Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species.
Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species.
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七氟醚暴露可通过细胞内活性氧种类的增加，诱导发育中大脑中 DNA 损伤引发的神经元细胞死亡
DOI：
10.3389/fncel.2020.583782
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发表时间：
2020
影响因子：
5.3
通讯作者：
Feng C
中科院分区：
文献类型：
--
作者：
Piao M;Wang Y;Liu N;Wang X;Chen R;Qin J;Ge P;Feng C
由于挥发性麻醉剂对发育中的大脑具有潜在的神经毒性，其在婴幼儿中的安全性已引起越来越多的关注。神经元死亡被认为是吸入七氟醚后发育神经毒性的主要因素，但其机制仍不清楚。副酒精症是一种新型的程序性细胞死亡，由DNA损伤引起的多聚腺苷二磷酸核糖聚合酶1(PARP-1)过度激活所致，是多种神经系统疾病的发病机制之一。然而，肝素在七氟醚诱导的新生儿神经细胞死亡中的作用尚未被研究。用2%、4%、8%七氟醚处理神经细胞6、12、24 h，以及出生后第7天2.5%七氟醚处理6 h。结果发现，七氟醚可致大鼠神经细胞死亡，并伴有PARP-1过度激活、胞浆聚合ADP-核糖(PAR)积聚、线粒体去极化和凋亡诱导因子(AIF)核移位。药物或遗传抑制PAPR-1可明显减轻七氟醚诱导的神经细胞死亡、PAR聚合体积聚和AIF核移位，符合肝病的特点。我们在体外和体内观察到，由于8-羟基脱氧鸟苷(8-OHdG)和组蛋白变异体H_2AX(γH_2AX)的磷酸化水平增加，七氟醚暴露导致了DNA损伤。此外，我们检测到七氟醚暴露与细胞内活性氧(ROS)的过量产生有关。用抗氧化剂NAC抑制ROS可明显减轻七氟醚所致的DNA损伤，提示ROS参与了七氟醚所致DNA损伤的调节。此外，七氟醚暴露导致肝素相关蛋白表达上调和神经细胞死亡，这一结果可被NAC预处理显著减弱。因此，这些结果表明，七氟醚可通过增加细胞内ROS水平，诱导发育中脑组织DNA损伤所致的神经细胞甲胎反应。
The safety of volatile anesthetics in infants and young children has been drawing increasing concern due to its potential neurotoxicity in the developing brain. Neuronal death is considered a major factor associated with developmental neurotoxicity after exposure to volatile anesthetics sevoflurane, but its mechanism remains elusive. Parthanatos, a new type of programmed cell death, resulting from poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation in response to DNA damage, was found to account for the pathogenesis of multiple neurological disorders. However, the role of Parthanatos in sevoflurane-induced neonatal neuronal cell death has not been investigated. To test it, neuronal cells treated with 2, 4, and 8% sevoflurane for 6, 12, and 24 h and postnatal day 7 rats exposed to 2.5% sevoflurane for 6 h were used in the present study. Our results found sevoflurane exposure induced neuronal cell death, which was accompanied by PARP-1 hyperactivation, cytoplasmic polymerized ADP-ribose (PAR) accumulation, mitochondrial depolarization, and apoptosis-inducing factor (AIF) nuclear translocation in the neuronal cells and hippocampi of rats. Pharmacological or genetic inhibition of PAPR-1 significantly alleviated sevoflurane-induced neuronal cell death and accumulation of PAR polymer and AIF nuclear translocation, which were consistent with the features of Parthanatos. We observed in vitro and in vivo that sevoflurane exposure resulted in DNA damage, given that 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylation of histone variant H2AX (γH2AX) were improved. Moreover, we detected that sevoflurane exposure was associated with an overproduction of intracellular reactive oxygen species (ROS). Inhibition of ROS with antioxidant NAC markedly alleviated DNA damage caused by sevoflurane, indicating that ROS participated in the regulation of sevoflurane-induced DNA damage. Additionally, sevoflurane exposure resulted in upregulation of Parthanatos-related proteins and neuronal cell death, which were significantly attenuated by pretreatment with NAC. Therefore, these results suggest that sevoflurane exposure induces neuronal cell Parthanatos initiated by DNA damage in the developing brain via the increase of intracellular ROS.
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DOI：
10.1126/science.aat8407
发表时间：
2018-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kam TI;Mao X;Park H;Chou SC;Karuppagounder SS;Umanah GE;Yun SP;Brahmachari S;Panicker N;Chen R;Andrabi SA;Qi C;Poirier GG;Pletnikova O;Troncoso JC;Bekris LM;Leverenz JB;Pantelyat A;Ko HS;Rosenthal LS;Dawson TM;Dawson VL
通讯作者：
Dawson VL
DOI：
10.1016/j.jtcvs.2016.03.095
发表时间：
2016-08
期刊：
The Journal of thoracic and cardiovascular surgery
影响因子：
--
作者：
Diaz LK;Gaynor JW;Koh SJ;Ittenbach RF;Gerdes M;Bernbaum JC;Zackai EH;Clancy RR;Rehman MA;Pennington JW;Burnham N;Spray TL;Nicolson SC
通讯作者：
Nicolson SC
影响因子：
9.8
作者：
Alvarado, M. C.;Murphy, K. L.;Baxter, M. G.
通讯作者：
Baxter, M. G.
影响因子：
5.8
作者：
Chiu, Ling-Ya;Ho, Feng-Ming;Lin, Wan-Wan
通讯作者：
Lin, Wan-Wan
影响因子：
2.9
作者：
Haddad, Marianne;Beray-Berthat, Virginie;Margaill, Isabelle
通讯作者：
Margaill, Isabelle