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Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina
Published: Friday, September 28, 2012
Author: Nils Schallner et al.

by Nils Schallner, Matthias Fuchs, Christian I. Schwer, Torsten Loop, Hartmut Buerkle, Wolf Alexander Lagrèze, Christian van Oterendorp, Julia Biermann, Ulrich Goebel

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)-?B, p38 and ERK-1/2 MAPK. NF-?B 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 Müller 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±0.3 vs. 1.4±0.2, p?=?0.028; caspase-3: 2.0±0.2 vs. 1.5±0.1, p?=?0.007; mean±S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2±0.2 vs. 1.6±0.2, p?=?0.001; mean±S.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-?B, microglia and Müller 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±S.D.: 1255±327 I/R only vs. 1956±157 immediate CO treatment, vs. 1830±109 1.5 h time lag and vs. 1626±122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm2: 1956±157 vs. 1931±124, mean±S.D., p?=?0.799).

Conclusion

Inhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.

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