期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 24, 期 18, 页码 10402-10419出版社
WILEY
DOI: 10.1111/jcmm.15654
关键词
inflammation; ischaemic stroke; melatonin; oxidative stress; Toll-like receptors
资金
- Chang Gung Memorial Hospital [CMRPG8H0061]
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 (SCB6), SCTLR4-/-, ISB6, ISTLR4-/-, ISB6 + Mel (i.p. daily administration) and ISTLR4-/-+ Mel (i.p. daily administration). By day 28 after IS, the protein expressions of inflammatory (HMBG1/TLR2/TLR4/MAL/MyD88/RAM TRIF/TRAF6/IKK-alpha/p-NF-kappa B/nuclear-NF-kappa B/nuclear-IRF-3&7/IL-1 beta/IL-6/TNF-alpha/IFN-gamma) 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 ISB6, lowest in groups SC(B6)and SCTLR4-/-, lower in group ISTLR4-/-+ Mel than in groups IS(TLR4-/-)and ISB6 + Mel and lower in group ISB6 + Mel than in group ISTLR4-/-(allP < .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 (allP < .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.
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