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 H 2 S 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 + /CD45 high 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 H 2 S-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 H 2 S.