Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: Dose-response relationships
Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: Dose-response relationships
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DOI：
10.1016/s0306-4522(02)00176-8
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发表时间：
2002-01-01
期刊：
影响因子：
3.3
通讯作者：
Abou-Donia, MB
中科院分区：
文献类型：
--
作者：
Abdel-Rahman, A;Shetty, AK;Abou-Donia, MB
我们假设单次接触 LD50 剂量的缎子会引起成人大脑广泛的早期神经病理变化。在这项研究中，我们评估了成人大脑在单次接触不同剂量的沙林后的早期变化。成年雄性大鼠以 1、0.5、0.1 和 0.0 1 x LD50 的剂量单次肌内注射，暴露于缎子。治疗后二十四小时，对经沙林治疗和媒介物治疗（对照）的动物进行以下分析：（i）血浆丁酰胆碱酯酶（BChE）活性； (ii) 脑乙酰胆碱酯酶 (AChE) 活性，(iii) m2 毒蕈碱乙酰胆碱受体 (m2 mAChR) 配体结合； (iv) 使用[H-3]碘化六甲铵摄取测定和内皮屏障抗原（EBA）免疫染色测定血脑屏障（BBB）通透性； (v) 使用 H&E 染色、微管相关蛋白 (MAP-2) 和胶质纤维酸性蛋白免疫染色观察大脑的组织病理学变化。在用 1 X LD50 沙林治疗的动物中，显着变化包括血浆 BChE 降低，大脑、脑干、中脑和小脑中的 AChE 降低，大脑中 m2 mAChR 配体结合减少，大脑、脑干、中脑和小脑中 BBB 通透性增加，与 EBA 表达减少相关，弥漫性神经元细胞死亡和 MAP-2 表达减少大脑皮层和海马体，以及小脑浦肯野神经元的变性。然而，用 0.5xLD(50) satin 处理的动物仅表现出一些变化，其中包括血浆 BChE 降低、中脑和脑干中 BBB 通透性增加但 EBA 表达没有降低，以及小脑中浦肯野神经元变性。相反，用 0.1 和 0.01 X LD50 治疗的动物没有表现出任何上述变化。然而，暴露于所有剂量的satin后，脑干中的m2 mAChR配体结合增加。总的来说，上述结果表明，急性暴露于沙林后的早期脑损伤明显具有剂量依赖性，并且暴露于1 X LD50沙林后早在暴露后24小时就在成年大鼠大脑的许多区域中引起有害变化。单剂量 1 X LD50 沙林后观察到的早期神经病理变化可能导致大脑许多区域发生深刻的长期神经退行性变化，并导致行为异常。 (C) 2002 国际广播组织。由爱思唯尔科学有限公司出版。保留所有权利。
We hypothesize that a single exposure to an LD50 dose of satin induces widespread early neuropathological changes in the adult brain. In this study, we evaluated the early changes in the adult brain after a single exposure to different doses of sarin. Adult male rats were exposed to satin by a single intramuscular injection at doses of 1, 0.5, 0.1 and 0.0 1 x LD50. Twenty-four hours after the treatment, both sarin-treated and vehicle-treated (controls) animals were analyzed for: (i) plasma butyrylcholinesterase (BChE) activity; (ii) brain acetylcholinesterase (AChE) activity, (iii) m2 muscarinic acetylcholine receptor (m2 mAChR) ligand binding; (iv) blood brain barrier (BBB) permeability using [H-3]hexamethonium iodide uptake assay and immunostaining for endothelial barrier antigen (EBA); and (v) histopathological changes in the brain using H&E staining, and microtubule-associated protein (MAP-2) and glial fibrillary acidic protein immunostaining. In animals treated with 1 X LD50 sarin, the significant changes include a decreased plasma BChE, a decreased AChE in the cerebrum, brainstem, midbrain and the cerebellum, a decreased m2 mAChR ligand binding in the cerebrum, an increased BBB permeability in the cerebrum, brainstem, midbrain and the cerebellum associated with a decreased EBA expression, a diffuse neuronal cell death and a decreased MAP-2 expression in the cerebral cortex and the hippocampus, and degeneration of Purkinje neurons in the cerebellum. Animals treated with 0.5xLD(50) satin however exhibited only a few alterations, which include decreased plasma BChE, an increased BBB permeability in the midbrain and the brain stem but without a decrease in EBA expression, and degeneration of Purkinje neurons in the cerebellum. In contrast, animals treated with 0.1 and 0.01 X LD50 did not exhibit any of the above changes. However, m2 mAChR ligand binding in the brainstem was increased after exposure to all doses of the satin.Collectively, the above results indicate that, the early brain damage after acute exposure to sarin is clearly dose-dependent, and that exposure to 1 X LD50 sarin induces detrimental changes in many regions of the adult rat brain as early as 24 hours after the exposure. The early neuropathological changes observed after a single dose of 1 X LD50 sarin could lead to a profound long-term neurodegenerative changes in many regions of the brain, and resulting behavioral abnormalities. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.