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
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
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DOI：
10.1089/neu.2007.0305
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Szabo, Csaba
中科院分区：
文献类型：
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作者：
Clark, Robert S. B.;Vagni, Vincent A.;Szabo, Csaba
聚（ADP-核糖）聚合酶-1 (PARP-1) 是一种酶，因其在 DNA 修复中的作用以及作为 NAD(+) 耗竭和能量衰竭诱导的细胞死亡的介质而闻名。我们测试了强效选择性艾代异喹诺酮 PARP-1 抑制剂 INO-1001 在小鼠受控皮质冲击 (CCI) 后的效果。对麻醉的成年雄性小鼠进行中度 CCI（速度 6 m/sec，深度 1.2 mm）或假损伤。 CCI或假损伤小鼠立即以随机方式通过脑内注射（5μl，5分钟内）接受INO1001（1.6mg/kg）或媒介物。 2小时后，解剖挫伤的脑组织并测量NAD(+)水平。单独的小鼠接受了神经病理学结果测试，包括空间记忆获取（莫里斯水迷宫第14-20天），以及第21天挫伤体积和海马细胞死亡的评估。CCI后2小时用INO-1001局部治疗保留了大脑NAD（+）水平（车辆= 67 +/- 7.6，INO-1001 = 95.8 +/- 4.4%未受伤半球；n = 6/组，p = 0.03）。在 Morris 水迷宫中，与 CCI 后的车辆相比，使用 INO-1001 进行治疗可缩短寻找隐藏平台的潜伏期，并增加在目标象限中花费的时间（n = 11/组，p
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