for TBI management.
