Inhibition of ceramide biosynthesis ameliorates pathological consequences of spinal cord injury.
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 24 g) 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-alpha and IL-1beta 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.
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
Salvatore
S
Cuzzocrea
Hans-Peter
HP
Deigner
Tiziana
T
Genovese
Emanuela
E
Mazzon
Emanuela
E
Esposito
Concetta
C
Crisafulli
Rosanna
R
Di Paola
Placido
P
Bramanti
George
G
Matuschak
Daniela
D
Salvemini
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002518:Ceramides / Q000096:biosynthesis* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D009636:Norbornanes; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011897:Random Allocation; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D001952:Bridged-Ring Compounds; D002227:Carbazoles; D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D053583:Interleukin-1beta; C493192:N,N,N-(3-carbazolylpropyl)-(p-methoxyphenylethyl)methylamine; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; D014409:Tumor Necrosis Factor-alpha; C056933:fumonisin B1; C046498:tricyclodecane-9-yl-xanthogenate; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013108:Sphingomyelin Phosphodiesterase