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首页> 外文期刊>BMC Neuroscience >Evidence for oxidative stress in the developing cerebellum of the rat after chronic mild carbon monoxide exposure (0.0025% in air)
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Evidence for oxidative stress in the developing cerebellum of the rat after chronic mild carbon monoxide exposure (0.0025% in air)

机译：慢性轻度一氧化碳暴露（空气中0.0025％）后大鼠发育中小脑氧化应激的证据

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Background The present study was designed to test the hypothesis that chronic very mild prenatal carbon monoxide (CO) exposure (25 parts per million) subverts the normal development of the rat cerebellar cortex. Studies at this chronic low CO exposure over the earliest periods of mammalian development have not been performed to date. Pregnant rats were exposed chronically to CO from gestational day E5 to E20. In the postnatal period, rat pups were grouped as follows: Group A: prenatal exposure to CO only; group B: prenatal exposure to CO then exposed to CO from postnatal day 5 (P5) to P20; group C: postnatal exposure only, from P5 to P20, and group D, controls (air without CO). At P20, immunocytochemical analyses of oxidative stress markers, and structural and functional proteins were assessed in the cerebellar cortex of the four groups. Quantitative real time PCR assays were performed for inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) nitric oxide synthases. Results Superoxide dismutase-1 (SOD1), SOD2, and hemeoxygenase-1 (HO-1) immunoreactivity increased in cells of the cerebellar cortex of CO-exposed pups. INOS and nitrotyrosine immunoreactivity also increased in blood vessels and Purkinje cells (PCs) of pups from group-A, B and C. By contrast, nNOS immunoreactivity decreased in PCs from group-B. Endothelial NOS immunoreactivity showed no changes in any CO-exposed group. The mRNA levels for iNOS were significantly up-regulated in the cerebellum of rats from group B; however, mRNA levels for nNOS and eNOS remained relatively unchanged in groups A, B and C. Ferritin-H immunoreactivity increased in group-B. Immunocytochemistry for neurofilaments (structural protein), synapsin-1 (functional protein), and glutamic acid decarboxylase (the enzyme responsible for the synthesis of the inhibitory neurotransmitter GABA), were decreased in groups A and B. Immunoreactivity for two calcium binding proteins, parvalbumin and calbindin, remained unchanged. The immunoreactivity of the astrocytic marker GFAP increased after prenatal exposure. Conclusion We conclude that exogenously supplied CO during the prenatal period promotes oxidative stress as indicated by the up-regulation of SOD-1, SOD-2, HO-1, Ferritin-H, and iNOS with increased nitrotyrosine in the rat cerebella suggesting that deleterious and protective mechanisms were activated. These changes correlate with reductions of proteins important to cerebellar function: pre-synaptic terminals proteins (synapsin-1), proteins for the maintenance of neuronal size, shape and axonal quality (neurofilaments) and protein involved in GABAergic neurotransmission (GAD). Increased GFAP immunoreactivity after prenatal CO-exposure suggests a glial mediated response to the constant presence of CO. There were differential responses to prenatal vs. postnatal CO exposure: Prenatal exposure seems to be more damaging; a feature exemplified by the persistence of markers indicating oxidative stress in pups at P20, following prenatal only CO-exposure. The continuation of this cellular environment up to day 20 after CO exposure suggests the condition is chronic. Postnatal exposure without prenatal exposure shows the least impact, whereas prenatal followed by postnatal exposure exhibits the most pronounced outcome among the groups.
机译：背景技术本研究旨在检验以下假设，即长期非常轻微的产前一氧化碳（CO）暴露量（百万分之25）会颠覆大鼠小脑皮质的正常发育。迄今为止，尚未在哺乳动物发育的最早阶段对这种慢性低CO暴露进行研究。从妊娠第5天到E20，怀孕的大鼠长期暴露于CO。在出生后，将幼鼠分为以下几组：A组：产前仅暴露于CO; B组：产前暴露于CO，然后从产后第5天（P5）至P20暴露于CO; C组：仅产后暴露，从P5至P20，D组为对照组（空气中不含CO）。在P20时，对四组小脑皮质的氧化应激标记物以及结构和功能蛋白进行免疫细胞化学分析。对诱导型（iNOS），神经元（nNOS）和内皮（eNOS）一氧化氮合酶进行了实时定量PCR分析。结果暴露于CO的幼仔的小脑皮层细胞中的超氧化物歧化酶-1（SOD1），SOD2和血氧合酶-1（HO-1）免疫反应性增加。 A组，B组和C组幼犬的血管和Purkinje细胞（PC）中的INOS和硝基酪氨酸免疫反应性也增加。相反，B组中PC的nNOS免疫反应性降低。内皮NOS免疫反应性在任何CO暴露组中均无变化。 B组大鼠小脑中iNOS的mRNA水平明显上调;然而，A，B和C组中nNOS和eNOS的mRNA水平相对保持不变。B组中铁蛋白H免疫反应性增加。 A和B组中神经丝（结构蛋白），突触蛋白1（功能蛋白）和谷氨酸脱羧酶（负责合成抑制性神经递质GABA的酶）的免疫细胞化学降低。两种钙结合蛋白，小白蛋白的免疫反应性和钙结合蛋白保持不变。产前暴露后星形细胞标记物GFAP的免疫反应性增加。结论我们得出的结论是，在产前阶段，外源供应的CO促进了氧化应激，这通过大鼠小脑中SOD-1，SOD-2，HO-1，铁蛋白H和iNOS的上调以及硝基酪氨酸的增加而表明，这表明有害和保护机制被激活。这些变化与对小脑功能重要的蛋白质减少有关：突触前末端蛋白质（synapsin-1），维持神经元大小，形状和轴突质量的蛋白质（神经丝）以及与GABA能神经传递（GAD）有关的蛋白质。产前CO暴露后GFAP免疫反应性增加表明对持续存在CO的神经胶质介导的反应。产前与产后CO暴露的反应不同：产前暴露似乎更具破坏性。仅在产前仅进行CO暴露后，P20上的幼犬的氧化应激持续存在，标志着这一特征。这种细胞环境持续到暴露于CO后的第20天，表明该病是慢性的。在没有产前暴露的情况下，产后暴露的影响最小，而在产后再进行产后暴露的人群中，结果最为明显。

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