PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.
PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.
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DOI：
10.1371/journal.pone.0134482
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fusco FR
中科院分区：
文献类型：
--
作者：
Cardinale A;Paldino E;Giampà C;Bernardi G;Fusco FR
聚（ADP-核糖）聚合酶1（PARP-1）是一种核酶，参与DNA修复，基因组稳定性和凋亡等生理过程。此外，已发表的研究表明，在某些病理条件下，PARP-1介导坏死细胞死亡，以响应过度的DNA损伤。在亨廷顿病的大脑中，神经元和神经胶质细胞中描述了PARP免疫反应性，从而表明HD中涉及细胞凋亡。在这项研究中，我们试图确定PARP-1抑制剂是否在R6/2突变小鼠中发挥神经保护作用，这在许多方面与人类HD相似。从4周龄开始，每天用PARP-1抑制剂INO-1001 mg/Kg处理转基因小鼠。经心脏灌注后，进行组织学和免疫组织化学研究。我们发现，INO 1001治疗的R6/2小鼠存活时间更长，神经功能障碍的症状比溶媒治疗的小鼠更轻。主要结果指标如纹状体萎缩、纹状体神经元形态、神经元核内包涵体和小胶质细胞反应证实了该化合物的神经保护作用。INO-1001有效地显著增加纹状体棘神经元中激活的CREB和BDNF，这可能是在该模型中观察到的有益效果的原因。我们的研究结果表明，PARP-1抑制可以被认为是HD的有效治疗方法。
Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington’s disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.