Abstract
PurposeIschemia 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).MethodsRetinal 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)-κB, p38 and ERK-1/2 MAPK. NF-κB 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.ResultsInhalation 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-κB, 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).ConclusionInhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.
Highlights
Stroke, an ischemic cerebral injury, is a leading cause of morbidity and mortality in the Western world and may occur in the perioperative period [1]
carbon monoxide (CO) preconditioning has been shown to protect neuronal cells in the brain [7] and the retina [8]. These protective effects of CO involve the modulation of numerous cellular targets including heme-containing enzymes [9], the mitogen-activated protein kinases (MAPKs) [10] and different transcription factors [11,12]
CO postconditioning suppresses I/R-induced apoptosis To first answer the question whether CO inhibits I/R-induced retinal apoptosis, mRNA and protein expression of Bax and Bcl-2 were determined
Summary
An ischemic cerebral injury, is a leading cause of morbidity and mortality in the Western world and may occur in the perioperative period [1]. Perioperative stroke is primarily associated with major cardiovascular procedures but has been reported after non-cardiac surgery, occurring with an incidence of 0.1% [2]. CO preconditioning has been shown to protect neuronal cells in the brain [7] and the retina [8]. These protective effects of CO involve the modulation of numerous cellular targets including heme-containing enzymes [9], the mitogen-activated protein kinases (MAPKs) [10] and different transcription factors [11,12]. Depending on stimulus and timing, their activity is differentially regulated by CO [4,8]
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