capsazepine and rofecoxib

Curcumin, a pleiotropic substance used for centuries in traditional medicine, exhibits antioxidant, anti-inflammatory and antiproliferative efficacy against various tumours, but the role of curcumin in gastroprotection is little studied. We determined the effect of curcumin against gastric haemorrhagic lesions induced by 75% ethanol and alterations in gastric blood flow (GBF) in rats with cyclooxygenase-1 (COX-1) and COX-2 activity inhibited by indomethacin, SC-560 or rofecoxib, inhibited NO-synthase activity, capsaicin denervation and blockade of TRPV1 receptors by capsazepine.. One hour after ethanol administration, the gastric mucosal lesions were assessed by planimetry, the GBF was examined by H. Curcumin, in a dose-dependent manner, reduced ethanol-induced gastric lesions and significantly increased GBF and plasma gastrin levels. Curcumin-induced protection was completely reversed by indomethacin and SC-560, and significantly attenuated by rofecoxib, L-NNA, capsaicin denervation and capsazepine. Curcumin downregulated Cdx-2 and Hif-1α mRNA expression and upregulated HO-1 and SOD 2, and these effects were reversed by L-NNA and further restored by co-treatment of L-NNA with L-arginine.. Curcumin-induced protection against ethanol damage involves endogenous PG, NO, gastrin and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor. This protective effect can be attributed to the inhibition of HIF-1α and Cdx-2 expression and the activation of HO-1 and SOD 2 expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcitonin Gene-Related Peptide; Capsaicin; CDX2 Transcription Factor; Curcumin; Cyclooxygenase 2 Inhibitors; Denervation; Down-Regulation; Ethanol; Female; Gastric Mucosa; Gastrins; Gene Expression; Heme Oxygenase (Decyclizing); Hypoxia-Inducible Factor 1, alpha Subunit; Indomethacin; Lactones; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandins; Pyrazoles; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stomach Diseases; Sulfones; Superoxide Dismutase; TRPV Cation Channels; Up-Regulation

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty-acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. It has been suggested that the mechanisms of action of NSAIDs could be due to inhibition of cyclooxygenase (COX) and also to an increase in endocannabinoid concentrations. In a previous study we have demonstrated that the local analgesic interaction between anandamide and ibuprofen (a non-specific COX inhibitor) was synergistic for the acute and inflammatory phases of the formalin test. To test this hypothesis further, we repeated similar experiments with rofecoxib (a selective COX-2 inhibitor) and also measured the local concentrations of anandamide, and of two fatty-acid amides, oleoylethanolamide and palmitoylethanolamide. We established the ED(50) for anandamide (34.52 pmol+/-17.26) and rofecoxib (381.72 pmol+/-190.86) and showed that the analgesic effect of the combination was synergistic. We also found that paw tissue levels of anandamide, oleoylethanolamide and palmitoylethanolamide were significantly higher when anandamide was combined with NSAIDs and that this effect was greater with rofecoxib. In conclusion, local injection of anandamide or rofecoxib was antinociceptive in a test of acute and inflammatory pain and the combination of anandamide with rofecoxib was synergistic. Finally, locally injected anandamide with either NSAID (ibuprofen or rofecoxib) generates higher amount of fatty-acid ethanolamides. The exact comprehension of the mechanisms involved needs further investigation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Capsaicin; Chromatography, High Pressure Liquid; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Edema; Endocannabinoids; Formaldehyde; Ibuprofen; Lactones; Male; Mass Spectrometry; Nitrobenzenes; Pain Measurement; Peripheral Nervous System; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sulfonamides; Sulfones; TRPV Cation Channels