Search

Background and Purpose: alpha-Humulene and trans-caryophyllene are sesquiterpene compounds identified in the essential oil of Cordia verbenacea which display topical and systemic anti-inflammatory effects in different experimental models. However, the molecular mechanisms through which they exert their anti-inflammatory activity still remain unclear. Here, we evaluate the effects of alpha-humulene and trans-caryophyllene on the acute inflammatory responses elicited by LPS., Experimental Approach: The biological activities of alpha-humulene and trans-caryophyllene were investigated in a model of acute inflammation in rat paw, induced by LPS and characterized by paw oedema, neutrophil recruitment, cytokine production, activation of MAP kinases and NF-kappaB and up-regulated expression of kinin B(1) receptors., Key Results: Treatment with either alpha-humulene or trans-caryophyllene effectively reduced neutrophil migration and activation of NF-kappaB induced by LPS in the rat paw. However, only alpha-humulene significantly reduced the increase in TNF-alpha and IL-1beta levels, paw oedema and the up-regulation of B(1) receptors following treatment with LPS. Both compounds failed to interfere with the activation of the MAP kinases, ERK, p38 and JNK., Conclusions and Implications: Both alpha-humulene and trans-caryophyllene inhibit the LPS-induced NF-kappaB activation and neutrophil migration, although only alpha-humulene had the ability to prevent the production of pro-inflammatory cytokines TNF-alpha and IL-1beta and the in vivo up-regulation of kinin B(1) receptors. These data provide additional molecular and functional insights into the beneficial effects of the sesquiterpenes alpha-humulene and trans-caryophyllene isolated from the essential oil of Cordia verbenacea as agents for the management of inflammatory diseases.

Experiments were designed to investigate the role of kinin B(1) and B(2) receptors in Freund's adjuvant (CFA)-induced inflammation and nociception responses by the use of B(1) and B(2) null mutant mice. Intradermal (i.d.) injection of CFA produced time-dependent and marked hyperalgesic responses in both ipsilateral and contralateral paws of wild-type mice. Gene disruption of the kinin B(2) receptor did not interfere with CFA-induced hyperalgesia, but ablation of the gene of the B(1) receptor reduced the hyperalgesia in both ipsilateral (48+/-13%, at 12 h) and contralateral (91+/-22%, at 12 h) paws. Treatment of wild-type mice with the selective B(1) antagonist des-Arg(9)-[Leu(8)]-BK (150 nmol/kg, s.c.) reduced CFA-evoked thermal hyperalgesia, to an extent which was similar to that observed in mice lacking kinin B(1) receptor. I.d. injection of CFA produced a time-related and long-lasting (up to 72 h) increase in paw volume in wild-type mice. A similar effect was observed in B(1) knockout mice. In mice lacking B(2) receptor, the earlier stage of the CFA-induced paw oedema (6 h) was significantly greater compared with the wild-type animals, an effect which was almost completely reversed (76+/-5%) by des-Arg(9)-[Leu(8)]-BK. This data demonstrates that kinin B(1) receptor, but not B(2) receptor, exerts a critical role in controlling the persistent inflammatory hyperalgesia induced by CFA in mice, while B(2) receptor appears to have only a minor role in the amplification of the earlier stage of CFA-induced paw oedema formation. The results of the present study, taken together with those of previous studies, suggest that B(1) receptor antagonists represent a potential target for the development of new drugs to treat persistent inflammatory pain.

The present study investigated hind paw oedema mediated by bradykinin B(1) and B(2) receptors in streptozotocin-diabetic rats. Paw oedema induced by intraplantar (i.pl.) injection of bradykinin or the selective bradykinin B(2) receptor agonist, Tyrosine(8)-bradykinin ([Tyr(8)]bradykinin) (both 3 nmol/paw), was significantly reduced at 4 weeks after streptozotocin treatment (34 +/- 8% and 40 +/- 7%). At 6 weeks after streptozotocin, when paw oedema caused by substance P or prostaglandin E(2) (both 10 nmol/paw) was unchanged, inhibition of bradykinin B(2) receptor-mediated oedema was maximal (66 +/- 6% and 72 +/ -2%, for bradykinin and [Tyr(8)]bradykinin, respectively). The selective bradykinin B(1) receptor agonist, [des-Arg(9)]bradykinin (100 nmol/paw), induced only slight paw oedema in non-diabetic controls. Responses to [des-Arg(9)]bradykinin were markedly enhanced 8 weeks after streptozotocin (from 0.09 +/- 0.01 to 0.38 +/- 0.05 ml), less so at 10 weeks (0.22 +/- 0.03 ml), and returning to basal values at 12 weeks (0.11 +/- 0.03 ml). Treatment with insulin protamine zinc (1-3 U/day/7 weeks, s.c.) did not reverse the inhibition of responses to [Tyr(8)]bradykinin or the potentiation of responses to [des-Arg(9)]bradykinin seen at 8 weeks. Thus, streptozotocin-induced diabetes induces long-lasting alterations in oedematogenic responsiveness to kinins in the rat, characterized by marked reduction of oedema involving activation of bradykinin B(2) receptors, associated with enhancement of bradykinin B(1) receptor-mediated oedema.

The aim of this article is to furnish a brief review of the role played by neurokinins in the inflammatory process. Further attention is given to the mechanisms, as well as to the receptor subtypes involved in neurokinin-mediated inflammation, in an attempt to clarify the participation of neurokinins in different models of acute and chronic inflammation. The involvement of SP, NKA and NKB is also examined in relation to the major signs of inflammation, including edema formation, protein plasma extravasation and vasodilatation. Finally, we provide a general overview on the potential clinical applications of neurokinin antagonists, along with the involvement of neurokinins in human diseases., (Copyright 2000 Harcourt Publishers Ltd.)

Intradermal (ID) injection of the natural tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) (0.3-30 nmol) resulted in a marked and dose-related rat paw edema, with mean ED50 values of 2.68 nmol, 1.17 nmol, and 0.80 nmol, respectively. The ID injection of the selective NK1, SP methyl-ester (1-30 nmol), NK2, [beta-Ala8]-neurokinin A4-10) (beta-Ala, 0.3-30 nmol), or NK3, senktide (1-10 nmol) agonists, caused extensive edema formation with mean ED50s of 0.48 nmol, 0.41 nmol, and 0.18 nmol, respectively. The ID injection of the selective NK1 antagonist FK888 (0.1-3 nmol) produced marked inhibition (94%, 52%, and 66%, respectively) of rat paw edema induced by SP, NKA, or SP methyl-ester. The ID co-injection of the NK2 receptor antagonist SR 48968 elicited a graded inhibition (52%, 67%, and 35%, respectively) of rat paw edema induced by NKA, beta-Ala and, to a lesser extent, the edema caused by SP. Finally, the ID co-injection of the NK, receptor antagonist SR 142801 significantly inhibited (53%, 76%, 53%, and 100%, respectively) the edema formation caused by NKB and NKA or by SP and senktide. Together, the data of the present study suggest that tachykinin-mediated rat paw edema depends on the activation of NK1, NK2 and NK3 receptor subtypes, with apparent major involvement of NK1 receptors subtypes.

The modulatory effects of IL-1beta and TNF alpha on the rat paw edema induced by B1 agonists have been analyzed. In naive rats, i.d. injection of B1 agonists, des-Arg9-bradykinin and des-Arg10-kallidin (up to 300 nmol), causes a minimal increase in paw volume, while the B2 agonist tyrosine8-bradykinin (0.3-10 nmol) induces graded paw edema. The injection of des-Arg9-bradykinin (10-100) nmol or des-Arg10-kallidin (1-100 nmol), in paws pre-treated with IL-1beta or TNF alpha (both 5 ng/paw; 60 and 30 min prior, respectively), caused a graded edema formation. The edemas induced by des-Arg9-bradykinin (100 nmol) were evident at 15 min, reaching the maximum 60 and 30 min after treatment with IL-1beta (0.64 +/- 0.06 ml) or TNF alpha (0.47 +/- 0.05 ml), respectively, being reduced at 360 min. The B1 antagonist des-Arg9-NPC 17731 (1-30 nmol), but not the B2 antagonist Hoe 140 (10 nmol), produced marked inhibition of des-Arg9-bradykinin-induced paw edema. Dexamethasone (0.5 mg/kg, s.c., 4 h) or cycloheximide (1.5 mg/kg, s.c., 6 h) significantly prevented the edema caused by des-Arg9-bradykinin (100 nmol) in rats treated with IL-1beta (81 +/- 5% and 59 +/- 3%) or TNF alpha (78 +/- 4% and 43 +/- 2%). Indomethacin (2 mg/kg, i.p.) or meloxicam (3 mg/kg, i.p.), 1 h prior, significantly reduced the edema induced by des-Arg9-bradykinin (100 nmol) in IL-1beta (40 +/- 6% and 69 +/- 8%) or TNF alpha (43 +/- 3% and 53 +/- 9%) treated rats. It is suggested that i.d. injection of the IL-1beta or TNF alpha, produced up-regulation of B1 receptor-mediated paw edema, being this effect sensitive to dexamethasone and cycloheximide and to cyclo-oxygenase pathway.

Objective: To study the acute anti-inflammatory and anti-allergic properties of an extract of D. winteri., Material and Methods: Paw oedema induced in rats with various stimuli and anaphylactic shock in mice., Results: The hydroalcoholic extract (HE) of D. winteri (Winteraceae) (30 to 100 mg/kg, p.o., 1 h prior) inhibited carrageenan (300 micrograms/paw) and dextran (100 micrograms/paw)-induced paw oedema formation in a dose-dependent manner, with mean ID50 values of 49 and < 30 mg/kg, respectively. The HE of D. winteri (30 to 100 mg/kg) also inhibited paw oedema induced by bradykinin (BK) (3 nmol), substance P (SP) (10 nmol) and PAF-acether (PAF) (10 nmol), in a dose-dependent manner, with mean ID50 values of 56, 63, and 58 mg/kg, respectively. However, the HE inhibited the rat paw oedema induced by prostaglandin E2 (PGE2) (10 nmol) (29 +/- 7 and 33 +/- 2% at 60 and 240 min) to a smaller extent, and had no effect on oedema elicited by histamine (100 nmol). In adrenalectomized animals, the inhibition by the HE of D. winteri (100 mg/kg, p.o., 1 h prior) of BK-elicited oedema (3 nmol/paw) was significantly smaller when compared with that observed in control animals. When assessed in rats actively sensitised to ovalbumin (OVO), the oedema caused by OVO (6 micrograms/paw) was significantly inhibited by HE of D. winteri (30 to 100 mg/kg, p.o.), with a mean ID50 of about 65 mg/kg. The HE of D. winteri (100 and 200 mg/kg, p.o.) significantly increased survival rate when assessed in anaphylactic shock in mice actively sensitised to the antigen. The protective effect was long-lasting, being observed for up to 15 h. Dexamethasone, used as positive control (0.5, 1 and 2 mg/kg) produced a long-lasting (up to 24 h) increase in the survival rate of the animals., Conclusions: These results confirm and extend our previous studies, and demonstrate the clear oral anti-inflammatory and anti-allergic properties of the active principle(s) present in the barks of D. winteri, thus confirming its reported medicinal use in folk medicine for the management of airway diseases.

1. The present study was designed to investigate the influence of long-term systemic treatment with Mycobacterium bovis bacillus Calmette-Guérin (BCG, 1 dose per animal, containing 6 x 10(4) colony-forming-units (CFu), 5 to 75 days beforehand) on oedema formation induced by intradermal injection of B1 and B2 selective agonists. The interaction between the B1 agonist des-Arg9-bradykinin and bradykinin was also investigated. 2. Intradermal injection (i.d.) of the B2 selective agonist tyrosine8-bradykinin (1-10 nmol) in naive (saline pretreated) animals, or in animals that had received BCG (30 days beforehand), caused dose-related and very similar oedema formation (ED50; 1.1 and 1.0 nmol/paw, respectively). I.d. injection of the selective B1 agonists des-Arg9-bradykinin (100 nmol) or des-Arg10-kallidin in naive animals caused very little paw oedema (0.04 +/- 0.06 and 0.07 +/- 0.02 ml, respectively, n = 5). However, i.d. injection of des-Arg9-bradykinin (10-300 nmol) or des-Arg10-kallidin (3-100 nmol) in animals pretreated with BCG, 30 days previously, resulted in dose-related and marked oedema formation, with mean ED50 values of 20.1 and 5.5 nmol/paw, respectively. 3. Oedema caused by i.d. injection of des-Arg9-bradykinin (100 nmol/paw) in rats pretreated with BCG was evident 5 days after treatment, reaching the maximum 30 days later, remaining stable for up to 45 days, and reduced markedly at 75 days. 4. The i.d. co-injection of the selective B1 antagonists des-Arg9[Leu8]-bradykinin (200 nmol), des-Arg10[Leu9]-bradykinin (30 nmol) and des-Arg9-NPC 17731 (30 nmol) significantly (18 +/- 3, 34 +/- 2 and 56 +/- 4%, respectively) prevented the paw oedema caused by i.d. injection of des-Arg9-bradykinin (100 nmol) in rats treated with BCG. These effects were selective, because the i.d. injection of the B1 selective antagonist des-Arg10[Leu9]-kallidin (30 nmol), at the same dose that consistently antagonized des-Arg9-bradykinin (100 nmol)-mediated paw oedema, had no significant effect against tyrosine8-bradykinin (3 nmol)-induced oedema in animals that had been treated previously with BCG. On the other hand, the i.d. co-injection of the selective B2 antagonist, Hoe 140 (10 nmol) at a dose which markedly inhibited tyrosine8-bradykinin (3 nmol)-induced oedema by 55 +/- 4%, did not significantly affect des-Arg9-bradykinin-induced paw oedema in animals pretreated with BCG. 5. Treatment of animals with dexamethasone (0.5 mg kg-1, s.c.) every 24 h, from day 0 to day 30, inhibited significantly (67 +/- 4%) the oedema caused by des-Arg9-bradykinin (100 nmol), but did not affect the paw oedema caused by tyrosine8-bradykinin (3 nmol) in animals pretreated with BCG. 6. Indomethacin (2 mg kg-1, i.p.), administered 1 h before experiments, significantly inhibited des-Arg9-bradykinin (100 nmol)-induced oedema formation, and, to a lesser extent, the paw oedema caused by tyrosine8-bradykinin (3 nmol) (44 +/- 4 and 20 +/- 4%, respectively). 7. These findings show that the long-term systemic treatment of rats with BCG promoted a time-dependent and consistent paw oedema formation to B1 agonists, des-Arg9-bradykinin and des-Arg10-kallidin, leaving responses to the B2 agonist tyrosine8-bradykinin unaffected. The upregulation of B1 receptors after BCG treatment was inhibited by dexamethasone, suggesting the possible involvement of de novo protein synthesis. Finally, our results also show that in BCG-treated animals, the B1 agonist des-Arg9-bradykinin interacts in a synergistic manner with bradykinin. Therefore, both B1 and B2 kinin receptors appear to play a relevant role in modulating chronic inflammatory processes.

1. The effect of pretreatment with bacterial endotoxin (LPS, 10 micrograms, i.v., 24 h) on the bradykinin B1 and B2 receptor-induced oedema in the rat paw, and the interaction of B1-mediated responses with other inflammatory mediators, was investigated. 2. Intraplantar (i.pl.) injection of the selective B1 agonist, des-Arg9-BK (DABK, 100 nmol) in naive animals pretreated with the angiotensin converting enzyme inhibitor, captopril caused a small increase in paw volume (0.04 +/- 0.003 ml, mean +/- s.e. mean, n = 6), while the B2-selective agonist, tyrosine8-bradykinin (T-BK, 3 nmol) induced marked oedema (0.36 +/- 0.02 ml). However, i.pl. injection of DABK (3-300 nmol) in rats pretreated with LPS (24 h beforehand) resulted in a marked dose- and time-related increase in paw volume, with mean ED50 of 24.1 nmol. In contrast, oedema caused by T-BK (3 nmol) was reduced by 79 +/- 4% in animals treated with LPS when compared with naive animals. 3. Oedema caused by prostaglandin E2 (PGE2, 10 nmol) was unaffected by LPS treatment, while oedema induced by histamine (100 nmol), 5-hydroxytryptamine (5-HT, 10 nmol) and substance P (SP, 3 nmol) was reduced (P < 0.05). 4. The selective B1 antagonist, des-Arg9[Leu8]-BK (100-300 nmol), produced dose-dependent inhibition of DABK (100 nmol)-induced paw oedema in LPS-treated animals with mean IC50 of 134 nmol, while the selective B2 antagonists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect. 5. Treatment of animals with dexamethasone (0.5 mg kg-1, s.c.) 24 or 48 h prior to LPS injection resulted in a graded inhibition of DABK (100 nmol)-induced oedema formation (58 +/- 3 and 82 +/- 2%, respectively), and almost reversed to control value oedema formation induced by T-BK (3 nmol) in LPS-pretreated rats. Cycloheximide (1 mg kg-1, s.c.) or indomethacin (2 mg kg-1, i.p.) pretreatment 24 and 1 h prior to LPS injection, respectively, markedly inhibited DABK (100 nmol)-induced paw oedema (98 +/- 2 and 50 +/- 4%, respectively). 6. Intraplantar injection of submaximal dose of DABK (10 nmol) in LPS-treated rats produced modest paw oedema (0.09 +/- 0.03 ml). However, i.pl. injections of PGE2, prostacyclin (PGI2), calcitonin-gene-related peptide (CGRP), SP, 5-HT, or platelet activating factor (PAF) (each 1 nmol), which alone caused little or no paw oedema, resulted in a potentiation of the DABK-induced oedema. The increases in paw volume (in ml) were: PGE2 + DABK (0.31 +/- 0.03), PGI2 + DABK (0.39 +/- 0.02), CGRP+DABK (0.35 +/- 0.04), DABK+SP (0.33 +/- 0.04), DABK + 5-HT (0.40 +/- 0.02) and DABK+PAF (0.38 +/- 0.016) ml. In contrast, histamine (1 nmol) was ineffective in potentiating the response to DABK. 7. The selective B1 receptor antagonist, DALBK (100-300 nmol), produced dose-dependent inhibition of paw oedema potentiation induced by co-injection of DABK and other mediators with mean ID50S (nmol) of: 180, 160, 139 and 135 in the presence of PGE2, PGI2, SP and 5-HT, respectively. 8. These results demonstrate that DABK-induced increase in paw volume in LPS-treated rats is probably mediated by induction of B1 receptors, associated with downregulation of B2 receptors. The induction of B1 receptors by LPS is sensitive to dexamethasone and cycloheximide treatment and requires activation of cyclo-oxygenase pathway. In addition, B1 receptors, when upregulated following LPS treatment, can interact in a synergistic manner with several inflammatory mediators such as PGI2, PGE2, CGRP, PAF and 5-HT. Such results indicate that induction of the B1 receptor might have a significant pathophysiological role in modulating chronic inflammatory diseases.

Bradykinin (BK) and Tyr8-BK induced graded rat paw edema with EC50 values of 1.9 and 1.1 nmol/paw, while des-Arg9-BK (DABK, up to 300 nmol/paw) was marginally effective. Tyr8-BK, but not DABK, also caused a dose-related increase in mouse paw edema, with an EC50 of 1.3 nmol/paw. The response to Tyr8-BK (10 nmol/paw) in rat paw edema was antagonized by B2 receptor antagonists (HOE-140 or NPC 17731, 30 nmol/paw) but not by the B1 antagonist des-Arg9[Leu8]BK (DALBK, 100 nmol/paw). Daily intraplantar injections of Tyr8-BK (10 nmol/paw) for 7 days caused progressive desensitization (D) of edema in sham-operated and adrenalectomized Wistar rats. DABK (100 nmol/paw) caused marked paw edema in D paws from both groups, which was inhibited by DALBK (100 nmol/paw) and by dexamethasone (0.5mg/kg, s.c.). Systemic injection of lipopolysaccharide (10 micrograms/mouse, 24 h prior) potentiated the first and second phases of Formalin-induced pain but had no effect on paw edema. Coinjection of DABK (2-22 nmol/paw) with low doses of Formalin in lipopolysaccharide-treated mice, which had no effect on naive animals, dose dependently potentiated both phases of Formalin-induced pain but did not modify paw edema. These effects were antagonized by DALBK with ID50 values of 21.9 (first phase) and 64.1 (second phase) nmol/paw. Thus, both progressive desensitization of B2 receptors and systemic treatment with lipopolysaccharide induce a glucocorticoid-sensitive upregulation of B1 receptors mediating paw edema in the rat and Formalin-induced nociception in mice. These results suggest that induction of upregulation of B1 receptors may play important roles in controlling inflammatory processes and hyperalgesia.

1. The mechanisms involved in bradykinin (BK)-induced oedema in the rat paw as well as the interactions between BK and several inflammatory mediators, have been investigated. 2. Intraplantar injection of BK (1 nmol/paw) in rats pretreated with captopril (5 mg kg-1, s.c.) caused a small amount of oedema formation (0.17 +/- 0.05 ml). Des-Arg9-BK (DABK, a selective B1 receptor agonist) up to 300 nmol/paw caused minimal oedema (0.03 +/- 0.01 ml). 3. Co-administration of prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), calcitonin gene-related peptide (CGRP), 5-hydroxytryptamine (5-HT), substance P (SP) or platelet activating factor (PAF) (1 pmol-1 nmol/paw) with BK (1 nmol/paw) dose-dependently potentiated BK-induced paw oedema. The rank order of potency (mean ED50, pmol/paw) for this effect was: SP (8.1) > PAF (13.7) > PGI2 (20.5) > 5-HT (23.8) > CGRP (25.7) > PGE2 (52.0). Co-administration of BK with the various inflammatory mediators resulted in maximal paw oedemas (ml) of: PGE2 (0.71 +/- 0.02); PGI2 (0.66 +/- 0.02); 5-HT (0.65 +/- 0.01); SP (0.63 +/- 0.05); CGRP (0.60 +/- 0.05) and PAF (0.47 +/- 0.02) ml. Histamine (up to 1 nmol/paw) was ineffective in potentiating the response to BK. 4. Hoe 140 or NPC 17731 (two selective B2 receptor antagonists, 0.1-3 nmol/paw) produced dose-dependent inhibition of paw oedema potentiation induced by co-injection of BK with other mediators with the following mean ID50s (nmol/paw): Hoe 140-1.4; 1.3; 1.5 and 1.1 and NPC 17731-1.0; 1.0; 0.9 and 0.7; in the presence of PGE2, PGI2, CGRP and SP, respectively. The selective B1 receptor antagonist des-Arg9 [Leu8]-BK (DALBK, up to 300 nmol/paw) had no effect.5. Daily intraplantar injections of BK (10 nmol/paw) once a day for 7 consecutive days caused a progressive and complete desensitization of the paw oedema, which was specific for BK, since paw oedema induced by PAF, PGE2, SP or histamine was not affected. In addition, the oedema caused by BK in the paw desensitized to the peptide was almost completely reversed if BK was co-injected with PGE2, PGI2 or SP (1 nmol/paw). Injection of PGE2 or SP (10 nmol/paw) together with the first BK injection (1O nmol/paw), partially prevented BK-induced desensitization.6. When animals were completely desensitized to BK, DABK (100nmol/paw) caused paw oedema(0.25 +/- 0.03 ml) which was consistently blocked by the B1 receptor antagonist, DALBK (100 nmol/paw).7. Treatment of animals with dexamethasone (0.5 mg kg-1, s.c., 24 h previously) antagonized paw oedema induced by DABK (100 nmol/paw) in desensitized paws, but not that induced by BK (3 nmol/paw) in naive paws. The steroid also prevented the recovery of oedema seen after co-injection of BK with PGE2 or PGI2 (1 nmol/paw) in desensitized paws.8. These results suggest that both B, and B2 receptors are involved in BK-induced rat paw oedema. The B2 receptors are constitutive, but induction of expression of B, receptors seems to occur only after complete desensitization of the paw to BK. In addition, very low doses of inflammatory mediators markedly potentiate BK-induced paw oedema and can attenuate BK-induced paw oedema desensitization.Such mechanisms may be relevant for the manifestation of acute and chronic inflammatory processes.

Background and Purpose: The effects of systemic treatment with indomethacin-loaded nanocapsules (IndOH-NC) were compared with those of free indomethacin (IndOH) in rat models of acute and chronic oedema.Experimental Approach: The following models of inflammation were employed: carrageenan-induced acute oedema (measured between 30 min and 4 h), sub-chronic oedema induced by complete Freund's adjuvant (CFA) (determined between 2 h and 72 h), and CFA-induced arthritis (oedema measured between 14 and 21 days).Key Results: IndOH or IndOH-NC produced equal inhibition of carrageenan-elicited oedema. However, IndOH-NC was more effective in both the sub-chronic (33 +/- 4% inhibition) and the arthritis (35 +/- 2% inhibition) model of oedema evoked by CFA, when compared with IndOH (21 +/- 2% and 14 +/- 3% inhibition respectively) (P < 0.01). In the CFA arthritis model, treatment with IndOH-NC markedly inhibited the serum levels of the pro-inflammatory cytokines tumour necrosis factor alpha and IL-6 (by 83 +/- 8% and 84 +/- 11% respectively), while the levels of the anti-inflammatory cytokine IL-10 were significantly increased (196 +/- 55%). The indices of gastrointestinal damage in IndOH-NC-treated animals were significantly less that those after IndOH treatment (58 +/- 16%, 72 +/- 6% and 69 +/- 2%, for duodenum, jejunum and ileum respectively).Conclusions and Implications: IndOH-NC produced an increased anti-inflammatory efficacy in long-term models of inflammation, allied to an improved gastrointestinal safety. This formulation might represent a promising alternative for treating chronic inflammatory diseases, with reduced undesirable effects. [ABSTRACT FROM AUTHOR]