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

J Neurotrauma. 2007 Aug;24(8):1399-405. doi: 10.1089/neu.2007.0305.


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 microl 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 < or = 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Brain Injuries / psychology*
  • Indoles / administration & dosage
  • Indoles / pharmacology*
  • Injections, Intralesional
  • Male
  • Maze Learning / drug effects*
  • Memory / drug effects
  • Mice
  • Mice, Inbred C57BL
  • NAD / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors*


  • INO 1001
  • Indoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • NAD