Journal
JOURNAL OF NEUROTRAUMA
Volume 24, Issue 8, Pages 1399-1405Publisher
MARY ANN LIEBERT INC
DOI: 10.1089/neu.2007.0305
Keywords
controlled cortical impact; head injury; ideno-isoquinolone; nicotinamide adenine dinucleotide; poly(ADP-ribose) synthetase
Funding
- NINDS NIH HHS [R44 NS37985, R01 NS38620, P50 NS30318] Funding Source: Medline
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Poly( ADP-ribose) polymerase-1 (PARP-1) is an enzyme best known for its role in DNA repair and as a mediator of NAD(+) depletion and energy failure- induced cell death. We tested the effect of the potent and selective ideno-isoquinolone PARP-1 inhibitor INO-1001 after controlled cortical impact (CCI) in mice. Anesthetized adult male mice were subjected to moderate CCI ( velocity 6 m/sec, depth 1.2 mm) or sham-injury. Immediately after CCI or sham-injury mice received either INO1001 (1.6 mg/kg) or vehicle via intracerebral injection (5 mu l over 5 min) in a randomized fashion. At 2 h, contused brain tissue was dissected and NAD(+) levels were measured. Separate mice underwent neuropathological outcome tests that included spatial memory acquisition ( Morris water maze days 14 - 20), and assessment of contusion volume and hippocampal cell death at day 21. Local treatment with INO-1001 preserved brain NAD(+) levels 2 h after CCI (vehicle = 67 +/- 7.6, INO-1001 = 95.8 +/- 4.4% uninjured hemisphere; n = 6/group, p = 0.03). In the Morris water maze, treatment with INO-1001 reduced the latency to find the hidden platform and increased the time spent in the target quadrant versus vehicle after CCI (n = 11/group, p <= 0.05). Histological damage did not differ between vehicle and INO-1001-treated mice after CCI. Treatment with INO-1001 prevented NAD(+) depletion and improved outcome, although modestly, identifying PARP-mediated energy failure as a contributor to the pathological sequelae of TBI. Further study testing the effects of PARP inhibitors is warranted, specifically in models of brain injury where energy failure is seen.
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