Castoldi Anna F, Coccini Teresa, Randine Giovanna, Hernández-Viadel Mariluz, Felipo Vicente, Manzo Luigi
Toxicology Division, IRCCS Salvatore Maugeri Foundation, Institute of Pavia, Via Ferrata 8, 27100 Pavia, Italy.
Life Sci. 2006 Mar 20;78(17):1915-24. doi: 10.1016/j.lfs.2005.08.032. Epub 2005 Nov 8.
Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neurotoxicity. The early and delayed effects of repeated and acute in vivo CO inhalation were investigated on COX activity, cGMP formation and MR binding in rat brain and lymphocytes to assess whether each endpoint was similarly affected both centrally and peripherally. Male Wistar rats either inhaled 500 ppm CO, 6 h/day, 5 days/week, 4 weeks (repeated exposure) or 2,400 ppm, 1 h (single exposure). Neither treatment altered brain or lymphocyte COX activity 1 and 7 days post-treatment. Also ineffective were repeated and acute CO treatments towards (3)H-quinuclidinyl benzilate (QNB) binding to MRs in cerebral cortex, hippocampus, striatum, cerebellum (respective controls, mean+/-S.D.: 171 +/- 45, 245 +/- 53, 263 +/- 14 and 77 +/- 7 fmol/mg protein) and lymphocytes (24 +/- 10 fmol/million cells) at the same time points. In lymphocytes control cGMP levels averaged 1.98 +/- 0.99 pmol/mg protein under basal conditions, and 3.94 +/- 0.55 pmol/mg protein after NO-stimulation. One day after chronic treatment cessation, the CO-treated group displayed about a 50% decrease in both basal and NO-stimulated cGMP values, which persisted up to 7 days after, compared to air-exposed rats. Acutely, CO caused a delayed enhancement (+140%) of NO-induced activation of soluble guanylate cyclase. The finding that the NO-cGMP pathway is a target for the delayed effects of CO in peripheral blood cells is in accordance with our data in brain [Hernández-Viadel, M., Castoldi, A.F., Coccini, T., Manzo, L., Erceg, S., Felipo, V., 2004. In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum. Journal of Neurochemistry 89, 1,157-1,165], and supports the use of this peripheral endpoint as a biomarker of CO central effects.
据报道，急性暴露于一氧化碳（CO）的啮齿动物大脑细胞色素氧化酶（COX）活性、一氧化氮（NO）-环磷酸鸟苷（cGMP）途径及胆碱能毒蕈碱受体（MRs）会发生变化。淋巴细胞中可测量的这些指标可能作为CO神经毒性的外周标志物。研究了重复和急性体内吸入CO对大鼠脑和淋巴细胞中COX活性、cGMP形成及MR结合的早期和延迟效应，以评估每个指标在中枢和外周是否受到相似影响。雄性Wistar大鼠要么吸入500 ppm CO，每天6小时，每周5天，共4周（重复暴露），要么吸入2400 ppm，1小时（单次暴露）。两种处理在处理后1天和7天均未改变脑或淋巴细胞的COX活性。重复和急性CO处理对（3）H-喹核醇基苯甲酸酯（QNB）与大脑皮层、海马体、纹状体、小脑（各自对照，平均值±标准差：171±45、245±53、263±14和77±7 fmol/mg蛋白质）及淋巴细胞（24±10 fmol/百万细胞）中MRs的结合在相同时间点也无效果。在淋巴细胞中，基础条件下对照cGMP水平平均为1.98±0.99 pmol/mg蛋白质，NO刺激后为3.94±0.55 pmol/mg蛋白质。慢性处理停止1天后，与空气暴露大鼠相比，CO处理组基础和NO刺激的cGMP值均下降约50%，这种情况一直持续到7天后。急性情况下，CO导致NO诱导的可溶性鸟苷酸环化酶激活延迟增强（+140%）。NO-cGMP途径是CO在外周血细胞中产生延迟效应的靶点这一发现与我们在脑中的数据一致[埃尔南德斯-维亚德尔，M.，卡斯托迪，A.F.，科奇尼，T.，曼佐，L.，埃尔采格，S.，费利波，V.，2004年。体内暴露于一氧化碳导致大鼠脑皮层和小脑中一氧化氮对可溶性鸟苷酸环化酶激活的延迟损伤。《神经化学杂志》89，1157 - 1165页]，并支持将这个外周指标用作CO中枢效应的生物标志物。
