Simvastatin and Indomethacin Have Similar Anti‐Inflammatory Activity in a Rat Model of Acute Local Inflammation

Abstract: Statins, such as simvastatin, lower circulating cholesterol levels and are widely prescribed for the treatment of hypercholesterolaemia. Several studies have shown unexpected effects of statins on inflammation. We studied the anti‐inflammatory effect of simvastatin using a standard model of an acute local inflammation, the carrageenan‐induced footpad oedema. Experimental groups (n = 6–8) were given simvastatin in a dose range 5–30 mg/kg, indomethacin 1–8 mg/kg and methylcellulose (control) per os. Footpad volume was measured with a plethysmograph and compared with the pre‐injection volume of the same paw. Swelling (in microlitres) was then calculated, and in drug‐treated animals, per cent inhibition was derived through comparison with the control group. Histopathological examination of the skin biopsies was performed to examine severity of paw skin lesions and to confirm the simvastatin‐induced inhibition of acute inflammation. Both simvastatin and indomethacin administered orally, 1 hr before carrageenan injection, significantly reduced the extent of footpad oedema. Indomethacin dose‐dependently blocked the swelling; the maximal effect was obtained with 8 mg/kg by 48.3% (P < 0.05). Simvastatin produced a comparable anti‐inflammatory activity at a dose of 5 mg/kg (32%), while 10 and 30 mg/kg caused a 47.6% and 51.7% reduction, respectively, with the maximal effect observed at 20 mg/kg by 57.2% (P < 0.05). The comparison of the ED₅₀ of these agents on molar basis showed equipotent anti‐inflammatory activity. Histopathological examination of the footpad skin biopsies revealed that simvastatin, dose‐dependently and comparablly to indomethacin, reduced polymorphonuclear leucocyte infiltration. These data support the hypothesis that simvastatin has an acute anti‐inflammatory activity.     

Peripheral Antinociception and Anti‐Inflammatory Effects of Sulphated Polysaccharides from the Alga Caulerpa mexicana

Sulphated polysaccharides from marine algae are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of sulphated polysaccharides from the green marine alga Caulerpa mexicana (Cm‐SPs) in nociceptive and inflammatory models in rodents. Cm‐SPs (10 or 20 mg/kg), administered i.v. in Swiss mice, significantly reduced nociceptive responses, as measured by the number of writhes in response to acetic acid. Cm‐SPs (10 or 20 mg/kg) also reduced second‐phase responses in the formalin test, but did not exhibit a significant antinociceptive effect in the hot plate test, suggesting that its antinociceptive action occurs through a peripheral mechanism. Cm‐SPs (5, 10 or 20 mg/kg), administered s.c. in wistar rats 1 hr before carrageenan, dextran, histamine or serotonin, were tested in paw oedema models. Cm‐SPs (10 or 20 mg/kg) reduced carrageenan‐induced paw oedema and myeloperoxidase activity in the paw. In addition, Cm‐SPs (20 mg/kg) inhibited dextran‐ or histamine‐induced paw oedema, but not serotonin‐induced oedema, suggesting that histamine is the major target of Cm‐SPs anti‐oedematogenic activity. Finally, Cm‐SPs (20 mg/kg) administered in mice did not show significant signs of toxicity. In conclusion, Cm‐SPs appear to be promising natural modulatory agents for pain and inflammatory conditions.     

Beneficial Pharmacological Effects of Levosimendan on Antioxidant Status of Acute Inflammation Induced in Paw of Rat: Involvement in Inflammatory Mediators

Levosimendan (LEVO) is a new calcium sensitizer with positive inotropic and vasodilating properties that represents a new pharmacological class of inotropic drugs that stimulate elevated cardiac output. The purpose of this study was to examine anti‐inflammatory effect and antioxidant activity of LEVO in a carrageenan (CAR)‐induced inflammatory paw oedema rat model. The CAR‐induced rat groups received LEVO 1, 2 and 3 mg/kg by intraperitonally and indomethacin (IND) 25 mg/kg by oral gavage. LEVO inhibited CAR‐induced paw oedema and suppressed the production of TNF‐α, IL‐1 and IL‐6 at doses of 2 and 3 mg/kg. In contrast to CAR‐injected paws, 2 and 3 mg/kg doses of LEVO and IND increased superoxide dismutase (SOD) activity and also both doses of LEVO, and IND decreased the 8‐isoprostaglandin F2α (8‐ISO) level. A 2 mg/kg dose of LEVO produced 39%, 46%, 61% and 64.7% anti‐inflammatory effects (p < 0.0001) for the 1st, 2nd, 3rd and 4th hours, respectively. Other results of our current study have shown that SOD and glutathione for CAR‐injected groups were lower, and 8‐ISO level was higher than those for the healthy rat group. LEVO may be provided as a pharmacological agent in the prevention or treatment of diseases in which acute or chronic inflammation occurs based on a pathogenic factor.     

Mechanisms involved in the antinociception caused by ethanolic extract obtained from the leaves of Melissa officinalis (lemon balm) in mice

The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or d-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the l-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.     

Effects of Amburoside A and Isokaempferide,Polyphenols from Amburana cearensis,on Rodent Inflammatory Processes and Myeloperoxidase Activity in Human Neutrophils

Abstract: The present study evaluated the anti‐inflammatory activity of amburoside A (a phenol glucoside) and isokaempferide (a flavonol) isolated from the trunk bark of Amburana cearensis, a medicinal plant used in northeast Brazil for the treatment of asthma. Animals (male Wistar rats or Swiss mice) pre‐treated with amburoside A (25 and 50 mg/kg) or isokaempferide (12.5, 25 and 50 mg/kg), orally or intraperitoneally, showed a significant inhibition of the paw oedema induced by carrageenan (1%), prostaglandin E₂ (30 nmol/paw), histamine (200 µg/paw) or serotonin (200 µg/paw). Histological and morphometric evaluations of the rat paw oedema induced by carrageenan showed that amburoside A and isokaempferide also inhibited the accumulation of inflammatory cells. Amburoside A reduced significantly the paw oedema and the increase in vascular permeability induced by dextran, as related to the control group. Similar results were observed with the isokaempferide pre‐treatment. Furthermore, amburoside A or isokaempferide inhibited both leucocyte and neutrophil migrations, in mouse peritoneal cavity, after the carrageenan injection. The polyphenols were not cytotoxic and blocked N‐formyl‐methyl‐leucyl‐phenylalanine‐induced myeloperoxidase release and activity in human neutrophils. In addition, amburoside A and isokaempferide at 50 and 100 µg/ml concentrations reduced significantly the lipopolysaccharide‐mediated increase in tumour necrosis factor‐α (TNF‐α) levels. These results provide, for the first time, evidence to support the anti‐inflammatory activity of amburoside A and isokaempferide that seems to be related to an inhibition of inflammatory mediators, such as TNF‐α, as well as histamine, serotonin and prostaglandin E₂, besides leucocyte infiltration in a dose‐ or concentration‐dependent manner. These anti‐inflammatory effects can be explained, at least in part, by the ability of these compounds to reduce neutrophil degranulation, myeloperoxidase activity, mediators as well as TNF‐α secretion.     

Isopropoxy‐Carvacrol,a Derivative Obtained from Carvacrol,Reduces Acute Inflammation and Nociception in Rodents

Monoterpenes, compounds mainly presented in essential oils, have important pharmacological actions. Isopropoxy‐carvacrol (IPC) is a derivative of the monoterpene carvacrol, and its pharmacological properties have not yet been investigated. The aim of this study was to analyse the acute anti‐inflammatory and antinociceptive properties of IPC. Mice (25–30 g) and rats (150–230 g) were pre‐treated (i.p.) with IPC at the doses of 10, 30 or 100 mg/kg or vehicle (Tween 80, 0.5%), 30 min. before injection of the phlogistic agents. Both the first and the second phases of formalin‐induced nociception were significantly reduced by IPC (100 mg/kg). Injection of carrageenan in mice paw reduced the threshold of stimulus intensity, applied with an analgesymeter, necessary to cause paw withdrawal, which was significantly reduced by 100 mg/kg of IPC. The area under curve (0–4 hr) of rat paw oedema induced by injection of carrageenan was also significantly diminished by the administration of IPC (100 mg/kg). Administration of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) markedly increased mice ear oedema and myeloperidase (MPO) activity. Topical co‐administration of IPC (0.3–3 mg/ear) during the induction did not affect TPA‐induced ear oedema, but significantly decreased MPO activity in the ears, when compared with the vehicle. In in vitro experiments, IPC reduced lipoperoxidation induced by different stimuli, showed nitric oxide scavenger activity and did not interfere with murine macrophage viability in concentrations up to 100 μg/mL. These results demonstrate that IPC exerts acute anti‐inflammatory and antinociceptive activities, suggesting that it may represent an alternative in the development of new future therapeutic strategies.     

Anti-inflammatory, analgesic and antipyretic effects of friedelin isolated from Azima tetracantha Lam. in mouse and rat models

Objectives Friedelin was isolated from Azima tetracantha Lam. leaves collected from Kallakurichi, Villuppuram district, Tamil Nadu, India. The anti‐inflammatory, analgesic and antipyretic activities of friedelin have been investigated in Wistar rats and mice. Methods Friedelin was isolated from the hexane extract of leaves of A. tetracantha using column chromatography. The effects of friedelin on inflammation were studied by using carrageenan‐induced hind paw oedema, croton oil‐induced ear oedema, acetic acid‐induced vascular permeability, cotton pellet‐induced granuloma and adjuvant‐induced arthritis. The analgesic effect of friedelin was evaluated using the acetic acid‐induced abdominal constriction response, formalin‐induced paw licking response and the hot‐plate test. The antipyretic effect of friedelin was evaluated using the yeast‐induced hyperthermia test in rats. Key findings In the acute phase of inflammation, maximum inhibitions of 52.5 and 68.7% (P < 0.05) were noted with 40 mg/kg friedelin in carrageenan‐induced paw oedema and croton oil‐induced ear oedema, respectively. Administration of friedelin (40 mg/kg) significantly (P < 0.05) decreased the formation of granuloma tissue induced by cotton pellet at a rate of 36.3%. In the adjuvant‐induced arthritis test friedelin inhibited 54.5% of paw thickness. Friedelin inhibited acetic acid‐induced vascular permeability in mice. Friedelin also produced significant (P < 0.05) analgesic activity in the acetic acid‐induced abdominal constriction response and formalin‐induced paw licking response. In the hot‐plate test, friedelin did not show any significant results when compared with control. Treatment with friedelin showed a significant (P < 0.05) dose‐dependent reduction in pyrexia in rats. Conclusions The results suggested that friedelin possessed potent anti‐inflammatory, analgesic and antipyretic activities.     

Gastric anti-ulcerative and anti-inflammatory activity of metyrosine in rats

In this study, the anti-inflammatory and anti-ulcerative effects of metyrosine, a selective tyrosine hydroxylase enzyme inhibitor, were investigated in rats. For ulcer experiments, indomethacin-induced gastric ulcer tests and ethanol-induced gastric ulcer tests were used. For these experiments, rats were fasted for 24 h. Different doses of metyrosine and 25 mg/kg doses of ranitidine were administered to rats, followed by indomethacin at 25 mg/kg for the indomethacin-induced ulcer test, or 50% ethanol for the ethanol-induced test. Results have shown that at all of the doses used (50,100 and 200 mg/kg), metyrosine had significant anti-ulcerative effects in both indomethacin and ethanol-induced ulcer tests. Metyrosine doses of 100 and 200 mg/kg (especially the 200 mg/kg dose) also inhibited carrageenan-induced paw inflammation even more effectively than indomethacin. In addition, to characterize the anti-inflammatory mechanism of metyrosine we investigated its effects on cyclooxygenase (COX) activity in inflammatory tissue (rat paw). The results showed that all doses of metyrosine significantly inhibited high COX-2 activity. The degree of COX-2 inhibition correlated with the increase in anti-inflammatory activity. In conclusion, we found that metyrosine has more anti-inflammatory effects than indomethacin and that these effects can be attributed to the selective inhibition of COX-2 enzymes by metyrosine. We also found that adrenalin levels are reduced upon metyrosine treatment, which may be the cause of the observed gastro-protective effects of this compound.     

Antiinflammatory Effects of Moringa oleifera Root Extract

A crude methanol extract of the root of the plant Moringa oleifera Lam. was screened for anti inflammatory effect using the rat paw edema and the rat 6-day air pouch inflammatory models. Following oral administration, the extract inhibited carrageenan-induced rat paw edema in a dose-dependent manner, with 50% inhibitory concentration - IC 50 (dose producing 50% inhibition) of 660 mg/kg. On the 6-day air pouch acute inflammation induced with carrageenan, the extract was much more potent, with IC 50 values of 302.0 mg/kg and 315.5 mg/kg, for the inhibition of cellular accumulation and fluid exudation, respectively. Maximum inhibition obtained with 600 mg/kg were 83.8% and 80.0%, respectively. When delayed (chronic) inflammation was induced in the 6-day air pouch model using Freund’s complete adjuvant, the extract was still effective though less than in acute inflammation. In contrast, a moderate dose of indomethacin (5 mg/kg) inhibited the acute, but not the delayed form of air pouch inflammation. Acute toxicity tests in mice suggest very low toxicity. These results suggest that the root of Moringa oleifera contains anti inflammatory principle(s) that may be useful in the treatment of both the acute and chronic inflammatory conditions.     

Acute and chronic anti-inflammatory properties of the stem bark aqueous and methanol extracts of Sclerocarya birrea (Anacardiaceae)

Sclerocarya birrea is used in folk medicine for the treatment of inflammatory disorders. The effect of the stem bark aqueous and methanol extracts of S. birrea (150 or 300 mg/kg) was evaluated on carrageenan-, histamine- or serotonin-induced paw oedema in rats. The methanol extract of S. birrea (300 mg/kg) being the most active, exhibited a maximum inhibition of 75.45 and 55.31% on carrageenan- and histamine-induced inflammation, respectively. When administered at 300 mg/kg, the methanol extract of S. birrea also exhibited 80.68% inhibition on the 10th day and 54.43% inhibition on the 21st day in formalin- or complete Freund’s adjuvant (CFA)-induced paw oedema in rats. GSH level was significantly increased (75.14%), while MAD level was significantly decreased (31.22%) in the liver of CFA rats treated with S. birrea (300 mg/kg). The results suggest that the anti-inflammatory activity of the aqueous and methanol extracts of S. birrea is due to the inhibition of histamine and prostaglandin pathways and to its antioxidant activity.     

Evaluation of the In Vivo Anti‐Inflammatory and Analgesic Activity of a Highly Water‐Soluble Aspirin Conjugate

Glucose‐aspirin (GA) was synthesized by conjugating aspirin (ASA) to the 3‐carbon of glucose to produce a stable water‐soluble aspirin derivative. The in vivo activities were compared with those of aspirin. The mouse tail flick assay showed that at 120 min., both aspirin and GA showed the maximum possible effect, and the higher dose (200 mg/kg) generally had less of an effect than the lower dose (100 mg/kg). Per cent inhibition of paw oedema was 63% and 69% for ASA and GA at 100 mg/kg, respectively. In the tail immersion test, the increase in reaction time was significantly greater with GA as compared to aspirin (100 mg/kg) at 60 min. In conclusion, there was significant anti‐inflammatory and analgesic activity for GA at the doses studied under the experimental conditions.     

Anti-inflammatory activities of aqueous/ethanol and methanol extracts of <Emphasis Type="Italic">Perna viridis</Emphasis> Linn. in mice

Anti-inflammatory effect of the edible mytilid bivalve Perna viridis was evaluated using formalin, carrageenan and dextran-induced paw oedema in mice. The whole mussel tissue without shell was first extracted with ethyl acetate and then successively with methanol and water:ethanol, 7:3 (aqueous/ethanol). Three doses (100, 500 and 1,000 mg/kg) of the extracts (methanol and aqueous/ethanol) were administered orally prior to the injection of inflammatory agents. The inflammation induced by formalin was inhibited by the administration of both extracts for 7 days and the activity was found to be higher for methanol than aqueous/ethanol extract. A dose-dependent reduction in paw thickness was observed for carrageenan-induced paw oedema on treatment with methanol and aqueous/ethanol extracts which was comparable to the standard drug diclofenac. The effect of extracts on dextran-induced oedema was less than that produced by the other two inflammatory stimulants.     

Anti-inflammatory activity of the non-peptidyl low molecular weight radical scavenger IAC in carrageenan-induced oedema in rats

Objective In this research we investigated the anti‐inflammatory activity of a non‐peptidyl low molecular weight radical scavenger (IAC) in an acute and chronic animal model of inflammation. Methods For this purpose the effect of IAC (10, 25, 50 mg/kg) was tested in rats on the associated behavioral responses to subsequent inflammatory and noxious challenges, such as hind paw oedema induced by intra‐plantar injection of carrageenan and granuloma induced by subcutaneous implant of a cotton pellet, using indometacin (2.5 mg/kg) as reference drug. Moreover, the serum level of several cytokines was tested in the animal treated (or not) with IAC (50 mg/kg) both in the absence and presence of carrageenan‐induced inflammation. Key findings IAC showed a significant anti‐inflammatory activity in both in acute and chronic models of inflammation. In addition IAC down regulated significantly the serum levels of interleukin (IL) 2 and IL6 whereas it increased the serum concentration of IL1α and glutathione. Conclusion Although it remains to be elucidated whether or not the antioxidant property of IAC is directly responsible for the modulation of the tested cytokines, these results suggest IAC to be a possible candidate for a novel anti‐inflammatory compound     

Evaluation of the Effect of Hydroalcoholic Extract of Zingiber officinale Rhizomes in Rat Collagen‐induced Arthritis

Abstract: Patients with chronic, painful diseases often seek alternative therapy. The purpose of this study was to investigate the potential of hydroalcoholic extract of Zingiber officinale rhizomes (Z. officinale extract) to ameliorate inflammatory process in rat collagen‐induced arthritis. Our results show that Z. officinale extract in doses higher than 50 mg/kg/day intraperitoneally starting from the dose of booster immunization and for 26 days can ameliorate the clinical scores, disease incidence, joint temperature and swelling, and cartilage destruction, together with reduction of serum levels of interleukin (IL)‐1β, IL‐2, IL‐6, tumour necrosis factor‐α, and anti‐CII antibodies. Moreover, Z. officinale extract at the dose of 200 mg/kg/day was superior to 2 mg/kg/day of indomethacin at most of the measured parameters. These observations might make Z. officinale extract a good alternative to non‐steroidal anti‐inflammatory drugs for patients with rheumatoid arthritis.     

Anti-inflammatory, analgesic and antipyretic activity of aqueous extract of fresh leaves of Coccinia indica

This study was aimed to evaluate both post- and pre-treatment anti-inflammatory activities of the aqueous extract of fresh leaves of Coccinia indica in rats using the carrageenan-induced paw oedema method at various dose levels. Analgesic and antipyretic properties were evaluated using tail flick model and yeast-induced hyperpyrexia, respectively. Ceiling effect of the extract was observed at 50 mg/kg in pre-treatment carrageenan test. In post-treatment studies, a dose-dependent anti-inflammatory effect was observed in the dose range of 25–300 mg/kg. The effect was equivalent to diclofenac (20 mg/kg) at 50 mg/kg but it was significantly pronounced at higher doses. Effectiveness of extract in the early phase of inflammation suggests the inhibition of histamine and serotonin release. The extract produced marked analgesic activity comparable to morphine at 300 mg/kg, which suggests the involvement of central mechanisms. A significant reduction in hyperpyrexia in rats was also produced by all doses of extract with maximum effect at 300 mg/kg comparable to paracetamol. In conclusion, this study has established the anti-inflammatory activity, analgesic and antipyretic activity of C. indica and, thus, justifies the ethnic uses of the plant.     

Antinociceptive and anti‐inflammatory properties of 7‐hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the antinociceptive, anti‐inflammatory and antipyretic effects of 7‐hydroxycoumarin (7‐HC) in animal models. Methods The effects of oral 7‐HC were tested against acetic acid‐induced writhing, formalin test, tail flick test, complete Freund's adjuvant (CFA)‐induced hypernociception, carrageenan‐induced paw oedema, lipopolysaccharide‐induced fever and the rota rod test. Key findings 7‐HC (3–60 mg/kg) produced a dose‐related antinociception against acetic acid‐induced writhing in mice and in the formalin test. In contrast, treatment with 7‐HC did not prevent thermal nociception in the tail flick test. A single treatment with 7‐HC, 60 mg/kg, produced a long‐lasting antinociceptive effect against CFA‐induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7‐HC produced a continuous antinociceptive effect against CFA‐induced hypernociception. 7‐HC (30–120 mg/kg) produced anti‐inflammatory and antipyretic effects against carrageenan‐induced inflammation and lipopolysaccharide‐induced fever, respectively. Moreover, 7‐HC was found to be safe with respect to ulcer induction. In the rota rod test, 7‐HC‐treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti‐inflammatory effects of 7‐HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.