Effect of Acute Poly(ADP-Ribose) Polymerase Inhibition by 3-AB on Blood-Brain Barrier Permeability and Edema Formation after Focal Traumatic Brain Injury in Rats
Effect of Acute Poly(ADP-Ribose) Polymerase Inhibition by 3-AB on Blood-Brain Barrier Permeability and Edema Formation after Focal Traumatic Brain Injury in Rats
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DOI：
10.1089/neu.2009.1188
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发表时间：
2010-06-01
影响因子：
4.2
通讯作者：
Marchand-Leroux, Catherine
中科院分区：
文献类型：
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作者：
Lescot, Thomas;Fulla-Oller, Laurence;Marchand-Leroux, Catherine
最近的证据支持基质金属蛋白酶-9（MMP-9）在创伤性脑损伤（TBI）后血脑屏障（BBB）破坏和血管源性水肿形成中的关键作用。虽然TBI后MMP-9上调的确切原因尚未完全了解，但有几种论点表明，聚（ADP-核糖）聚合酶（PARP）在导致MMP-9活化的神经炎症反应中起作用。本研究的目的是评价3-氨基苯甲酰胺（3-AB）抑制PARP的作用（1）对MMP-9上调和BBB完整性的影响，（2）对水肿形成的影响（通过磁共振成像（MRI）评估），（3）对神经元存活的影响（通过H-1磁共振波谱（H-1-MRS）评估），以及（4）对TBI急性期神经功能缺损的影响。Western印迹和酶谱显示，钝化MMP-9上调后6小时TBI。与溶剂处理的大鼠相比，3-AB处理的大鼠在同一时间点的BBB通透性降低。脑MRI显示TBI后6小时，3-AB治疗组大鼠的“游离”水少于溶媒治疗组大鼠。TBI后24小时的MRI结果表明主要的细胞毒性水肿，在这个时间点，没有发现3-AB-和溶剂处理的大鼠之间的MMP-9上调，BBB通透性，或MRI的变化有显着差异。在6和24小时，3-AB处理的大鼠的神经功能优于溶剂处理的大鼠。这些数据表明，PARP抑制3-AB保护BBB对MMP-9上调诱导的高通透性，从而减少血管源性水肿形成后6小时TBI。此外，我们的数据证实了3-AB在TBI的非常急性期的神经保护作用。
Recent evidence supports a crucial role for matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) disruption and vasogenic edema formation after traumatic brain injury (TBI). Although the exact causes of MMP-9 upregulation after TBI are not fully understood, several arguments suggest a contribution of the enzyme poly(ADP-ribose) polymerase (PARP) in the neuroinflammatory response leading to MMP-9 activation. The objectives of this study were to evaluate the effect of PARP inhibition by 3-aminobenzamide (3-AB) (1) on MMP-9 upregulation and BBB integrity, (2) on edema formation as assessed by magnetic resonance imaging (MRI), (3) on neuron survival as assessed by H-1 magnetic resonance spectroscopy (H-1-MRS), and (4) on neurological deficits at the acute phase of TBI. Western blots and zymograms showed blunting of MMP-9 upregulation 6 h after TBI. BBB permeability was decreased at the same time point in 3-AB-treated rats compared to vehicle-treated rats. Cerebral MRI showed less "free" water in 3-AB-treated than in vehicle-treated rats 6 h after TBI. MRI findings 24 h after TBI indicated predominant cytotoxic edema, and at this time point no significant differences were found between 3-AB-and vehicle-treated rats with regard to MMP-9 upregulation, BBB permeability, or MRI changes. At both 6 and 24 h, neurological function was better in the 3-AB-treated than in the vehicle-treated rats. These data suggest that PARP inhibition by 3-AB protected the BBB against hyperpermeability induced by MMP-9 upregulation, thereby decreasing vasogenic edema formation 6 h after TBI. Furthermore, our data confirm the neuroprotective effect of 3-AB at the very acute phase of TBI.