Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

Abstract

Endogenously produced hydrogen sulfide (H2S) may have multiple functions in the brain including potent anti-inflammatory effects. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic injuries in the developing brain. The aim of this study is to investigate the potential role of H2S in altering hypoxia-induced neurotoxicity via its anti-inflammatory actions as examined in vitro and in vivo models. Using the BV-2 microglial cell line, we found that sodium hydrosulfide (NaHS), a H2S donor, significantly inhibited hypoxia-induced microglial activation and suppressed subsequent pro-inflammatory factor release. In addition, treating murine primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, an effect that was reversed by CM treated with NaHS. Further, NaHS inhibited phosphorylation of the p65 subunit of NF-κB, phosphorylation of ERK and p38 but not JNK MAPK in these hypoxia-induced microglia. When administered in vivo to neonatal mice subjected to hypoxia, NaHS was found to attenuate neuron death, an effect that was associated with suppressed microglial activation, pro-inflammatory cytokines and NO levels. Taken together, H2S exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effect in microglia. This effect appears to be attributable to inhibition of iNOS, NF-κB, ERK and p38 MAPK signaling pathways. Our results suggest a potential therapeutic application of H2S releasing drugs in hypoxic brain damage treatment.

• Authors: Qun Zhang, Lin Yuan, Dexiang Liu, Jianmei Wang, Shuanglian Wang, Qingrui Zhang, Yanfen Gong, Hongda Liu, Aijun Hao, Zhen Wang
• Journal: Pharmacological research (Pharmacol Res) Vol. 84 Pg. 32-44 (Jun 2014) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 24788079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Mitogen-Activated Protein Kinases
• Hydrogen Sulfide

Topics

• Animals
• Cell Survival (drug effects)
• Hydrogen Sulfide (pharmacology)
• Hypoxia (metabolism, prevention & control)
• Interleukin-6 (metabolism)
• Macrophage Activation (drug effects)
• Mice
• Mice, Inbred BALB C
• Microglia (drug effects)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Neurons (drug effects)
• Nitric Oxide (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)