l-Cysteine suppresses hypoxia-ischemia injury in neonatal mice by reducing glial activation, promoting autophagic flux and mediating synaptic modification via H2S formation.

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.

• 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
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 73 Pg. 222-234 (10 2018) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 29751053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Neuroprotective Agents
• Synaptophysin
• Syp protein, mouse
• Aminooxyacetic Acid
• Cysteine
• Hydrogen Sulfide

Topics

• Aminooxyacetic Acid (pharmacology)
• Animals
• Animals, Newborn
• Astrocytes (metabolism)
• Autophagy (drug effects)
• Cysteine (metabolism, pharmacology)
• Hydrogen Sulfide
• Hypoxia
• Hypoxia-Ischemia, Brain (drug therapy, metabolism)
• Mice
• Microglia (metabolism)
• Neuroglia (drug effects)
• Neuroprotective Agents (pharmacology)
• Synaptic Vesicles (drug effects)
• Synaptophysin (analysis)