Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8960736 | Brain, Behavior, and Immunity | 2018 | 52 Pages |
Abstract
We previously reported that l-Cysteine, an H2S donor, significantly alleviated brain injury after hypoxia-ischemic (HI) injury in neonatal mice. However, the mechanisms underlying this neuroprotective effect of l-Cysteine against HI insult remain unknown. In the present study, we tested the hypothesis that the protective effects of l-Cysteine are associated with glial responses and autophagy, and l-Cysteine attenuates synaptic injury as well as behavioral deficits resulting from HI. Consistent with our previous findings, we found that treatment with l-Cysteine after HI reduced early brain injury, improved behavioral deficits and synaptic damage, effects which were associated with an up-regulation of synaptophysin and postsynaptic density protein 95 expression in the lesioned cortex. l-Cysteine attenuated the accumulation of CD11b+/CD45high cells, activation of microglia and astrocytes and diminished HI-induced increases in reactive oxygen species and malondialdehyde within the lesioned cortex. In addition, l-Cysteine increased microtubule associated protein 1 light chain 3-II and Beclin1 expression, decreased p62 expression and phosphor-mammalian target of rapamycin and phosphor-signal transducer and activator of transcription 3. Further support for a critical role of l-Cysteine was revealed from results demonstrating that treatment with an inhibitor of the H2S-producing enzyme, amino-oxyacetic acid, reversed the beneficial effects of l-Cysteine described above. These results demonstrate that l-Cysteine effectively alleviates HI injury and improves behavioral outcomes by inhibiting reactive glial responses and synaptic damage and an accompanying triggering of autophagic flux. Accordingly, l-Cysteine may provide a new a therapeutic approach for the treatment of HI via the formation of H2S.
Keywords
RT-PCRPSD-95STAT3RIPAPFAPMSFHBSSCBSDAPITTCAOAALC3-IImTORGFAPCD86H2S3-MSTcluster of differentiation 86MDAphenylmethane-sulfonyl fluoride3-mercaptopyruvate sulfurtransferase4,6-diamidino-2-phenylindoled-amino acid oxidaseHanks balanced salt solutionIba-1ROSAutophagyaminooxyacetic acidinterleukintumor necrosis factor-αDAOCNSpostnatal dayradioimmunoprecipitation assayHydrogen sulfideCystathionine β synthasecentral nervous systemSynaptophysinSynTNF-αGlial activationmalondialdehydesignal transducer and activator of transcription 3ionized calcium binding adaptor molecule-1Behavioral deficitsNORTmammalian target of rapamycinSynapsehypoxic-ischemicreverse transcription–polymerase chain reactionNovel Object Recognition taskparaformaldehydeGlial fibrillary acidic proteinpostsynaptic density protein 95Reactive oxygen species
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Authors
Danqing Xin, Xili Chu, Xuemei Bai, Weiwei Ma, Hongtao Yuan, Jie Qiu, Changxing Liu, Tong Li, Xin Zhou, Wenqiang Chen, Dexiang Liu, Zhen Wang,