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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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Effect of INO-1001 treatment on forelimb dexterity. Rats were subjected to TBI or sham surgery, and were treated with INO-1001 or vehicle for 12 days beginning 1 day after surgery. Behavioral assessments were made 8 weeks after TBI. (A) Time to remove an adhesive tape from the contralateal forelimb was markedly increased by TBI, and this time was reduced in the animals treated with INO-1001. n = 6-9; *P < 0.05. (B) Scoring of vermicelli test results. n = 6-9. *P < 0.05, P **P < 0.01, #P < 0.05 vs. sham, vehicle-treated.
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Figure 6: Effect of INO-1001 treatment on forelimb dexterity. Rats were subjected to TBI or sham surgery, and were treated with INO-1001 or vehicle for 12 days beginning 1 day after surgery. Behavioral assessments were made 8 weeks after TBI. (A) Time to remove an adhesive tape from the contralateal forelimb was markedly increased by TBI, and this time was reduced in the animals treated with INO-1001. n = 6-9; *P < 0.05. (B) Scoring of vermicelli test results. n = 6-9. *P < 0.05, P **P < 0.01, #P < 0.05 vs. sham, vehicle-treated.

Mentions: Studies using the initial TBI protocol showed no detectable forelimb dysfunction at the 8 week post-injury time point (data not shown). Consequently, a second study was performed using increased impactor depth and dwell time. Rats were subjected to either TBI or sham TBI, and treated with either vehicle or INO-1001 on post-surgery days 1 through 13 (12 days of treatment). Forelimb dexterity was evaluated 8 weeks after TBI using the cylinder test, the sticky tape test, and the vermicelli test. The cylinder test again showed no effect of TBI on paw preference (not shown). However, the sticky tape test showed a large increase in time taken to remove tape applied to the right forepaw in the TBI rats, and this increase was significantly attenuated in rats treated with INO-100 (Figure 6A). Similarly, the vermicelli test, which is sensitive to deficits in fine coordination of the forepaws, showed abnormalities in several parameters in the TBI rats, and these were also attenuated by INO-1001 treatment (Figure 6B). Other parameters of the vermicelli test evaluated (head tilt, single paw use, and total feeding time, and total number of pauses) showed no significant difference between TBI and sham surgery groups and were therefore not included in the composite score analysis. Evaluation of the brains after behavioral testing (11 weeks after TBI) showed lesion cavity size to be not significantly different in the vehicle and INO-treated groups; 39.7 ± 3.1 and 43.7 ± 1.8 mm3, respectively.


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)

Effect of INO-1001 treatment on forelimb dexterity. Rats were subjected to TBI or sham surgery, and were treated with INO-1001 or vehicle for 12 days beginning 1 day after surgery. Behavioral assessments were made 8 weeks after TBI. (A) Time to remove an adhesive tape from the contralateal forelimb was markedly increased by TBI, and this time was reduced in the animals treated with INO-1001. n = 6-9; *P < 0.05. (B) Scoring of vermicelli test results. n = 6-9. *P < 0.05, P **P < 0.01, #P < 0.05 vs. sham, vehicle-treated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Effect of INO-1001 treatment on forelimb dexterity. Rats were subjected to TBI or sham surgery, and were treated with INO-1001 or vehicle for 12 days beginning 1 day after surgery. Behavioral assessments were made 8 weeks after TBI. (A) Time to remove an adhesive tape from the contralateal forelimb was markedly increased by TBI, and this time was reduced in the animals treated with INO-1001. n = 6-9; *P < 0.05. (B) Scoring of vermicelli test results. n = 6-9. *P < 0.05, P **P < 0.01, #P < 0.05 vs. sham, vehicle-treated.
Mentions: Studies using the initial TBI protocol showed no detectable forelimb dysfunction at the 8 week post-injury time point (data not shown). Consequently, a second study was performed using increased impactor depth and dwell time. Rats were subjected to either TBI or sham TBI, and treated with either vehicle or INO-1001 on post-surgery days 1 through 13 (12 days of treatment). Forelimb dexterity was evaluated 8 weeks after TBI using the cylinder test, the sticky tape test, and the vermicelli test. The cylinder test again showed no effect of TBI on paw preference (not shown). However, the sticky tape test showed a large increase in time taken to remove tape applied to the right forepaw in the TBI rats, and this increase was significantly attenuated in rats treated with INO-100 (Figure 6A). Similarly, the vermicelli test, which is sensitive to deficits in fine coordination of the forepaws, showed abnormalities in several parameters in the TBI rats, and these were also attenuated by INO-1001 treatment (Figure 6B). Other parameters of the vermicelli test evaluated (head tilt, single paw use, and total feeding time, and total number of pauses) showed no significant difference between TBI and sham surgery groups and were therefore not included in the composite score analysis. Evaluation of the brains after behavioral testing (11 weeks after TBI) showed lesion cavity size to be not significantly different in the vehicle and INO-treated groups; 39.7 ± 3.1 and 43.7 ± 1.8 mm3, respectively.

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