Abstract | BACKGROUND: Preliminary studies in our laboratories indicate that a recently discovered synthetic drug, TBC-1269, acts as a multiple selectin blocker and provides protection against tissue damage in rats that are subjected to severe liver ischemia/reperfusion. Here, we report that this effect is dose and time dependent, with its effects acting through the modulation of tumor necrosis factor ( TNF)-alpha and interleukin (IL)-10. MATERIAL AND METHODS: Mice subjected to 90 min of partial (70-80%) hepatic ischemia and 3 h of reperfusion were divided into eight groups (n=6/group): sham, ischemic control (IC), three groups of TBC-1269-treated animals at different concentrations (10, 20, 40, mg/kg) and another three groups of TBC-1269 given at 40 mg/kg at different times of administration: 15 min prereperfusion but after ischemia (no pretreatment), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured at 3 h of reperfusion included liver function tests ( alanine aminotransferase and aspartate aminotransferase), histopathology analysis and measurements using enzyme-linked immunosorbent assay in serum of TNF-alpha and IL-10. Statistical analysis included analysis of variance with P values of <0.05 for significance. Results were expressed as mean +/- SD. RESULTS: The liver function tests showed statistically significant differences between the ischemic control group and both the sham group and the group treated with 40 mg/kg at the time of reperfusion (40@RP). These results correlated well with the histopathological analysis in that we found no difference in vacuolization, congestion, and necrosis between the 40@RP group and the sham group. The TNF-alpha and the IL-10 also reflected the protection observed in histopathology, with a decrease in TNF- alpha from the high levels observed in the IC (32 +/- 2.32 pg/mL) to a lower level of 8.5 +/- 4.04 mg observed in the 40@RP group, and an increment in the levels of the protective IL-10 from 2.8 +/- 2.9 pg/mL in the IC group versus 37.9 +/- 11.6 pg/mL in the 40@RP treated group (P<0.05). Lower doses and different times of administration of TBC-1269 did not show a protective effect. The IC group showed no difference in damage by histopathology or liver enzymes compared to the rest of the groups, except the 40@RP group. CONCLUSION: In this work, we demonstrated that the small molecule multiple selectin inhibitor (TBC-1269) offered significant protection for the ischemic liver when given at 40 mg/kg at the time of perfusion. Lower doses and different times of administration did not show the optimal drug effect. The protection observed in the liver function tests ( alanine aminotransferase and aspartate aminotransferase) and histopathology in this group was also reflected in the significant decrease in serum TNF-alpha and equally significant increase in serum protective IL-10.
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Authors | Fernando López-Neblina, Luis H Toledo-Pereyra |
Journal | The Journal of surgical research
(J Surg Res)
Vol. 138
Issue 2
Pg. 275-83
(Apr 2007)
ISSN: 0022-4804 [Print] United States |
PMID | 17254609
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Biphenyl Compounds
- Mannosides
- Selectins
- Tumor Necrosis Factor-alpha
- Interleukin-10
- bimosiamose disodium
- Mannose
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Topics |
- Animals
- Biphenyl Compounds
(pharmacology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Interleukin-10
(metabolism)
- Liver
(immunology, metabolism, pathology)
- Male
- Mannose
(analogs & derivatives)
- Mannosides
(pharmacology)
- Mice
- Mice, Inbred C57BL
- Reperfusion Injury
(drug therapy, immunology, pathology)
- Selectins
(metabolism)
- Tumor Necrosis Factor-alpha
(metabolism)
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