Effects of ceramide inhibition on experimental radiation-induced oral mucositis.
OBJECTIVE
Oral mucositis (OM) is a common toxicity of ionizing radiation (IR), which is used as treatment for head and neck cancer. Ceramide-mediated apoptosis may contribute to the pathogenesis of mucositis. In response to IR or other cellular stresses, ceramide production occurs either by the hydrolytic action of sphingomyelinase (SMase) or de novo via ceramide synthase.


METHODS
Male golden Syrian hamsters (10 per group) exposed to a single dose of 40 Gy ionizing radiation (day 0) were treated with subcutaneous 0.2 mL injections of either neutral SMase, acidic SMase, or ceramide synthase inhibitor (5 mmol/L glutathione, 5 micromol/L desipramine, or 1 micromol/L fumonisin B1, respectively) from day -1 to day 16. A control group was treated with saline. Two blinded examiners assessed clinical OM development from day 6 to day 26. Two animals per group were killed on days 3, 10, and 16 for immunohistochemical detection of ceramide expression in both the epithelium and in the connective tissue.


RESULTS
The group exposed to fumonisin B1 exhibited a statistically significant reduction in mean daily weight gain, mean mucositis score, duration of mucositis, and expression of ceramide in the epithelium on day 3 as well as in the connective tissue on days 10 and 16 relative to control. Immunohistologic analysis also revealed significant differences in ceramide expression on days 3 and 16 for animals treated with glutathione in both the epithelial and connective tissue when compared to the control.


CONCLUSIONS
These results suggest that IR triggers early de novo ceramide production and that inhibition of this process attenuates OM on a clinical level.
Hwang
Debby
D
Department of Periodontology, School of Dental Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Popat
Rishi
R
Bragdon
Christopher
C
O'Donnell
Kathryn E
KE
Sonis
Stephen T
ST
D000818:Animals; D017209:Apoptosis; D002518:Ceramides / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D016371:Cranial Irradiation / Q000009:adverse effects*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D037341:Fumonisins / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D008647:Mesocricetus; D052016:Mucositis / Q000188:drug therapy / Q000209:etiology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013280:Stomatitis / Q000188:drug therapy* / Q000209:etiology*
D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D010726:Phosphodiesterase Inhibitors; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013108:Sphingomyelin Phosphodiesterase