Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 73, Issue -, Pages 222-234Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2018.05.007
Keywords
H2S; Behavioral deficits; Glial activation; Synapse; Autophagy
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Funding
- National Natural Science Foundation of China [81671213, 81770436]
- Key Research and Development Foundation of Shandong Province [2017GSF218091]
- Natural Science Foundation of Shandong Province [ZR2016HM33]
- National Key Project of Chronic Non-Communicable Disease of China [2016YFC1300403]
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We previously reported that L-Cysteine, art 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(+)/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 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.T
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