Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.
Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.
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在药理学上增加的微管乙酰化校正了有机磷酸盐对神经元的应激效果。
DOI：
10.1111/tra.12489
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Baas PW
中科院分区：
文献类型：
--
作者：
Rao AN;Patil A;Brodnik ZD;Qiang L;España RA;Sullivan KA;Black MM;Baas PW
1990-1991年海湾战争的许多退伍军人感染了海湾战争病，这是一种主要影响神经系统的多症状疾病。在这里，我们用二异丙基氟磷酸盐（DFP）处理人类或大鼠神经元的培养物，DFP是沙林的类似物，沙林是退伍军人接触的有机磷毒物之一。所有观察到的DFP产生的细胞缺陷都因皮质酮或皮质醇的预处理而加剧，皮质酮或皮质醇分别在大鼠和人类神经元中，在我们的实验中用于模拟战争期间士兵所承受的身体压力。为了最好地模拟疾病，使用低于抑制乙酰胆碱酯酶所需水平的DFP。我们观察到乙酰化的微管蛋白与总微管蛋白的比率减少，这可以通过用微管蛋白酶（tubacin）治疗来纠正，微管蛋白酶是一种抑制HDAC 6（微管蛋白脱乙酰酶）的药物。微管乙酰化的减少与微管动力学的缺陷相结合，这可以通过HDAC 6抑制来纠正。线粒体转运和多巴胺释放的缺陷也得到改善。因此，毒物/应激暴露的各种负面影响至少部分可通过将微管乙酰化恢复到更正常的状态来纠正。这种方法可能对患有GWI或与有机磷暴露相关的其他神经系统疾病的个体具有治疗益处。
Many veterans of the 1990–1991 Gulf War contracted Gulf War Illness, a multi-symptom disease that primarily affects the nervous system. Here we treated cultures of human or rat neurons with diisopropylfluorophosphate (DFP), an analog of sarin, one of the organophosphate toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in the rat and human neurons respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to organophosphate exposure.
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DOI：
10.1124/jpet.115.230839
发表时间：
2016-03-01
影响因子：
3.5
作者：
Gao, Jie;Naughton, Sean X.;Terry, Alvin V., Jr.
通讯作者：
Terry, Alvin V., Jr.
影响因子：
5.1
作者：
Lockridge, Oksana;Schopfer, Lawrence M.
通讯作者：
Schopfer, Lawrence M.
DOI：
10.1523/jneurosci.3463-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Morfini GA;Burns M;Binder LI;Kanaan NM;LaPointe N;Bosco DA;Brown RH Jr;Brown H;Tiwari A;Hayward L;Edgar J;Nave KA;Garberrn J;Atagi Y;Song Y;Pigino G;Brady ST
通讯作者：
Brady ST
影响因子：
82.9
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
通讯作者：
Van Den Bosch, Ludo
影响因子：
3.4
作者：
Heaton, Kristin J.;Palumbo, Carole L.;White, Roberta F.
通讯作者：
White, Roberta F.