Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice

Robert S.B. Clark, Vincent A. Vagni, Paula D. Nathaniel, Larry W. Jenkins, C. Edward Dixon, Csaba Szabó

    Research output: Contribution to journalArticle

    41 Scopus citations

    Abstract

    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 INO-1001 (1.6 mg/kg) or vehicle via intracerebral injection (5 μl 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.

    Original languageEnglish (US)
    Pages (from-to)1399-1405
    Number of pages7
    JournalJournal of neurotrauma
    Volume24
    Issue number8
    DOIs
    StatePublished - Aug 2007

    Keywords

    • Controlled cortical impact
    • Head injury
    • Ideno-isoquinolone
    • Nicotinamide adenine dinucleotide
    • Poly(ADP-ribose) synthetase

    ASJC Scopus subject areas

    • Clinical Neurology

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