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
| Autor: | Csaba Szabó, Larry W. Jenkins, Paula D. Nathaniel, C. Edward Dixon, Robert S. B. Clark, Vincent Vagni |
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| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Programmed cell death Indoles Traumatic brain injury Morris water navigation task Water maze Injections Intralesional Poly(ADP-ribose) Polymerase Inhibitors Nicotinamide adenine dinucleotide Poly (ADP-Ribose) Polymerase Inhibitor Mice chemistry.chemical_compound Memory Internal medicine medicine Animals Maze Learning chemistry.chemical_classification NAD medicine.disease Mice Inbred C57BL Enzyme Endocrinology chemistry Brain Injuries Anesthesia Neurology (clinical) NAD+ kinase |
| Zdroj: | Journal of Neurotrauma. 24:1399-1405 |
| ISSN: | 1557-9042 0897-7151 |
| Popis: | 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, por = 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. |
| Databáze: | OpenAIRE |
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