Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters
Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters
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DOI：
10.1016/j.taap.2011.07.017
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发表时间：
2011-11-01
影响因子：
3.8
通讯作者：
Abou-Donia, M. B.
中科院分区：
文献类型：
--
作者：
Damodaran, T. V.;Attia, M. K.;Abou-Donia, M. B.
有机磷酯诱导的迟发性神经毒性(OPIDN)是一种神经退行性疾病，其特征是共济失调进展为瘫痪，并伴有中枢性和外周性、远端轴突无力。氟化二异丙基磷(DFP)在鸡体内产生OPIDN，在7-14天内导致轻度共济失调，随着疾病的发展，单次注射会导致严重瘫痪。用生理盐水中的阿托品(1 mg/kg，sc)和二甲基亚砜中的eserine(1 mg/kg，sc)进行预防处理后，再用DFP(1.7 mg/kg，sc)处理来航蛋母鸡。对照组给予车用丙二醇组(0.1ml/kg，sc)、生理盐水中的阿托品和二甲基亚砜中的艾司林。分别于第1、2、5、10、20d处死母鸡，取大脑、中脑、小脑、脑干、脊髓组织，快速解剖，冰冻，用于mRNA(Northern)研究。用BCL2、GADD45、β肌动蛋白和28S RNA进行Northern杂交，研究它们的表达模式。另一组母鸡被处理了一系列的时间点，并用磷酸盐缓冲盐水和固定剂进行组织学研究。采用苏木精-伊红(H&E)、Sevier-Munger、Cresyl echt Violet(尼氏物质染色)、Gallocynin染色(尼氏颗粒染色)等多种染色方法评价细胞死亡和退行性改变的不同模式。神经元和轴突的变性可能涉及复杂的细胞死亡机制。这些数据表明BCL2(抗凋亡基因)和GADD45(DNA损伤诱导基因)在不同组织中的表达发生了变化和差异。易感区域(脊髓和小脑)比抵抗区域(大脑)的细胞死亡和其他退行性变化增加，可能是通过改变bcl2和GADD45基因表达而导致细胞存活和细胞死亡机制之间的动态平衡失衡。半定量分析显示，损伤的严重程度从脊髓-小脑、腹侧和背侧分别递减，提示神经解剖学上的特异性。因此，细胞死亡和细胞存活过程的早期激活可能在OPIDN的临床进展和综合征临床表现中起重要作用。由爱思唯尔公司出版。
Organophosphorus-ester induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by ataxia progressing to paralysis with a concomitant central and peripheral, distal axonapathy. Diisopropylphosphorofluoridate (DFP) produces OPIDN in the chicken that results in mild ataxia in 7-14 days and severe paralysis as the disease progresses with a single dose. White leghorn layer hens were treated with DFP (1.7 mg/kg, sc) after prophylactic treatment with atropine (1 mg/kg, sc) in normal saline and eserine (1 mg/kg, sc) in dimethyl sulfoxide. Control groups were treated with vehicle propylene glycol (0.1 ml/kg, sc), atropine in normal saline and eserine in dimethyl sulfoxide. The hens were euthanized at different time points such as 1, 2, 5, 10 and 20 days, and the tissues from cerebrum, midbrain, cerebellum, brainstem and spinal cord were quickly dissected and frozen for mRNA (northern) studies. Northern blots were probed with BCL2, GADD45, beta actin, and 28S RNA to investigate their expression pattern. Another set of hens was treated for a series of time points and perfused with phosphate buffered saline and fixative for histological studies. Various staining protocols such as Hematoxylin and Eosin (H & E); Sevier-Munger; Cresyl echt Violet for Nissl substance; and Gallocynin stain for Nissl granules were used to assess various patterns of cell death and degenerative changes. Complex cell death mechanisms may be involved in the neuronal and axonal degeneration. These data indicate altered and differential mRNA expressions of BCL2 (anti apoptotic gene) and GADD45 (DNA damage inducible gene) in various tissues. Increased cell death and other degenerative changes noted in the susceptible regions (spinal cord and cerebellum) than the resistant region (cerebrum), may indicate complex molecular pathways via altered BCL2 and GADD45 gene expression, causing the homeostatic imbalance between cell survival and cell death mechanisms. Semi quantitative analysis revealed that the order of severity of damage declines from the spino-cerebellar, ventral, and dorsal tract respectively, suggesting neuroanatomical specificity. Thus, early activation of cell death and cell survival processes may play significant role in the clinical progression and syndromic clinical feature presentation of OPIDN. Published by Elsevier Inc.