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

d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA - J Neuroinflammation (2012)

Bottom Line: INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Neurology, Veterans Affairs Medical Center, San Francisco, California 94121, USA.

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.

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No rebound inflammation after INO-1001 is discontinued. Rats were treated with INO-1001 (or vehicle) beginning 1 day after TBI in one of two regimens: i) for 12 days, then euthanized, or ii) for 12 days followed by 4 days without treatment. (A) Confocal immunostaining of microglia (CD11b) and astrocytes (GFAP) in peri-lesion cortex. (B) Quantification shows no significant increase in microglial or astrocyte activation after stopping INO-1001. (C) Confocal immunostaining of microglia and astrocytes in the ipsilateral hippocampus dentate gyrus. (D) Quantification shows no increase in microglial or astrocyte activation after stopping INO-1001. Bars represents 20 μm. n = 4-5; *P < 0.05, **P < 0.01 vs. vehicle treatment.
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Figure 4: No rebound inflammation after INO-1001 is discontinued. Rats were treated with INO-1001 (or vehicle) beginning 1 day after TBI in one of two regimens: i) for 12 days, then euthanized, or ii) for 12 days followed by 4 days without treatment. (A) Confocal immunostaining of microglia (CD11b) and astrocytes (GFAP) in peri-lesion cortex. (B) Quantification shows no significant increase in microglial or astrocyte activation after stopping INO-1001. (C) Confocal immunostaining of microglia and astrocytes in the ipsilateral hippocampus dentate gyrus. (D) Quantification shows no increase in microglial or astrocyte activation after stopping INO-1001. Bars represents 20 μm. n = 4-5; *P < 0.05, **P < 0.01 vs. vehicle treatment.

Mentions: We next considered the possibility that INO-1001 might induce a "rebound" inflammation when discontinued after the peak interval of microglial activation. One group of rats was treated with INO-1001 (or vehicle) for 12 days following TBI, at which time microglial activation had largely waned. A second group of rats was treated with INO-1001 (or vehicle) for 12 days, followed by 4 days of no treatment before brain harvest. The four-day interval was chosen because this interval is long enough to observe rebound inflammation when it occurs in other settings [33-36]. INO-1001 was in all cases initiated 20-24 hours after TBI. Results of these studies showed no rebound increase in microglial or astrocyte activation, in either cortex or hippocampus, following cessation of INO-1001 treatment (Figure 4).


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

d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA - J Neuroinflammation (2012)

No rebound inflammation after INO-1001 is discontinued. Rats were treated with INO-1001 (or vehicle) beginning 1 day after TBI in one of two regimens: i) for 12 days, then euthanized, or ii) for 12 days followed by 4 days without treatment. (A) Confocal immunostaining of microglia (CD11b) and astrocytes (GFAP) in peri-lesion cortex. (B) Quantification shows no significant increase in microglial or astrocyte activation after stopping INO-1001. (C) Confocal immunostaining of microglia and astrocytes in the ipsilateral hippocampus dentate gyrus. (D) Quantification shows no increase in microglial or astrocyte activation after stopping INO-1001. Bars represents 20 μm. n = 4-5; *P < 0.05, **P < 0.01 vs. vehicle treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298794&req=5

Figure 4: No rebound inflammation after INO-1001 is discontinued. Rats were treated with INO-1001 (or vehicle) beginning 1 day after TBI in one of two regimens: i) for 12 days, then euthanized, or ii) for 12 days followed by 4 days without treatment. (A) Confocal immunostaining of microglia (CD11b) and astrocytes (GFAP) in peri-lesion cortex. (B) Quantification shows no significant increase in microglial or astrocyte activation after stopping INO-1001. (C) Confocal immunostaining of microglia and astrocytes in the ipsilateral hippocampus dentate gyrus. (D) Quantification shows no increase in microglial or astrocyte activation after stopping INO-1001. Bars represents 20 μm. n = 4-5; *P < 0.05, **P < 0.01 vs. vehicle treatment.
Mentions: We next considered the possibility that INO-1001 might induce a "rebound" inflammation when discontinued after the peak interval of microglial activation. One group of rats was treated with INO-1001 (or vehicle) for 12 days following TBI, at which time microglial activation had largely waned. A second group of rats was treated with INO-1001 (or vehicle) for 12 days, followed by 4 days of no treatment before brain harvest. The four-day interval was chosen because this interval is long enough to observe rebound inflammation when it occurs in other settings [33-36]. INO-1001 was in all cases initiated 20-24 hours after TBI. Results of these studies showed no rebound increase in microglial or astrocyte activation, in either cortex or hippocampus, following cessation of INO-1001 treatment (Figure 4).

Bottom Line: INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Neurology, Veterans Affairs Medical Center, San Francisco, California 94121, USA.

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.

Show MeSH
Related in: MedlinePlus