The Carbon monoxide releasing molecule ALF-186 mediates anti-inflammatory and neuroprotective effects via the soluble guanylate cyclase ß1 in rats’ retinal ganglion cells after ischemia and reperfusion injuryReportar como inadecuado




The Carbon monoxide releasing molecule ALF-186 mediates anti-inflammatory and neuroprotective effects via the soluble guanylate cyclase ß1 in rats’ retinal ganglion cells after ischemia and reperfusion injury - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Neuroinflammation

, 14:130

First Online: 27 June 2017Received: 19 August 2016Accepted: 18 June 2017

Abstract

BackgroundThe endogenously produced gaseous molecule carbon monoxide is able to promote organ protection after ischemia-reperfusion injuries IRI. The impact of carbon monoxide releasing molecules CORM regarding inflammation in neuronal tissues has not been studied in detail. In this investigation, we aimed to analyze the effects of the CORM ALF-186 on neuro-inflammation and hypothesized that the soluble guanylate cyclase sGC is playing a decisive role.

MethodsRetinal ischemia-reperfusion injury was performed for 60 min in Sprague-Dawley rats. Thereafter, the CORM ALF-186 10 mg-kg in the presence or absence of the sGC inhibitor ODQ was injected via a tail vein. Retinal tissue was harvested 24 h later to analyze mRNA or protein expression of sGC-β1 subunit, transcription factors NF-κB and CREB, the inflammatory cytokines TNF-α and IL-6, as well as the heat shock proteins HSP HSP-70 and HSP-90. Immunohistochemistry was performed on frozen sections of the retina. The overall neuroprotective effect of ALF-186 was assessed by counting fluorogold-pre-labeled retinal ganglion cells RGC 7 days after IRI.

ResultsIschemia-reperfusion mediated loss of vital RGC was attenuated by the administration of ALF-186 after injury. ALF-186 treatment after IRI induced sGC-ß1 leading to a decreased NF-κB and CREB phosphorylation. Consecutively, ALF-186 mitigated IRI induced TNF-α and IL-6 expression in the retina and in the rats’ serum. Moreover, ALF-186 attenuated heat shock protein 70 Hsp-70 while increasing Hsp-90. The sGC-inhibitor ODQ attenuated the anti-inflammatory effects of ALF-186 and increased retinal loss of ganglion cells. These results were confirmed by immunohistochemistry.

ConclusionThe CORM ALF-186 protected RGC from IRI induced loss. Furthermore, ALF-186 reduced IRI mediated neuroinflammation in the retina and in the serum by activating sGC. Inhibition of sGC stopped the beneficial and protective effects of ALF-186. ALF-186 may present a promising therapeutic alternative in treating inflammation after neuronal IRI.

KeywordsIschemia-reperfusion injury Carbon monoxide Neuro-inflammation Neuroprotection sGC-ß1 Heat shock proteins AbbreviationsAMCActivated microglia

COCarbon monoxide

CORMCarbon monoxide releasing molecule

CREBcAMP responsive element binding protein

DMSODimethylsulfoxid

FGFluorogold

GCLGanglion cell layer

HSPHeat shock protein

IL-6Interleukin 6

MAPKMitogen activated protein kinase

NF-κBNuclear factor κB

ODQsGC inhibitor

PBSPhosphate buffered saline

RGCRetinal ganglion cell

sGCSoluble guanylate cyclase, IRI, ischemia-reperfusion injury

TNF-αTumor necrosis factor-α

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Autor: Felix Ulbrich - Claus Hagmann - Hartmut Buerkle - Carlos C. Romao - Nils Schallner - Ulrich Goebel - Julia Biermann

Fuente: https://link.springer.com/







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