Preconditioning with inhalative carbon monoxide protects rat retinal ganglion cells from ischemia/reperfusion injury.
PURPOSE. Retinal ischemia/reperfusion (I/R) injury damages retinal neurons. Carbon monoxide (CO) recently attracted attention as cytoprotective because of its anti-inflammatory and antiapoptotic effects. Rapid preconditioning of retinal neurons by inhaled CO before I/R injury may reduce inflammation and apoptosis in retinal ganglion cells (RGCs). METHODS. I/R injury was performed on the left eyes of rats (n = 8) with or without inhaled CO preconditioning (250 ppm) for 1 hour before ischemia. Densities of fluorogold-prelabeled RGCs were analyzed 7 days after injury in whole-mounts. Retinal tissue was further harvested to analyze protein expression of TNF-alpha, HSP-70, and mitogen-activated protein kinases (MAPKs) pERK1/2 and p-p38. DNA-binding activities of the transcription factors NF-kappaB, AP-1, CREB, and HSF-1 were determined to elucidate a possible pathway of neuroprotection. RESULTS. Seven days after I/R injury, RGC death decreased by 52% in the CO preconditioning group compared with controls receiving room air (P < 0.001). Similarly, CO inhalation resulted in attenuated caspase-3 activity and TNF-alpha protein expression. In contrast, HSP-70 protein expression was elevated in the retina after CO. CREB and HSF-1 showed CO-dependent regulation and p-p38 MAPK. CONCLUSIONS. Rapid preconditioning with CO mediates anti-inflammatory and antiapoptotic effects in retinal I/R injury, thus making it neuroprotective. Further studies are needed to evaluate whether CO posttreatment may represent a therapeutic option counteracting ischemic neuronal injury.
Biermann
Julia
J
University Eye Hospital Freiburg, University Medical Center, Killianstrasse 5, 79106 Freiburg, Germany. julia.biermann@uniklinik-freiburg.de
Lagrèze
Wolf A
WA
Dimitriu
Cornelia
C
Stoykow
Christian
C
Goebel
Ulrich
U
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000378:metabolism; D002248:Carbon Monoxide / Q000008:administration & dosage*; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002248:Carbon Monoxide; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3