Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat.
Alpha-2 adrenoceptor agonists have previously been shown to enhance neuronal survival in an optic nerve mechanical injury model and to protect photoreceptors in a light-induced degeneration model. The purpose of this study was to examine the effect of the alpha-2 adrenoceptor agonist in a pressure-induced retinal ischemia model. Brown-Norway rats were treated systemically or topically with alpha-2 adrenoceptor specific agonist brimonidine. Retinal ischemia was induced by increasing the intraocular pressure to 110 mm Hg for 50 min. The effect of brimonidine on retinal ischemic injury was functionally assessed in the rats 7 d later using electroretinography (ERG). Ischemia-induced retinal cell death was studied using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. We found that brimonidine treatment significantly protected the retina from retinal ischemic injury in a dose- and time-dependent manner. This protection can be achieved either by systemic or topical application and can be blocked by pretreatment with the alpha-2 adrenoceptor antagonist, yohimbine. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, we found that brimonidine can up-regulate the expression of basic fibroblast growth factor, bcl-2 and bcl-xl in the retina. The drug also can activate two major cell survival signaling pathways in the retina: the extracellular-signal-regulated kinases (ERKs) and phosphatidylinositol-3' kinase/protein kinase Akt pathways. All these aforementioned factors may potentially contribute in mediating brimonidine's protective effect in this acute retinal ischemia model.
Lai
Ronald K
RK
Department of Biological Sciences, Allergan, Inc., Irvine, CA 92612, USA. Lai_Ronald@Allergan.com
Chun
Teresa
T
Hasson
Dain
D
Lee
Steve
S
Mehrbod
Farrokh
F
Wheeler
Larry
L
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D004596:Electroretinography; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051020:bcl-X Protein
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D012333:RNA, Messenger; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; D000068438:Brimonidine Tartrate