Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats
Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats
复制标题
DOI：
10.1038/sj.jcbfm.9600437
复制
发表时间：
2007-07-01
影响因子：
6.3
通讯作者：
Busija, David W.
中科院分区：
文献类型：
--
作者：
Lenzser, Gabor;Kis, Bela;Busija, David W.
核酶聚（ADP-核糖）聚合酶（PARP）由氧化应激激活，在缺血后脑损伤中发挥重要作用。我们评估了 PARP 激活对缺血再灌注后血脑屏障 (BBB) 破坏和水肿形成的影响。在雄性 Wistar 大鼠中，通过闭塞颈动脉并降低动脉血压 20 分钟来实现全脑缺血。用盐水或PARP抑制剂N-(6-氧代-5,6-二氢菲啶-2-yi)-N,N-二甲基乙酰胺.HCl(PJ34)治疗动物；缺血前（10mg/kg，静脉注射）。再灌注40分钟、24小时和48小时后，给予伊文思蓝(EB)和荧光素钠(NaF)后测定皮质BBB的通透性。还测量了大脑的含水量。与再灌注 24 和 48 小时后的非缺血动物相比，缺血再灌注后 BBB 对 EB 的通透性增加，但 PARP 抑制在 48 小时减弱了这种增加（非缺血：170 +/- 9，盐水：760 +/- 95，PJ34：472 +/- 61 ng/mg 组织）。 NaF 的外渗表现出类似的变化，PJ34 处理后甚至在 24 小时时也减弱了渗透性的增加。 PARP 抑制减少了 48 小时时观察到的脑水肿。由于 PARP 具有促炎特性，因此测定了皮质的中性粒细胞浸润，在 PJ34 治疗后显示出较低的值。此外，PJ34 处理减少了 24 小时和 48 小时紧密连接蛋白 occludin 的损失。 PARP 活性的抑制伴随着缺血后 BBB 紊乱的减少和水肿形成的减少，表明该酶在脑血管功能障碍的发展中发挥着重要作用。
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yi)-N, N-dimethylacetamide.HCl (PJ34); (10mg/kg, i.v.) before ischemia. After 40mins, 24, and 48h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170 +/- 9, saline: 760 +/- 95, PJ34: 472 +/- 61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24h. PARP inhibition decreased the brain edema seen at 48h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction.