Acute Molecular Perturbation of Inducible Nitric Oxide Synthase with an Antisense Approach Enhances Neuronal Preservation and Functional Recovery after Contusive Spinal Cord Injury
Acute Molecular Perturbation of Inducible Nitric Oxide Synthase with an Antisense Approach Enhances Neuronal Preservation and Functional Recovery after Contusive Spinal Cord Injury
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DOI：
10.1089/neu.2012.2371
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发表时间：
2012-08-01
影响因子：
4.2
通讯作者：
Pearse, Damien D.
中科院分区：
文献类型：
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作者：
Maggio, Dominic M.;Chatzipanteli, Katina;Pearse, Damien D.
诱导型一氧化氮合酶 (iNOS) 是病理条件下产生的炎症和氧化应激的关键介质，包括神经退行性疾病和中枢神经系统 (CNS) 损伤。 iNOS 负责形成高水平的一氧化氮 (NO)。高活性和细胞毒性 NO 物质（例如过氧亚硝酸盐）的产生在继发性组织损伤中发挥着重要作用。我们之前已经证明，中度挫伤性脊髓损伤（SCI）后3小时急性施用iNOS反义寡核苷酸（ASO）可有效抑制iNOS介导的NO水平增加，导致血液脊髓屏障通透性降低、中性粒细胞积累减少和神经元细胞死亡减少。在当前的研究中，我们调查了 iNOS ASO 是否也可以在中度胸部 18 挫伤性 SCI 后提供长期（10 周）组织学和行为改善。成年大鼠被随机分为三组（n = 10/组）：单独 SCI、SCI 和混合碱基对照寡核苷酸 (MBO) 或 SCI 和 iNOS ASO (200 nM)。损伤后3小时通过脊髓灌注施用寡核苷酸。 SCI 后 10 周内每周进行行为分析（Basso-Beattie-Bresnahan [BBB] 评分和子评分）。尽管用 iNOS ASO 治疗的动物与对照组相比，BBB 评分没有显着差异，但子评分分析显示足部定位、躯干稳定性和尾部间隙有显着改善。组织学上，虽然未观察到保留的白质和灰质的总体改善，但 iNOS ASO 处理的动物中，与对照组相比，在病变部位附近存在更多数量的存活神经元。这些结果支持急性靶向 iNOS 作为 SCI 后治疗方法的有效性。
Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation and oxidative stress produced during pathological conditions, including neurodegenerative diseases and central nervous system (CNS) injury. iNOS is responsible for the formation of high levels of nitric oxide (NO). The production of highly reactive and cytotoxic NO species, such as peroxynitrite, plays an important role in secondary tissue damage. We have previously demonstrated that acute administration of iNOS antisense oligonucleotides (ASOs) 3 h after moderate contusive spinal cord injury (SCI) potently inhibits iNOS-mediated increases in NO levels, leading to reduced blood spinal cord barrier permeability, decreased neutrophil accumulation, and less neuronal cell death. In the current study we investigated if iNOS ASOs could also provide long-term (10-week) histological and behavioral improvements after moderate thoracic 18 contusive SCI. Adult rats were randomly assigned to three groups (n = 10/group): SCI alone, SCI and mixed base control oligonucleotides (MBOs), or SCI and iNOS ASOs (200 nM). Oligonucleotides were administered by spinal superfusion 3 h after injury. Behavioral analysis (Basso-Beattie-Bresnahan [BBB] score and subscore) was employed weekly for 10 weeks post-SCI. Although animals treated with iNOS ASOs demonstrated no significant differences in BBB scores compared to controls, subscore analysis revealed a significant improvement in foot positioning, trunk stability, and tail clearance. Histologically, while no gross improvement in preserved white and gray matter was observed, greater numbers of surviving neurons were present adjacent to the lesion site in iNOS ASO-treated animals than controls. These results support the effectiveness of targeting iNOS acutely as a therapeutic approach after SCI.