Inhibition of ceramide biosynthesis ameliorates pathological consequences of spinal cord injury

Salvatore Cuzzocrea, Hans Peter Deigner, Tiziana Genovese, Emanuela Mazzon, Emanuela Esposito, Concetta Crisafulli, Rosanna Di Paola, Placido Bramanti, George Matuschak, Daniela Salvemini

Research output: Contribution to journalArticle

Abstract

Ceramide is a sphingolipid signaling molecule with powerful proinflammatory and proapoptotic properties. The aim of this study was to investigate the role of altered ceramide metabolism in spinal cord injury. Spinal cord injury was induced by application of vascular clips (force of 24g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Fumonisin B1, tyclodecan-9-xanthogenate (D609), and (3-carbazol-9-yl-propyl)-[2-(3,4- dimethoxy-phenyl)-ethyl]-methylamine (NB6) inhibitors of, respectively, ceramide synthase, acid sphingomyelinase, and the secretory form of acid sphingomyelinase significantly reduced the degree of (i) ceramide formation, (ii) tissue injury, (iii) neutrophil infiltration, (iv) nitrotyrosine formation, (v) TNF-α and IL-1β production and apoptosis (TUNEL staining and Bax and Bcl-2 expression). Significant improvement of motor function was observed in mice treated with inhibitors of the de novo (fumonisin B1) and sphingomyelin (D609, NB6) pathways. These results implicate ceramide in the pathogenesis of spinal cord injury, providing the rationale for development of candidates for its therapeutic inhibition.

Original languageEnglish
Pages (from-to)634-644
Number of pages11
JournalShock
Volume31
Issue number6
DOIs
Publication statusPublished - Jun 2009

Keywords

  • (3-carbazol-9-yl- propyl)-[2-(3,4-dimethoxyphenyl)-ethyl]-methylamine (NB6)
  • Cytokines
  • Fumonisin B1 (FB1)
  • Peroxynitrite
  • Tyclodecan-9-xanthogenate (D609)

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

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  • Cite this

    Cuzzocrea, S., Deigner, H. P., Genovese, T., Mazzon, E., Esposito, E., Crisafulli, C., Di Paola, R., Bramanti, P., Matuschak, G., & Salvemini, D. (2009). Inhibition of ceramide biosynthesis ameliorates pathological consequences of spinal cord injury. Shock, 31(6), 634-644. https://doi.org/10.1097/SHK.0b013e3181891396