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Pentobarbital and other anesthetic agents induce opposite regulations of MAP kinases p-MEK and p-ERK, and upregulate p-FADD/FADD neuroplastic index in brain during hypnotic states in mice.
Neurochemistry international ( IF 4.2 ) Pub Date : 2018-11-10 , DOI: 10.1016/j.neuint.2018.11.008
Glòria Salort 1 , María Álvaro-Bartolomé 1 , Jesús A García-Sevilla 1
Affiliation  

Midazolam and ketamine-induced anesthesia were recently shown to induce a disruption of MEK/ERK sequential phosphorylation with parallel upregulation of p-FADD in the mouse brain. The present study was designed to assess whether other structurally diverse anesthetic agents (pentobarbital, ethanol, chloral hydrate, isoflurane) also impair brain p-MEK to p-ERK signal and increase p-FADD during the particular time course of 'sleep' in mice. Pentobarbital (50 mg/kg)-, ethanol (4000 mg/kg)-, chloral hydrate (400 mg/kg)-, and isoflurane (2% in O2)-induced anesthesia (range: 24-60 min) were associated with unaltered or increased p-MEK1/2 (up to +155%) and decreased p-ERK1/2 (up to -60%) contents, revealing disruption of MEK to ERK activation in mouse brain cortex. These anesthetic agents also upregulated cortical p-FADD (up to +110%), but not total FADD (moderately decreased), which resulted in increased neuroplastic/survival p-FADD/FADD ratios (up to +2.8 fold). The inhibition of pentobarbital metabolism with SKF525-A (a cytochrome P450 inhibitor) augmented barbiturate anesthesia (2.6 times) and induced a greater and sustained upregulation of p-MEK with p-ERK downregulation, as well as prolonged increases of p-FADD content and p-FADD/FADD ratio (effects lasting for more than 240 min). Pentobarbital also upregulated significantly the cortical contents of other markers of neuroplasticity such as the ERK inhibitor p-PEA-15 (up to +46%), the transcription factor NF-κB (up to +27%) and the synaptic density protein PSD-95 (up to +20%) during 'sleep'. The results reveal a paradoxical stimulation of p-MEK without the concomitant (canonical) activation of p-ERK (e.g. with pentobarbital and isoflurane), for which various molecular mechanisms are discussed. The downregulation of brain p-ERK may participate in the manifestations of adverse effects displayed by most hypnotic/anesthetic agents in clinical use (e.g. amnesia).

中文翻译:

戊巴比妥和其他麻醉剂在小鼠的催眠状态下诱导MAP激酶p-MEK和p-ERK的相反调节,并上调脑中的p-FADD / FADD神经塑性指数。

最近显示咪达唑仑和氯胺酮诱导的麻醉可诱导MEK / ERK顺序磷酸化的破坏,并在小鼠脑中同时平行上调p-FADD。本研究旨在评估其他结构多样的麻醉剂(戊巴比妥,乙醇,水合氯醛,异氟烷)是否也在小鼠“睡眠”的特定时间段内损害脑p-MEK的p-ERK信号并增加p-FADD。 。戊巴比妥(50 mg / kg)-,乙醇(4000 mg / kg)-,水合氯醛(400 mg / kg)-和异氟烷(O2中为2%)诱导的麻醉(范围:24-60分钟)与p-MEK1 / 2含量不变或升高(最高+155%),p-ERK1 / 2含量降低(最高-60%),揭示了MEK对小鼠大脑皮层ERK激活的破坏。这些麻醉剂还上调了皮质p-FADD(最高+ 110%),但并非总FADD(适度降低),导致神经增生/存活p-FADD / FADD比值增加(高达+2.8倍)。SKF525-A(一种细胞色素P450抑制剂)对戊巴比妥代谢的抑制作用增强了巴比妥酸盐麻醉(2.6倍),并诱导p-MEK更大而持续地上调,同时p-ERK下调,并延长了p-FADD含量和p-FADD / FADD比率(效果持续超过240分钟)。戊巴比妥还显着上调了其他神经可塑性标记的皮质含量,例如ERK抑制剂p-PEA-15(最高+ 46%),转录因子NF-κB(最高+ 27%)和突触密度蛋白PSD- “睡眠”期间为95(最高+ 20%)。结果表明,p-MEK受到反常的刺激,而没有同时激活p-ERK(例如)(戊巴比妥和异氟烷),讨论了各种分子机制。脑p-ERK的下调可能参与大多数催眠药/麻醉药在临床使用(例如健忘症)中表现出的不良反应。
更新日期:2018-11-10
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