The CORM ALF-186 Mediates Anti-Apoptotic Signaling via an Activation of the p38 MAPK after Ischemia and Reperfusion Injury in Retinal Ganglion CellsReport as inadecuate




The CORM ALF-186 Mediates Anti-Apoptotic Signaling via an Activation of the p38 MAPK after Ischemia and Reperfusion Injury in Retinal Ganglion Cells - Download this document for free, or read online. Document in PDF available to download.

Purpose

Ischemia and reperfusion injury may induce apoptosis and lead to sustained tissue damage and loss of function, especially in neuronal organs. While carbon monoxide is known to exert protective effects after various harmful events, the mechanism of carbon monoxide releasing molecules in neuronal tissue has not been investigated yet. We hypothesize that the carbon monoxide releasing molecule CORM ALF-186, administered after neuronal ischemia-reperfusion injury IRI, counteracts retinal apoptosis and its involved signaling pathways and consecutively reduces neuronal tissue damage.

Methods

IRI was performed in rats retinae for 1 hour. The water-soluble CORM ALF-186 10 mg-kg was administered intravenously via a tail vein after reperfusion. After 24 and 48 hours, retinal tissue was harvested to analyze mRNA and protein expression of Bcl-2, Bax, Caspase-3, ERK1-2, p38 and JNK. Densities of fluorogold pre-labeled retinal ganglion cells RGC were analyzed 7 days after IRI. Immunohistochemistry was performed on retinal cross sections.

Results

ALF-186 significantly reduced IRI mediated loss of RGC. ALF-186 treatment differentially affected mitogen-activated protein kinases MAPK phosphorylation: ALF-186 activated p38 and suppressed ERK1-2 phosphorylation, while JNK remained unchanged. Furthermore, ALF-186 treatment affected mitochondrial apoptosis, decreasing pro-apoptotic Bax and Caspase-3-cleavage, but increasing anti-apoptotic Bcl-2. Inhibition of p38-MAPK using SB203580 reduced ALF-186 mediated anti-apoptotic effects.

Conclusion

In this study, ALF-186 mediated substantial neuroprotection, affecting intracellular apoptotic signaling, mainly via MAPK p38. CORMs may thus represent a promising therapeutic alternative treating neuronal IRI.



Author: Felix Ulbrich, Kai B. Kaufmann, Alexander Meske, Wolf A. Lagrèze, Michael Augustynik, Hartmut Buerkle, Carlos C. Ramao, Julia Bi

Source: http://plos.srce.hr/



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