RGD Reference Report - Neuroprotective mechanisms of minocycline against sphingomyelinase/ceramide toxicity: Roles of Bcl-2 and thioredoxin. - Rat Genome Database

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Neuroprotective mechanisms of minocycline against sphingomyelinase/ceramide toxicity: Roles of Bcl-2 and thioredoxin.

Authors: Tang, CM  Hwang, CS  Chen, SD  Yang, DI 
Citation: Tang CM, etal., Free Radic Biol Med. 2011 Mar 15;50(6):710-21. Epub 2010 Dec 22.
RGD ID: 5133706
Pubmed: PMID:21184825   (View Abstract at PubMed)
DOI: DOI:10.1016/j.freeradbiomed.2010.12.024   (Journal Full-text)

In this study, we determined whether minocycline may protect rat cortical cultures against neurotoxicity induced by sphingomyelinase/ceramide and explored the underlying mechanisms. We found that minocycline exerted strong neuroprotective effects against toxicity induced by bacterial sphingomyelinase and synthetic C2 ceramide. Minocycline enhanced the production of nitric oxide (NO) with resultant increases in cellular cGMP content. Consistently, minocycline-dependent neuroprotection was abolished by the nitric oxide synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) and the soluble guanylate cyclase (sGC) inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). Western blotting revealed that minocycline restored the expression levels of cGMP-dependent protein kinase (PKG)-1, antioxidative thioredoxin-1, and antiapoptotic Bcl-2 that were down-regulated by bacterial sphingomyelinase. Accordingly, the PKG inhibitor KT5823, the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), and a Bcl-2 inhibitor significantly abolished the minocycline neuroprotection. The minocycline-dependent restoration of Bcl-2 was abolished by L-NAME, ODQ, and KT5823, but not by DNCB, suggesting the involvement of NO/sGC/PKG but not thioredoxin. Furthermore, minocycline-dependent recovery of thioredoxin-1 was PKG-independent. Taken together, our results indicate that minocycline protects rat cortical neurons against bacterial sphingomyelinase/ceramide toxicity via an NO/cGMP/PKG pathway with induction of Bcl-2 and PKG-independent stimulation of thioredoxin-1.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Txn1Ratcellular response to antibiotic  IEP minocyclineRGD 

Objects Annotated

Genes (Rattus norvegicus)
Txn1  (thioredoxin 1)


Additional Information