Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

• Published in: Biochemical and biophysical research communications 2011-11, Vol.414 (4), p.727-732
• Main Authors: Kurokawa, Yuko, Sekiguchi, Fumiko, Kubo, Satoko, Yamasaki, Yoshiko, Matsuda, Sachi, Okamoto, Yukari, Sekimoto, Teruki, Fukatsu, Anna, Nishikawa, Hiroyuki, Kume, Toshiaki, Fukushima, Nobuyuki, Akaike, Akinori, Kawabata, Atsufumi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APOPTOSIS; bcl-Associated Death Protein - biosynthesis; c-Jun amino-terminal kinase; CALCIUM; Calcium - metabolism; Calcium channels (T-type); Cell culture; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Condensation; Cortex; DEATH; Extracellular signal-regulated kinase; Fetal cortical neuron; Glutamic acid receptors (ionotropic); Hydrogen sulfide; Hydrogen sulfide (H2S); Hydrogen Sulfide - metabolism; HYDROGEN SULFIDES; MAP kinase; MAP Kinase Signaling System; MEK inhibitors; MICE; Mice, Inbred ICR; MITOCHONDRIA; N-Methyl-D-aspartic acid receptors; NERVE CELLS; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neurotoxicity; NITRIC OXIDE; Nitric-oxide synthase; Nuclear transport; PHOSPHORYLATION; RECEPTORS; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; SODIUM HYDRIDES; Src protein; Sulfides - toxicity; TOXICITY; TRANSLOCATION; TRYPAN BLUE; Up-Regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.09.144

► Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. ► Activation of ERK mediates the toxicity of hydrogen sulfide. ► Apoptotic mechanisms are involved in the hydrogen-induced cell death. Hydrogen sulfide (H2S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H2S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H2S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.