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SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer's Disease-Like Pathology in OXYS Rats.
Antioxidants ( IF 6.0 ) Pub Date : 2020-07-28 , DOI: 10.3390/antiox9080676
Natalia A Muraleva 1 , Natalia A Stefanova 1 , Nataliya G Kolosova 1, 2
Affiliation  

Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable, and mitogen-activated protein kinase (MAPK) p38 is implicated in the pathogenesis of AD. p38 MAPK inhibition is considered a promising strategy against AD, but there are no safe inhibitors capable of penetrating the blood–brain barrier. Earlier, we have shown that mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) at nanomolar concentrations can prevent, slow down, or partially alleviate AD-like pathology in accelerated-senescence OXYS rats. Here we confirmed that dietary supplementation with SkQ1 during active progression of AD-like pathology in OXYS rats (aged 12–18 months) suppresses AD-like pathology progression, and for the first time, we showed that its effects are associated with suppression of p38 MAPK signaling pathway (MAPKsp) activity. Transcriptome analysis, western blotting, and immunofluorescent staining revealed that SkQ1 suppresses p38 MAPKsp activity in the hippocampus at the level of expression of genes involved in the p38 MAPKsp and reduces the phosphorylation of intermediate kinases (p38 MAPK and MK2) and a downstream protein (αB-crystallin). Thus, the anti-AD effects of SkQ1 are associated with improvement in the functioning of relevant signaling pathways and intracellular processes, thus making it a promising therapeutic agent for human AD.

中文翻译:

SkQ1抑制了OXYS大鼠的阿尔茨海默氏病样病理学涉及的p38 MAPK信号通路。

阿尔茨海默氏病(AD)是最常见的痴呆类型,目前无法治愈,促分裂原激活蛋白激酶(MAPK)p38与AD的发病机制有关。p38 MAPK抑制被认为是抗AD的有前途的策略,但尚无能够穿透血脑屏障的安全抑制剂。早些时候,我们已经表明,纳摩尔浓度的针对线粒体的抗氧化剂质体醌基-癸基三苯基phosph(SkQ1)可以预防,减缓或部分缓解加速衰老的OXYS大鼠的AD样病理。在这里,我们证实,在OXYS大鼠(年龄为12-18个月)的AD样病理活跃发展过程中,通过饮食补充SkQ1可以抑制AD样病理发展,这是第一次,我们证明其作用与抑制p38 MAPK信号通路(MAPKsp)活性有关。转录组分析,蛋白质印迹和免疫荧光染色显示,SkQ1在参与p38 MAPKsp的基因表达水平抑制海马中的p38 MAPKsp活性,并减少中间激酶(p38 MAPK和MK2)和下游蛋白(αB)的磷酸化-crystallin)。因此,SkQ1的抗AD作用与相关信号通路和细胞内过程的功能改善有关,因此使其成为人AD的有希望的治疗剂。免疫荧光染色显示,SkQ1在参与p38 MAPKsp的基因表达水平抑制海马中的p38 MAPKsp活性,并减少中间激酶(p38 MAPK和MK2)和下游蛋白(αB-crystallin)的磷酸化。因此,SkQ1的抗AD作用与相关信号通路和细胞内过程的功能改善有关,因此使其成为人AD的有希望的治疗剂。免疫荧光染色表明,SkQ1在参与p38 MAPKsp的基因表达水平抑制海马中的p38 MAPKsp活性,并减少中间激酶(p38 MAPK和MK2)和下游蛋白(αB-crystallin)的磷酸化。因此,SkQ1的抗AD作用与相关信号通路和细胞内过程的功能改善有关,因此使其成为人AD的有希望的治疗剂。
更新日期:2020-07-28
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