Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress.
Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress.
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DOI：
10.1186/1742-2094-11-8
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发表时间：
2014-01-11
影响因子：
9.3
通讯作者：
Leza JC
中科院分区：
文献类型：
--
作者：
Gárate I;García-Bueno B;Madrigal JL;Caso JR;Alou L;Gómez-Lus ML;Leza JC
先天免疫反应是抵御微生物入侵的第一道防线，它也在不同的神经/神经退行性病理情况下被激活。因此，先天免疫 Toll 样受体 (TLR) 家族，特别是 TLR-4 信号通路的遗传/药理学操作成为一种潜在的治疗策略。越来越多的证据表明压力暴露与免疫反应改变有关，但 TLR-4 的确切作用仍然部分未知。本研究旨在阐明大鼠大脑额叶皮层急性应激暴露后TLR-4信号通路元件是否被激活，以及通过静脉注射TLR-4特异性抑制剂TAK-242对其进行药理调节在调节应激诱导的神经炎症反应中的作用。考虑到 TLR-4 主要对革兰氏阴性菌的脂多糖有反应，我们检查了肠道通透性增加和由此产生的细菌易位是否是应激诱导 TLR-4 激活的潜在调节机制。急性束缚应激暴露会在 mRNA 和蛋白质水平上调 TLR-4 表达。为减少胃肠道微生物群而制定的抗生素肠道净化方案可以防止应激诱导的 TLR-4 上调，这表明细菌易位在 TLR-4 信号通路激活中发挥着作用。 TAK-242 预应激给药可防止大鼠大脑额叶皮质中潜在有害的炎症和氧化/亚硝化介质的积累。 TAK-242或其他TLR-4信号通路抑制化合物的使用可被视为一种潜在的治疗辅助策略，以限制应激暴露后以及应激相关神经精神疾病中发生的炎症过程。
The innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown. The present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation. Acute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. The use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases.
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DOI：
10.1152/ajpgi.00328.2004
发表时间：
2005-05-01
影响因子：
4.5
作者：
Fukata, M;Michelsen, KS;Abreu, MT
通讯作者：
Abreu, MT
DOI：
10.1016/0885-4505(87)90035-1
发表时间：
1987-04-01
期刊：
BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY
影响因子：
--
作者：
DAS, NP;RATTY, AK
通讯作者：
RATTY, AK
影响因子：
15.1
作者：
Fleshner, Monika
通讯作者：
Fleshner, Monika
影响因子：
5
作者：
Kawamoto, Tomohiro;Ii, Masayuki;Kimura, Hiroyuki
通讯作者：
Kimura, Hiroyuki
影响因子：
2
作者：
Griffiths MR;Gasque P;Neal JW
通讯作者：
Neal JW