The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation.
BACKGROUND
The antagonists of 5HT(3) receptors have shown impressive efficacy in rheumatoid arthritis, osteoarthritis or fibromyalgia. The mechanistic relationships between 5HT(3) receptors, angiogenesis and sequence of cytokine expression, and leukocyte recruitment during inflammation are not clear. We evaluate the effects of granisetron on inflammatory parameters and angiogenesis in rat air-pouch model.


METHODS
Male Wistar rats were anesthetized, and then 20 ml and 10 ml of sterile air were injected subcutaneously in the back on day 0 and day 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 6 and 72 h, the rats were sacrificed; pouch fluid was collected in order to determine exudate volume, the number of accumulated cells and TNFalpha/PGE(2) concentration. Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using a hemoglobin kit.


RESULTS
Leukocyte accumulation was dose-dependently inhibited by granisetron both at 6 and 72 h after induction of inflammation. All doses of granisetron decreased hemoglobin level in the whole granulation tissue in a bell-shaped manner. Vascular network formation was also inhibited by granisetron. Granisetron increased PGE(2) level at a lower dose (50 microg/pouch) but higher doses (100 and 200 microg/pouch) inhibited the release. At the same time, TNFalpha production was decreased by the lower dose and increased by higher doses of granisetron in a reciprocal fashion.


CONCLUSIONS
Anti-inflammatory activities of 5HT(3) receptor antagonist, granisetron probably are mediated through modulation of TNFalpha/PGE(2) production and leukocyte infiltration.
Maleki-Dizaji
Nasrin
N
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. malekins@tbzmed.ac.ir
Eteraf-Oskouei
Tahereh
T
Fakhrjou
Ashraf
A
Maljaie
Seyyed Hadi
SH
Garjani
Alireza
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan / Q000008:administration & dosage; D015232:Dinoprostone / Q000032:analysis; D017829:Granisetron / Q000494:pharmacology* / Q000627:therapeutic use; D006097:Granulation Tissue / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D015232:Dinoprostone; D017829:Granisetron; D058831:Serotonin 5-HT3 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha