title: Alpha2-Adrenergic-Agonist Brimonidine Stimulates Negative Feedback and Attenuates Injury-Induced Phospho-ERK and Dedifferentiation of Chicken Müller Cells.
abstract: OBJECTIVE
  Retinal injury induces Müller cell dedifferentiation by activating extracellular signal-regulated kinase (ERK) signaling. Stimulation of α2-adrenergic receptors protects against injury but also activates ERK in Müller cells. The purpose of this work was to study the effect of α2-adrenergic signaling on injury-induced ERK and Müller cell dedifferentiation. We tested the hypothesis that α2-stimulation triggers negative feedback regulation of the injury-induced ERK pathway that attenuates Müller cell dedifferentiation.
  
  
  METHODS
  Chicken retina injured by N-methyl-D-aspartate and cultured primary Müller cells were stimulated by the α2-adrenergic agonist brimonidine. Immunostaining, quantitative RT-PCR, and Western blot techniques in combination with receptor blockers were used for analysis of the cellular responses.
  
  
  RESULTS
  Alpha2-adrenergic receptor stimulation attenuated injury-induced ERK activation and dedifferentiation of Müller cells as seen by decreased phospho-ERK, expression of transitin, and retinal progenitor cell genes. The attenuation was concomitant with a synergistic upregulation of several negative ERK-signal feedback regulators including ERK-phosphatases, Raf1-, and growth factor receptor-binding proteins. The results were also seen in cultures of primary Müller cells.
  
  
  CONCLUSIONS
  Alpha2-adrenergic signaling on Müller cells elicits an intracellular attenuation of the injury response that comprises negative ERK-signaling feedback leading to attenuated Müller cell dedifferentiation. The implications of this study are that adrenergic stress signals may directly modulate glial function in retina and that α2-adrenergic receptor pharmacology may be used to control glial injury response.
authors.affiliation: Department of Neuroscience Uppsala University, Uppsala, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Harun-Or-Rashid
authors.affiliation: Department of Neuroscience Uppsala University, Uppsala, Sweden.
authors.forename: Marta
authors.initials: M
authors.lastname: Díaz-DelCastillo
authors.affiliation: Department of Neuroscience Uppsala University, Uppsala, Sweden 2Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Caridad
authors.initials: C
authors.lastname: Galindo-Romero
authors.affiliation: Department of Neuroscience Uppsala University, Uppsala, Sweden.
authors.forename: Finn
authors.initials: F
authors.lastname: Hallböök
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D000068438:Brimonidine Tartrate / Q000494:pharmacology*; D054337:Cell Dedifferentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002645:Chickens; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D012160:Retina / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000068438:Brimonidine Tartrate