4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration.
4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration.
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DOI：
10.1016/j.neuro.2014.06.001
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发表时间：
2014-09
期刊：
影响因子：
3.4
通讯作者：
Eterovic, Vesna A.
中科院分区：
文献类型：
--
作者：
Ferchmin, P. A.;Andino, Myrna;Salaman, Rebeca Reyes;Alves, Janaina;Velez-Roman, Joyce;Cuadrado, Brenda;Carrasco, Marimee;Torres-Rivera, Wilmarie;Segarra, Annabell;Martins, Antonio Henrique;Lee, Jae Eun;Eterovic, Vesna A.
关键词：
许多用于工业、农业或战争应用的有机磷酯对乙酰胆碱酯酶具有不可逆转的抑制作用，这些化合物的急性中毒会导致危及生命的胆碱能过度刺激。在使用阿托品、肟类和苯二氮卓类药物进行经典的紧急治疗后，幸存的受害者通常会遭受脑神经退化。目前，还没有药物治疗来预防这种脑损伤。在这里，我们显示了一种环状二萜类化合物(1S，2E，4R，6R，7E，11E)-cembra-2，7，11-triene-4，6-diol(4R)可以改善二异丙基氟磷酸盐(DFP)引起的海马区CA1区损伤。DFP经常被用作战争神经毒剂沙林的替代品。在老鼠身上，DFP在导致大脑损伤的剂量下是致命的。因此，为了观察幸存者的脑损伤，预先给予外周作用解毒剂吡斯的明和甲基阿托品或其类似物异丙托品来降低死亡率。分别以0.1 mg/kg、20 mg/kg、23 mg/kg的剂量肌肉注射吡斯的明、硝酸甲基阿托品和异丙托品。DFP(9 mg/kg)冷水溶液腹腔注射。4R(6 mg/kg)溶于DMSO，于DFP前1h或DFP后5h或24h皮下注射。用荧光素B和氨基铜银染色评价神经退行性变；用激活的星形胶质细胞标志物巢蛋白的表达来评价神经炎症反应。给药48小时后，在给药前或给药后给药，4R可使死亡神经元数量减半。4R还可显著减少活化星形胶质细胞的数量。这些数据表明，4R是一种很有前途的新药，它可以在经典的对抗性治疗之后，通过实施第二阶段干预来改变有机磷化合物急性中毒的治疗模式。
Many organophosphorous esters synthesized for applications in industry, agriculture, or warfare irreversibly inhibit acetylcholinesterase, and acute poisoning with these compounds causes life-threatening cholinergic overstimulation. Following classical emergency treatment with atropine, an oxime, and a benzodiazepine, surviving victims often suffer brain neurodegeneration. Currently, there is no pharmacological treatment to prevent this brain injury. Here we show that a cyclic diterpenoid, (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) ameliorates the damage caused by diisopropylfluorophosphate (DFP) in the hippocampal area CA1. DFP has been frequently used as a surrogate for the warfare nerve agent sarin. In rats, DFP is lethal at the dose used to cause brain damage. Therefore, to observe brain damage in survivors, the death rate was reduced by pre-administration of the peripherally acting antidotes pyridostigmine and methyl atropine or its analogue ipratropium. Pyridostigmine bromide, methyl atropine nitrate, and ipratropium bromide were dissolved in saline and injected intramuscularly at 0.1 mg/kg, 20 mg/kg, and 23 mg/kg, respectively. DFP (9 mg/kg) dissolved in cold water was injected intraperitoneally. 4R (6 mg/kg) dissolved in DMSO was injected subcutaneously, either 1 hour before or 5 or 24 hours after DFP. Neurodegeneration was assessed with Fluoro-Jade B and amino cupric silver staining; neuroinflammation was measured by the expression of nestin, a marker of activated astrocytes. Forty-eight hours after DFP administration, 4R decreased the number of dead neurons by half when injected before or after DFP. 4R also significantly decreased the number of activated astrocytes. These data suggest that 4R is a promising new drug that could change the therapeutic paradigm for acute poisoning with organophosphorous compounds by the implementation of a second-stage intervention after the classical countermeasure treatment.
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影响因子：
5.8
作者：
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通讯作者：
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