Inhibition of carrageenan edema by carrageenan itself]

The influence of two kinin forming agents: iota carrageenan and ellagic acid, on the paw oedema induced by 48/80, an amino-liberator, or by carrageenan iota, has been studied, in the Rat. Ellagic acid and carrageenan, by intraperitoneal injection, reduce the paw oedema induced respectively by 48/80 and carrageenan itself. This inhibition depends on a non-specific "counter-irritation" and not on kininogen stores depletion. Ellagic acid, by intravenous injection, diminishes the oedema induced by carrageenan; swelling due to 48/80, is not affected. So kininogen activation plays some role in the inflammatory processes induced by iota carrageenan. Carrageenan by intravenous injection, suppresses his own inflammatory action but does not influence at all the similar action of 48/80. The anti-inflammatory effect of carrageenan does not exclusively depend on kininogen stores depletion.     

Anti-inflammatory activity of amylin and CGRP in different experimental models of inflammation

The anti-inflammatory activity of amylin was studied in different models of inflammation, and compared to that of CGRP. Both peptides were active against mouse ear oedema induced by croton oil and acetic acid-induced peritonitis in the rat. CGRP was more potent than amylin in both models. Pretreatment with CGRP 8–37 fragment blocked the anti-inflammatory activity of both peptides in croton oil ear oedema. No anti-inflammatory activity was evidenced against serotonin-induced rat paw oedema and plasma protein extravasation induced by dextran in rat skin. Our results suggest that amylin exerts anti-inflammatory activity only in inflammatory models characterized by a vascular component. This effect appears to be mediated by the involvement of CGRP receptors.     

Increase in serum level of interleukin-1 alpha mediates morphine anti-inflammatory effect in carrageenan-induced paw oedema in mice

In the present studies we examined the effects of an intra-peritoneal injection of morphine (7 mg/kg) on carrageenan-induced paw oedema in mice. Carrageenan-induced paw oedema was measured by mercury plethysmometer and was maximal at hour 3, and pretreatment with morphine could reduce the oedema significantly. At the same time the serum levels of interleukin-1 alpha (IL-1 alpha) were increased. Pretreatment with naloxone and dexamethasone abolished morphine anti-inflammatory while decreasing IL-1 alpha serum levels, significantly. These findings suggest that an increase in serum levels of IL-1 alpha plays an important role in the anti-inflammatory effect of morphine.     

Suppressions of Ischemic Paw Oedema in Mice, Rats and Guinea Pigs by Superoxide Dismutases from Different Sources

Various sources of superoxide dismutases (SOD) suppressed ischaemic paw oedemata (tourniquet poditis) of mice, rats and guinea pigs with different potencies. Intravenous (i.v.) dosing of mouse Cu, Zn-SOD had no effect on mouse ischaemic oedema, yet rat and guinea pig Cu, Zn-SOD suppressed ischaemic oedemata of rats and guinea pigs. Homologous SOD was anti-inflammatory at least in these two models. Guinea pig SOD was one of the most potent in all models, but showed a very narrow range of effective dose. This bell-shape suppressive pattern was ameliorated by concomitant catalase injection. Bovine and human Cu, Zn-SOD had a rather broad range of effective dose. Bacterial Mn-SODS were suppressive in mice, as well as the oxygen radical scavenger MK-447 and cytochrome c. Dexamethasone was effective only when administered more than 3 hrs in advance. As ischaemic paw oedema of mice was not sensitive to cyclooxy-genase and lipoxygenase inhibitors, this model could serve for screening new types of anti-inflammatory or anti-ischaemic drugs.     

Participation of the adrenal gland in the anti-inflammatory effect of polyunsaturated diets

The effect of an n-3 (fish) and n-6 (soybean) fatty acid-rich diet on carrageenin paw oedema in rats, and the participation of adrenal gland, corticosterone and alpha(2)-macroglobulin (alpha(2)-M) in this process were studied. A significant inhibition of carrageenin oedema was observed not only in rats fed a diet rich in fish oil but also in the soybean group. alpha(2)-M was not detectable before carrageenin injection, suggesting that this putative antiinflammatory factor does not participate in the observed anti-inflammatory effect. Corticosterone levels were higher in fat-fed than in control rats, before carrageenin stimulus and adrenalectomy abolished the anti-inflammatory response in fat-fed animals, showing the important role of the adrenocortical hormones in this process.     

Suppressions of Ischemic Paw Oedema in Mice,Rats and Guinea Pigs by Superoxide Dismutases from Different Sources

Various sources of superoxide dismutases (SOD) suppressed ischaemic paw oedemata (tourniquet poditis) of mice, rats and guinea pigs with different potencies. Intravenous (i.v.) dosing of mouse Cu, Zn-SOD had no effect on mouse ischaemic oedema, yet rat and guinea pig Cu, Zn-SOD suppressed ischaemic oedemata of rats and guinea pigs. Homologous SOD was anti-inflammatory at least in these two models. Guinea pig SOD was one of the most potent in all models, but showed a very narrow range of effective dose. This bell-shape suppressive pattern was ameliorated by concomitant catalase injection. Bovine and human Cu, Zn-SOD had a rather broad range of effective dose. Bacterial Mn-SODS were suppressive in mice, as well as the oxygen radical scavenger MK-447 and cytochrome c. Dexamethasone was effective only when administered more than 3 hrs in advance. As ischaemic paw oedema of mice was not sensitive to cyclooxy-genase and lipoxygenase inhibitors, this model could serve for screening new types of anti-inflammatory or anti-ischaemic drugs.     

Involvement of steroids in anti-inflammatory effects of peripheral benzodiazepine receptor ligands

Mouse paw oedema induced by carrageenan is used to determine if glucocorticoids are involved in the anti-inflammatory effects of peripheral benzodiazepine receptor ligands. The anti-inflammatory responses elicited by i.p. treatment with 1-(2-chlorophenyl)-N-methyl-N (1-methyl-propyl)-3-isoquinoline carboxamide (PK11195) and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2-H-1, 4-benzodiazepin-2 (Ro5-4864) were reversed by aminoglutethimide, an inhibitor of steroidal synthesis. Intraplantar injection into the ipsilateral paw of Ro5-4864, but not PK11195, inhibited the formation of paw oedema and this effect was reversed by aminoglutethimide. These results suggest that glucocorticoids are involved in the systemic and local anti-inflammatory effects of Ro5-4864 and only in the systemic response to PK11195.     

Fibrinogen and plantar edema induced by lambda carrageenan

1. Batroxobine which induces fibrinogen consumption, accelerates the development of 48/80 and lambda carrageenan oedema: in the rat the various products released from fibrinogen and fibrin increase these inflammatory reactions. 2. Heparin and epsilon-aminocaproic acid have no influence on carrageenan oedema: the derivatives of fibrinogen do not take part in the constitution of the inflammatory reaction induced by carrageenan. 3. The anti-inflammatory action of this sulfated polygalactose does not depend on its anti-coagulant activity.     

Dietary n-3 Fatty Acids Inhibit Fever Induced by Inflammation in the Rat

Modification of endogenous eicosanoid synthesis by dietary n-3 fatty acid supplementation reduces febrile responses, but the mechanisms underlying these effects in vivo have not been determined. In the present study, local inflammation was induced by intramuscular injection ofturpentine in rats fed control or n-3 supplemented diets for 8-9 weeks. In animals fed the control diet, turpentine induced fever, hypermetabolism, marked local inflammation (oedema), increased plasma IL-6 concentrations and raised cerebrospinal fluid (CSF) concentrations of PGE2. N-3 fatty acid supplementation significantly inhibited the rise in CSF PGE2, fever and hypermetaboHsm induced by turpentine. Local inflammation and increased plasma IL-6 concentrations were not affected by n-3 supplementation. These findings suggest that modification of dietary fat intake inhibits fever via reduced release of prostaglandins, probably within the brain, but does not affect the local or afferent signals involved in fever generation.     

'Antiflammins': two nonapeptide fragments of uteroglobin and lipocortin I have no phospholipase A2-inhibitory and anti-inflammatory activity

The 'antiflammin' nonapeptides P1 and P2 [(1988) Nature 335, 726-730] were synthesized and tested for inhibition of phospholipase A2 and release of prostaglandin E2 and leukotriene C4 in stimulated cells in vitro, and in vivo for anti-inflammatory activity in rats with carrageenan-induced paw oedema. Porcine pancreatic phospholipase A2 was not inhibited at concentrations of 0.5-50 microM. Prostaglandin E2 and leukotriene C4 release by mouse macrophages stimulated with zymosan or ATP was not affected up to a concentration of 10 microM, nor was prostaglandin release by interleukin 1 beta-stimulated mesangial cells and angiotensin II-stimulated smooth muscle cells. Both peptides exhibited no anti-inflammatory activity in carrageenan-induced rat paw oedema after topical (250 micrograms/paw) or systemic administration (1 or 4 mg/kg s.c.). These results do not support the claim of potent phospholipase A2-inhibitory and anti-inflammatory activity of the 'antiflammins' P1 and P2.     

Anti-inflammatory, antioxidant and antimicrobial activity of Ophthacare brand, an herbal eye drops.

In the present study, the herbal preparation of Ophthacare brand eye drops was investigated for its anti-inflammatory, antioxidant and antimicrobial activity, using in vivo and in vitro experimental models. Ophthacare brand eye drops exhibited significant anti-inflammatory activity in turpentine liniment-induced ocular inflammation in rabbits. The preparation dose-dependently inhibited ferric chloride-induced lipid peroxidation in vitro and also showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus and antifungal activity against Candida albicans. All these findings suggest that Ophthacare brand eye drops can be used in the treatment of various ophthalmic disorders.     

Haptoglobin and lipoperoxides in rabbit plasma under turpentine- and endotoxin-induced inflammation

Inflammation was induced in rabbits by injection of turpentine or/and endotoxin. Haptoglobin (Hp) and lipoperoxide (as malondialdehyde - MDA) concentrations in rabbit plasma, were measured. In some experiments indomethacin was administered, as a specific control of anti-inflammatory action. In the course of the reagents-induced inflammation there existed positive correlation between changes in Hp and MDA levels. Indomethacin was found to eliminate this effect. Under the model system of experiments, Hp as presumed endogenous inhibitor of prostaglandin synthesis, even in concentrations in rabbits' blood 15-20 times higher than normal, did not exert any protective action against inflammation.     

Effects of simulated microgravity conditions on carrageenin-induced oedema in rat

The effects of simulated microgravity conditions, using a three-dimensional clinostat (Random Positioning Machine, RPM), on carrageenin-induced paw oedema in rats as a model of local inflammation were evaluated. RPM-exposed animals showed a significant reduction of oedema and a more pronounced decrease in body weight with respect to control groups. Moreover, aspirine (ASA) treatment, an anti-inflammatory agent, on RPM-exposed rats did not exhibit any activity after carrageenin challenge with respect to RPM control animals on the ground. ASA activity on RPM could be prevented by RPM-induced anti-oedematous effect. RPM-induced anti-oedematous effect did not reversed by pre-treatment with the non-selective glucocorticoid receptor antagonist, mifepristone ruling out the supposed influence of an of cortisol release during the RPM treatment.     

Anti--Histaminic potentila of fractions from Hedranthera Barteri [(Hook F.) Pichon] root in laboratory rodents

Hedranthera barteri, anti-inflammatory activity, anti-nociceptive activity, anti-histaminic activityL. (HB) is used in the treatment of painful conditions and oedema amongst its folkloric use. The hexane and ethyl acetate fractions of the root of H. barteri were investigated for anti-nociceptive and antiinflammatory properties and probable mechanism of action. Hot plate, tail flick, formalin-induced oedema and acetic acidinduced writhing tests were employed to investigate the anti-nociceptive activity while the anti-inflammatory activity was investigated using carrageenan-induced paw oedema. Anti-histaminic potential of HB root extracts on the rat peritoneal mast cells (RPMCs) was explored through pectrofluorometric method. The root was screened for its phytochemical components. The HB root contains alkaloids,cardenolides and saponins. HXHBR exhibited higher anti-inflammatory potentials (P <0.001). HXHBR dose-dependently (P <0.01) reduced the histamine release from the rat peritoneal mast cells which is comparable with a standard anti-histaminic drug, ketotifen. These results showed that EAHBR and HXHBR possess anti-nociceptive and anti-inflammatory activities, and suggested its mechanism of action through the inhibition of histamine, an inflammatory mediator, usually released during the early phase of allergic responses and chronic phase of inflammatory pain. Flavonoids, alkaloids and/or saponins present in HB root may be responsible for its anti-nociceptive and anti-inflammatory properties.     

Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.     

Increase of sialyltransferase activity in the serum and liver of inflamed rates

Induction of inflammation by turpentine injection caused 1.5–2-fold increase of both sialy- and galactosyltransferase activity in liver homogenates. The effect was apparent after 12 h turpentine treatment. Serum sialytransferase activity started to increase in the inflamed rats after 18 h, reaching a maximum of 4-fold at 48 h. In contrast, galactosyltransferase activity in serum showed no significant increase. The coordinated and temporal increase of sialytransferase activity in liver and serum suggest involvement of a specific mechanism for the preferential release of this enzyme into serum.     

Increase of sialyltransferase activity in the serum and liver of inflamed rats

Induction of inflammation by turpentine injection caused 1.5-2-fold increase of both sialyl- and galactosyltransferase activity in liver homogenates. The effect was apparent after 12 h of turpentine treatment. Serum sialyltransferase activity started to increase in the inflamed rats after 18 h, reaching a maximum of 4-fold at 48 h. In contrast, galactosyltransferase activity in serum showed no significant increase. The coordinated and temporal increase of sialyltransferase activity in liver and serum suggest involvement of a specific mechanism for the preferential release of this enzyme into serum.     

Extract and compounds obtained from Mandevilla velutina inhibit arachidonic acid-induced ear oedema in mice, but not rat stomach contraction

This study was designed to analyse the effect of crude extract (CE) and some pure compounds isolated from M. velutina on arachidonic acid (AA)-induced ear oedema in mice. The effect of these compounds on contractions in the rat stomach induced by AA and prostaglandin E2 (PGE2) was also investigated. The CE given orally to mice (50-400 mg/kg) 1h before inhibited the ear oedema in a dose-dependent manner, with a maximal inhibition (MI) of 56%. Given topically, compound MV8612 (200-600 mg/ear) isolated from this plant inhibited the oedema in a concentration-dependent manner with a MI of 66%, while compounds MV8608 and MV8610 (100-600 mg/ear) caused less inhibition, MI 29% and 39% respectively. Compound MV8612, given i.p. (3-30 mg/kg) 30 min before, also caused a dose-dependent inhibition of AA-induced ear oedema (MI of 60.5% compared with 28% and 49% for MV8608 and MV8610). Indomethacin (0.25-1.0 mg/ear) applied topically had no effect, but orally (1-10 mg/kg) gave MI of 66%. Phenidone given orally (10-100 mg/kg) gave a MI of 30% but it was very potent topically (0.5-2 mg/ear) (MI 66%). Nordihydroguaiaretic acid applied either topically (0.5-2.0 mg/ear) or orally (10-100 mg/kg) caused MI of 63% and 47%, respectively. BW 755C, orally (10-100 mg/kg), inhibited the AA-induced oedema in a dose-dependent manner (MI 48%), but was less effective when applied topically (0.25-1 mg/ear) (MI 32%). In the rat stomach preparation, compounds MV8608 and MV8612 (0.1-20 micrograms/ml) had no significant effect on contractions to AA or PGE2, while indomethacin (0.01-3 micrograms/ml) potently inhibited AA contraction, but had no effect on the PGE2 response. These results indicate that MV8608 and MV8612 exhibit both a topical and a systemic anti-inflammatory profile, presumably by a mechanism not related to inhibition of cyclooxygenase.     

Leguminous lectins as tools for studying the role of sugar residues in leukocyte recruitment

The natural physiological ligands for selectins are oligosaccharides found in glycoprotein or glycolipid molecules in cell membranes. In order to study the role of sugar residues in the in vivo lectin anti-inflammatory effect, we tested three leguminous lectins with different carbohydrate binding affinities in the peritonitis and paw oedema models induced by carrageenin in rats. L. sericeus lectin was more anti-inflammatory than D. virgata lectin, the effects being reversed by their specific binding sugars (N-acetylglucosamine and alpha-methylmannoside, respectively). However, V. macrocarpa, a galactose-specific lectin, was not anti-inflammatory. The proposed anti-inflammatory activity of lectins could be due to a blockage of neutrophil-selectin carbohydrate ligands. Thus, according to the present data, we suggest an important role for N-acetylglucosamine residue as the major ligand for selectins on rat neutrophil membranes.     

Effect of ricinoleic acid in acute and subchronic experimental models of inflammation

Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.