%0 Journal Article %T Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina %A Nils Schallner %A Matthias Fuchs %A Christian I. Schwer %A Torsten Loop %A Hartmut Buerkle %A Wolf Alexander Lagr¨¨ze %A Christian van Oterendorp %A Julia Biermann %A Ulrich Goebel %J PLOS ONE %D 2012 %I Public Library of Science (PLoS) %R 10.1371/journal.pone.0046479 %X Purpose Ischemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury (¡®postconditioning¡¯) would protect retinal ganglion cells (RGC). Methods Retinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-¦ÊB, p38 and ERK-1/2 MAPK. NF-¦ÊB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and M¨¹ller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining. Results Inhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9¡À0.3 vs. 1.4¡À0.2, p = 0.028; caspase-3: 2.0¡À0.2 vs. 1.5¡À0.1, p = 0.007; mean¡ÀS.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2¡À0.2 vs. 1.6¡À0.2, p = 0.001; mean¡ÀS.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-¦ÊB, microglia and M¨¹ller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm2; mean¡ÀS.D.: 1255¡À327 I/R only vs. 1956¡À157 immediate CO treatment, vs. 1830¡À109 1.5 h time lag and vs. 1626¡À122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm2: 1956¡À157 vs. 1931¡À124, mean¡ÀS.D., p = 0.799). Conclusion Inhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects. %U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046479