Open AccessMelatonin against acute ischaemic stroke dependently via suppressing both inflammatory and oxidative stress downstream signallings
Author(s) -
Chen KuanHung,
Lin KunChen,
Ko SheungFat,
Chiang John Y.,
Guo Jun,
Yip HonKan
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15654
Subject(s) - tlr4 , oxidative stress , trif , inflammation , endocrinology , medicine , proinflammatory cytokine , chemistry , pharmacology , biology , receptor , innate immune system , toll like receptor
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.