title: Involvement of K(ATP)/PI (3)K/AKT/Bcl-2 pathway in hydrogen sulfide-induced neuroprotection against the toxicity of 1-methy-4-phenylpyridinium ion.
abstract: We previously reported that hydrogen sulfide (H(2)S) produces protection in PC12 cells during 1-methy-4-phenylpyridinium ion (MPP(+)) challenge. The present study aims to clarify the mechanisms underlying the neuroprotective effects of H(2)S. We showed that both glybenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker, and LY294002, a specific PI(3)K-AKT pathway inhibitor, reversed the neuroprotective effect of NaHS (a H(2)S donor) against MPP(+)-induced cytotoxicity to PC12 cells and that NaHS up-regulated the activity of AKT in PC12 cells, which was abolished by blockade of K(ATP) channels with glybenclamide. In addition, NaHS up-regulated the expression of Bcl-2 and blocked MPP(+)-induced down-regulation of Bcl-2, and this augmentation of Bcl-2 expression was prevented by both glybenclamide and LY294002. These data provided the evidence that the neuroprotective action of H(2)S against MPP(+) toxicity to PC12 cells is via the K(ATP)/PI(3)K/AKT/Bcl-2 pathway. We also demonstrated that NaHS attenuated the inhibitory effect of MPP(+) ERK1/2 activation in PC12 cells, whereas U0126, a specific MEK inhibitor, did not reverse the neuroprotective effect of NaHS, which indicated that attenuating MPP(+)-triggered down-regulation of ERK1/2 activation is involved in the protection of H(2)S against MPP(+) neurotoxicity, but ERK1/2 is not an essential effector mediating the neuroprotective effect of H(2)S. In conclusion, the present observations identify a crucial role of the K(ATP)/PI(3)K/AKT/Bcl-2 pathway in H(2)S-exerted neuroprotection against the toxicity of MPP(+). Findings from the present study will help shed light on the mechanisms of H(2)S-elicited neuroprotective effects on MPP(+) toxicity.
authors.affiliation: Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, 421001, People's Republic of China. txq01001@gmail.com
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Tang
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhuang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Fan
authors.forename: Heng-Rong
authors.initials: HR
authors.lastname: Fang
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Bi
authors.initials: B
authors.lastname: Hu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D066298:In Vitro Techniques; D054086:KATP Channels / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020267:MPTP Poisoning / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D002070:Butadienes; D005905:Glyburide; D006862:Hydrogen Sulfide; D054086:KATP Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C113580:U 0126; C494920:Akt1 protein, rat