European journal of pharmacology
-
Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a highly nuclear receptor expressed in the colon, may participate in the control of inflammation, especially in regulating the production of immunomodulatory and inflammatory mediators, cellular proliferation and apoptosis. In order to delve into the anti-inflammatory mechanisms and signalling pathways of PPARgamma agonists, we have studied the effects of rosiglitazone, a PPARgamma agonist on the extent and severity of acute ulcerative colitis caused by intracolonic administration of 2,4,6-trinitribenzene sulfonic acid (TNBS) in rats. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-alpha) levels and a histological study of the lesions. ⋯ A high expression of NF-kappaB p65 and p38 MAPK proteins appeared in colon mucosa from control TNBS-treated rats; nevertheless, PPARgamma agonist treatment drastically decreased them. There were no significant changes in apoptosis after rosiglitazone treatment when compared to TNBS group. In conclusion, rosiglitazone seems to modulate the acute colitis through NF-kappaB p65 and p38 MAPK signalling pathways.
-
Effects of different doses of aspirin, compared to equimolar doses of nitric oxide (NO)-donating aspirin (NCX 4016), and of a single dose of paracetamol, compared to an equimolar dose of NO-donating paracetamol (NCX 701) were investigated in acute zymosan-induced air pouch inflammation in rats. Treatments were administered by orogastric route, and interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) levels in the exudates were analysed 4 h after zymosan injection by enzyme immunoassay (EIA). Aspirin, at 10, 30 and 100 mg/kg doses, increased IL-1beta levels in exudates, however, only the highest dose lead to a significant increase when compared to control, whereas a significant increase in TNF-alpha level was observed at all doses tested. ⋯ Paracetamol and NO-paracetamol did not cause any change in the number of polymorphonuclear leukocytes in exudate. These results indicated that aspirin and NCX 4016 possessed different effects on cytokine production or release, despite the fact that both drugs inhibited the synthesis of PGE(2) in a similar way. Unlike paracetamol, which increased exudate TNF-alpha level, NCX 701 had no effect on TNF-alpha level in the exudates.
-
In skeletal muscle sarcoplasmic reticulum vesicles, 3,5-di-t-butyl catechol (DTCAT) promotes the release of Ca(2+) through the activation of ryanodine receptor Ca(2+) channels. DTCAT mechanical and electrophysiological effects have now been investigated in rat aorta rings and single tail artery myocytes. Rat aorta rings incubated with either 30 microM ryanodine or 100 microM DTCAT developed tension, which averaged 36% and 7%, respectively, of that induced by phenylephrine. ⋯ DTCAT (>100 microM) was also able to antagonise the contractions induced by phorbol 12-myristate, 13-acetate. In conclusion, this is the first demonstration that DTCAT inhibits vascular smooth muscle voltage-operated Ca(2+) channels and promotes the release of endothelial nitric oxide. Ryanodine receptor Ca(2+) channels activation or the impairment of the contractile apparatus by DTCAT seem to play a secondary role in its vascular activity.
-
Earlier, we reported that morphine-nimodipine combination produces significantly higher antinociception after intrathecal but not after systemic administration in mice. Different doses of morphine and nimodipine (5 microg of morphine, 5 microg of nimodipine, 5 microg each of morphine and nimodipine, 10 microg of morphine, 10 microg of nimodipine, 10 microg morphine with 5 microg nimodipine and 5 microg of morphine with 10 microg of nimodipine) were now injected intrathecally in Wistar rats to further characterise this antinociceptive effect. The acute antinociceptive effect was measured by the tail-flick test between 15 min to 7 h. ⋯ Naloxone (5 mg/kg) could reverse this antinociceptive effect of morphine-nimodipine combination though it failed to reverse nimodipine (5 microg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 mug did not increase antinociception except between 6:30-7:00 h. No obvious side effect was noted after administration of either morphine or nimodipine or both.
-
Peroxisome proliferator activated receptors (PPAR) are ligand-regulated transcription factors that control the expression of many genes. The antiinflammatory activity of fibrates, PPARalpha agonists, and thiazolidinediones, PPARgamma agonists, has been demonstrated in many in vitro and a few in vivo studies. In the present study, we evaluated the effect of acute (100 or 300 mg/kg, p.o.) or prolonged (100 or 300 mg/kg day, 7 days, p.o.) treatment with fenofibrate and acute treatment with pioglitazone (doses ranging from 1 to 50 mg/kg, i.p.), PPARalpha and PPARgamma agonists, respectively, on experimental models of nociception and edema, in order to expand the knowledge of their potential antiinflammatory activities. ⋯ Fenofibrate did not inhibit mechanical allodynia or paw edema induced by phorbol-12,13-didecanoate (PDD), a protein kinase C activator, in rats. Pioglitazone inhibited paw edema, but not mechanical allodynia, induced by PDD. The results represent the first demonstration of the antinociceptive and antiedematogenic activities of fenofibrate and pioglitazone and give further support to the potential use of PPAR agonists in the treatment of different inflammatory diseases.