TY - JOUR
T1 - Inhibition of ceramide biosynthesis ameliorates pathological consequences of spinal cord injury
AU - Cuzzocrea, Salvatore
AU - Deigner, Hans Peter
AU - Genovese, Tiziana
AU - Mazzon, Emanuela
AU - Esposito, Emanuela
AU - Crisafulli, Concetta
AU - Di Paola, Rosanna
AU - Bramanti, Placido
AU - Matuschak, George
AU - Salvemini, Daniela
PY - 2009/6
Y1 - 2009/6
N2 - 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.
AB - 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.
KW - (3-carbazol-9-yl- propyl)-[2-(3,4-dimethoxyphenyl)-ethyl]-methylamine (NB6)
KW - Cytokines
KW - Fumonisin B1 (FB1)
KW - Peroxynitrite
KW - Tyclodecan-9-xanthogenate (D609)
UR - http://www.scopus.com/inward/record.url?scp=68049113646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68049113646&partnerID=8YFLogxK
U2 - 10.1097/SHK.0b013e3181891396
DO - 10.1097/SHK.0b013e3181891396
M3 - Article
C2 - 18838947
AN - SCOPUS:68049113646
VL - 31
SP - 634
EP - 644
JO - Shock
JF - Shock
SN - 1073-2322
IS - 6
ER -