Hydrogen sulfide protects PC12 cells against reactive oxygen species             and extracellular signal-regulated kinase 1/2-mediated downregulation of glutamate             transporter-1 expression induced by chemical hypoxia.
Hypoxia and/or ischemia are implicated in neurodegenerative disorders. In these diseases, hypoxia/ischemia may induce oxidative stress, including production of reactive oxygen species (ROS), which result in a decrease in glutamate transporter expression. Hydrogen sulfide (H2S), as the third gasotransmitter, has neuroprotective effects and potent antioxidant properties. In the present study, we investigated the role of glutamate transporter-1 (GLT-1) in the protection of H2S against chemical hypoxia-induced injury in PC12 cells. We found that cobalt chloride (CoCl2), a chemical hypoxia agent, reduced the expression of GLT-1 in a time-dependent manner. Pretreatment with NaHS (a donor of H2S) reversed the CoCl2-induced downregulation of GLT-1 expression. Pretreatment with DHK (a selective inhibitor of GLT-1) for 30 min prior to NaHS preconditioning significantly inhibited the cytoprotection of H2S against CoCl2-induced injuries, leading to an increase in cytotoxicity and apoptosis as well as to a loss of mitochondrial membrane potential (MMP). In addition, we found that similar to the effect of NaHS, pretreatment with NAC (a ROS scavenger) or U0126 (a MEK1/2 inhibitor) blocked the downregulation of GLT-1 expression induced by CoCl2. Collectively, we demonstrated for the first time that ROS and extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated reduction of GLT-1 expression may be involved in chemical hypoxia-induced neural injury and that H2S attenuates this injury partly by upregulating GLT-1 expression in PC12 cells.
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, PR China.
Liangcan
L
Xiao
Aiping
A
Lan
Liqiu
L
Mo
Wenming
W
Xu
Nan
N
Jiang
Fen
F
Hu
Jianqiang
J
Feng
Changran
C
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D003035:Cobalt; C020889:dihydrokainic acid; D048049:Extracellular Signal-Regulated MAP Kinases; C018021:cobaltous chloride; D007608:Kainic Acid; D006862:Hydrogen Sulfide