title: The D₁ dopamine receptor agonist, SKF83959, attenuates hydrogen peroxide-induced injury in RGC-5 cells involving the extracellular signal-regulated kinase/p38 pathways.
abstract: OBJECTIVE
  Oxidative stress is widely implicated in the death of retinal ganglion cells associated with various optic neuropathies. Agonists of the dopamine D(1) receptor have recently been found to be potentially neuroprotective against oxidative stress-induced injury. The goal of this study was to investigate whether SKF83959, a next-generation high-affinity D(1) receptor agonist, could protect retinal ganglion cell 5 (RGC-5) cells from H(2)O(2)-induced damage and the molecular mechanism involved.
  
  
  METHODS
  We examined expression of the D(1) receptor in RGC-5 cells with reverse-transcription-PCR and immunoblotting and assessed neuroprotection using propidium iodide staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, we monitored the activation and involvement of members of mitogen-activated protein kinase family, extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase, with western blot and specific inhibitors.
  
  
  RESULTS
  We found that the D(1) receptor was expressed in RGC-5 cells, but the sequence analysis suggested this cell line is from mouse and not rat origin. SKF83959 exhibited a remarkable neuroprotective effect on H(2)O(2)-damaged RGC-5 cells, which was blocked by the specific D(1) receptor antagonist, SCH23390. ERK and p38 were activated by SKF83959, and pretreatment with their inhibitors U0126 and SB203580, respectively, significantly blunted the SKF83959-induced cytoprotection. However, the specific c-Jun NH(2)-terminal kinase inhibitor, SP600125, had no effect on the SKF83959-induced protection.
  
  
  CONCLUSIONS
  We conclude that SKF83959 attenuates hydrogen peroxide-induced injury in RGC-5 cells via a mechanism involving activation of the ERK and p38 pathways and the D(1) receptor is a potential molecular target for developing neuroprotective drugs.
authors.affiliation: Department of Ophthalmology, Second Hospital of JiLin University, Changchun, China.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Fan
authors.forename: Yong-Chen
authors.initials: YC
authors.lastname: Zheng
authors.forename: Tong-Hui
authors.initials: TH
authors.lastname: Ma
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D001552:Benzazepines; D002070:Butadienes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007093:Imidazoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C113580:U 0126; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580