This study tested the hypothesis that melatonin (Mel) therapy preserved the brain architectural and functional integrity against ischaemic stroke (IS) dependently through suppressing the inflammatory/oxidative stress downstream signalling pathways. Adult male B6 (n = 6 per each B6 group) and TLR4 knockout (ie TLR4^−/−) (n = 6 per each TLR4^−/− group) mice were categorized into sham control (SC^B6), SC^TLR4−/−, IS^B6, IS^TLR4−/−, IS^B6 + Mel (i.p. daily administration) and IS^TLR4−/− + Mel (i.p. daily administration). By day 28 after IS, the protein expressions of inflammatory (HMBG1/TLR2/TLR4/MAL/MyD88/RAM TRIF/TRAF6/IKK‐α/p‐NF‐κB/nuclear‐NF‐κB/nuclear‐IRF‐3&7/IL‐1β/IL‐6/TNF‐α/IFN‐γ) and oxidative stress (NOX‐1/NOX‐2/ASK1/p‐MKK4&7/p‐JNK/p‐c‐JUN) downstream pathways as well as mitochondrial‐damaged markers (cytosolic cytochrome C/cyclophilin D/SRP1/autophagy) were highest in group IS^B6, lowest in groups SC^B6 and SC^TLR4−/−, lower in group IS^TLR4−/− + Mel than in groups IS^TLR4−/− and IS^B6 + Mel and lower in group IS^B6 + Mel than in group IS^TLR4−/− (all P < .0001). The brain infarct volume, brain infarct area and the number of inflammatory cells in brain (CD14/F4‐88) and in circulation (MPO+//Ly6C+/CD11b+//Ly6G+/CD11b+) exhibited an identical pattern, whereas the neurological function displayed an opposite pattern of inflammatory protein expression among the six groups (all P < .0001). In conclusion, TLR inflammatory and oxidative stress signallings played crucial roles for brain damage and impaired neurological function after IS that were significantly reversed by Mel therapy.

中文翻译：

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褪黑素可通过抑制下游信号传导中的炎症和氧化应激，来抵抗急性缺血性中风。

这项研究验证了褪黑激素（Mel）治疗通过抑制下游炎症信号/氧化应激信号通路依赖于缺血性卒中（IS）的作用，从而保留了大脑的结构和功能完整性的假设。成年男性B6（每个B6组n = 6）和TLR4敲除（即，TLR4 ^{- / -} ）（每组n = 6每个TLR4 ^{- / -}组）小鼠分为假控制（SC ^B6），SC ^{TLR4 - / -}，IS ^B6，IS ^TLR4-/-，IS ^B6  + Mel（每日IP给药）和IS ^TLR4-/-+梅尔（每日IP给药）。IS后第28天，炎症蛋白（HMBG1 / TLR2 / TLR4 / MAL / MyD88 / RAM TRIF / TRAF6 / IKK‐α / p‐NF‐κB / nuclear‐NF‐κB / nuclear‐IRF‐3＆7 / IL的蛋白表达-1β/ IL-6 /TNF-α/IFN-γ）和氧化应激（NOX-1 / NOX-2 / ASK1 / p-MKK4＆7 / p-JNK / pc-JUN）下游途径以及线粒体IS ^B6组中受损的标志物（胞质细胞色素C /亲环素D / SRP1 /自噬）最高，SC ^B6和SC ^TLR4-/-组最低，IS ^TLR4-/- + Mel组低于IS ^{TLR4- / -}和IS ^B6  + Mel，在IS ^B6  + Mel组中低于在IS ^{TLR4-/-组中}（所有P <.0001）。脑梗死体积，脑梗塞面积和大脑中（CD14 / F4-88）和循环中（MPO + // Ly6C + / CD11b + // Ly6G + / CD11b +）的炎症细胞数量呈现出相同的模式，而神经功能表现为六组中炎症蛋白表达的相反模式（所有P  <.0001）。总之，TLR炎性和氧化应激信号在IS后脑损伤和神经功能受损中起关键作用，而梅尔疗法可逆转这种信号。