Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.
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.
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Qun
Q
Zhang
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Lin
L
Yuan
Department of Medical Psychology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Dexiang
D
Liu
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Jianmei
J
Wang
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Shuanglian
S
Wang
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Qingrui
Q
Zhang
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Yanfen
Y
Gong
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Hongda
H
Liu
Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
Aijun
A
Hao
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China; Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, PR China. Electronic address: wangzhen@sdu.edu.cn.
Zhen
Z
Wang
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D006862:Hydrogen Sulfide
Hydrogen sulfide; Hypoxia; Microglial activation; Neurotoxicity; Nuclear factor κB