Abstract
Hydrogen sulfide (H2S) has been proposed as a novel neuromodulator and neuroprotective agent. Cobalt chloride (CoCl2) is a well-known hypoxia mimetic agent. We have demonstrated that H2S protects against CoCl2-induced injuries in PC12 cells. However, whether the members of mitogen-activated protein kinases (MAPK), in particular, extracellular signal-regulated kinase1/2(ERK1/2) and p38MAPK are involved in the neuroprotection of H2S against chemical hypoxia-induced injuries of PC12 cells is not understood. We observed that CoCl2 induced expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α), decreased cystathionine-β synthase (CBS, a synthase of H2S) expression, and increased generation of reactive oxygen species (ROS), leading to injuries of the cells, evidenced by decrease in cell viability, dissipation of mitochondrial membrane potential (MMP) , caspase-3 activation and apoptosis, which were attenuated by pretreatment with NaHS (a donor of H2S) or N-acetyl-L cystein (NAC), a ROS scavenger. CoCl2 rapidly activated ERK1/2, p38MAPK and C-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 or p38MAPK or JNK with kinase inhibitors (U0126 or SB203580 or SP600125, respectively) or genetic silencing of ERK1/2 or p38MAPK by RNAi (Si-ERK1/2 or Si-p38MAPK) significantly prevented CoCl2-induced injuries. Pretreatment with NaHS or NAC inhibited not only CoCl2-induced ROS production, but also phosphorylation of ERK1/2 and p38MAPK. Thus, we demonstrated that a concurrent activation of ERK1/2, p38MAPK and JNK participates in CoCl2-induced injuries and that H2S protects PC12 cells against chemical hypoxia-induced injuries by inhibition of ROS-activated ERK1/2 and p38MAPK pathways. Our results suggest that inhibitors of ERK1/2, p38MAPK and JNK or antioxidants may be useful for preventing and treating hypoxia-induced neuronal injury.
Highlights
Hydrogen sulfide (H2S) is a well- known cytotoxic gas
H2S protects astrocytes against H2O2-induced neural injury via suppressing extracellular signalregulated protein kinase1/2 (ERK1/2) activation [14]. These findings mentioned above suggest that the inhibition of ERK1/2 pathway or p38/Jun N-terminal kinase (JNK) pathways may be involved in H2S neuroprotective effect in different cell models. Whether both ERK1/2 and p38MAPK pathways participate in neuroprotection of H2S against chemical hypoxia-induced injury in PC12 cells is unclear
It is well documented that hypoxia/ischemia is one of the main causes of secondary neuronal injury because this condition results in the production of reactive oxygen species (ROS) which can attack nucleic acids, proteins
Summary
There is increasing evidence that it is an endogenously produced gaseous messenger and, in particular, serves as a novel neuromodulator in the central nervous system (CNS) [1,2]. H2S is usually stored as bound sulfane sulfur in neurons and astrocytes [3]. Upon neuron excitation or other stimuli, the bound sulfane sulfur releases free H2S. A more recent study indicated that the estimated physiological concentration (free concentration) of H2S in the mice brain was around 1463.0 nM [4] which is consistent with values reported by another group that tested H2S concentration using a novel method [3]. Physiological concentrations of H2S can potentiate the activity of the N-methyl-D-aspartate (NMDA) receptor and increase the induction of hippocampal long-term potentiation (LTP) [5,6], which is associated with learning and memory. H2S can induce calcium waves / elevation in both astrocytes and microglia [7,8]
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