Poly(ADP-Ribose) polymerase-1 activation in a primate model of multiple sclerosis
Poly(ADP-Ribose) polymerase-1 activation in a primate model of multiple sclerosis
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DOI：
10.1002/jnr.20525
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发表时间：
2005-07-15
影响因子：
4.2
通讯作者：
Swanson, RA
中科院分区：
文献类型：
--
作者：
Kauppinen, TM;Suh, SW;Swanson, RA
多发性硬化症（MS）是一种免疫介导的致残性神经系统疾病，涉及炎症、脱髓鞘、轴突损伤和神经变性。聚ADP-核糖聚合酶-1（PARP-1）是一种与DNA修复相关的核酶，已被证明可通过与核因子-κ B相互作用来调节细胞炎症反应。广泛的PARP-1激活也可以通过不同的机制导致细胞死亡。大脑中的PARP-1激活发生在与氧化应激和DNA损伤相关的几种环境中，并且PARP-1抑制已显示出在这些环境中减轻炎症并改善神经元存活。在这里，我们研究了在非人灵长类动物模型的MS，绒猴（Callithrix jacchus）实验性过敏性脑脊髓炎（EAE）的PARP-1的激活模式。该模型的特征是人类MS典型的复发和缓解性局灶性脱髓鞘。对PARP-1的酶促产物聚（ADP-核糖）的免疫染色显示PARP-1在EAE脑的斑块区域特异性活化。在脱髓鞘EAE斑块周围的星形胶质细胞和分散在附近的小胶质细胞，少突胶质细胞和神经元中发现了强大的免疫染色。免疫染色还表明PARP-1在被小胶质细胞或浸润性外周血细胞包围的偶尔内皮细胞中活化。鉴于PARP-1在炎症和细胞死亡过程中的重要性，这些发现表明PARP-1活化可能是MS发病机制中的重要因素。
Multiple sclerosis (MS) is an immune-mediated disabling neurological disorder involving inflammation, demyelination, axonal damage, and neurodegeneration. Poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme linked to DNA repair, has been shown to regulate the cellular inflammatory response through interactions with nuclear factor-kappa B. Extensive PARP-1 activation can, by separate mechanisms, also cause cell death. PARP-1 activation in brain occurs in several settings associated with oxidative stress and DNA damage, and PARP-1 inhibition has been shown to attenuate inflammation and improve neuronal survival in these settings. Here we studied the pattern of PARP-1 activation in a nonhuman primate model of MS, marmoset (Callithrix jacchus) experimental allergic encephalomyelitis (EAE). Characteristic of this model is relapsing and remitting focal demyelination typical of human MS. Immunostaining for poly(ADP-ribose), the enzymatic product of PARP-1, showed PARP-1 activation specifically in plaque areas of EAE brains. Robust immunostaining was found in astrocytes surrounding demyelinated EAE plaques and in scattered nearby microglia, oligodendrocytes, and neurons. The immunostaining also suggested PARP-1 activation in occasional endothelial cells surrounded by microglia or infiltrating peripheral blood cells. Given the importance of PARP-1 in both inflammation and cell death processes, these findings suggest that PARP-1 activation may be a significant factor in the pathogenesis of MS. (c) 2005 Wiley-Liss, Inc.