Studies on the anti-inflammatory effect of fluoxetine in the rat.

The anti-inflammatory activity of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was studied on the carrageenan-induced paw inflammation in the rat. Fluoxetine (10-60 mg kg(-1)) given intraperitoneally (i.p.) 30 min before carrageenan, displayed marked anti-inflammatory activity, inhibiting paw oedema by 38.6-77.7% at 2 h post-carrageenan. Fluoxetine administered at time of carrageenan injection or 30 min after carrageenan challenge, markedly inhibited the paw oedema response. Rats administered daily fluoxetine (20 mg kg(-1), i.p.) showed significantly decreased inflammatory response to subplantar carrageenan when examined on the 5th and 14th day of fluoxetine injection. Fluoxetine (10 or 20 mg kg(-1), i.p.) co-administered with indomethacin (IND) (20 mg kg(-1), i.p.), celecoxib (10 mg kg(-1), i.p.) or rofecoxib (4.5 mg kg(-1), i.p.) before carrageenan reduced the anti-oedema effect of indomethacin or celecoxib, but had additive effect to that of rofecoxib. The anti-oedema effects of fluoxetine and melatonin or the tricyclic antidepressant imipramine were additive. In contrast, administration of both fluoxetine and the heterocyclic antidepressant trazodone had no greater anti-inflammatory effect than fluoxetine alone. The anti-oedema effect of fluoxetine was partially suppressed by the opioid antagonist naloxone (4 mg kg(-1), i.p.). Fluoxetine (360 or 720 microg per paw) given into the rat paw with carrageenan reduced the oedema response by 25.4 and 35.3% 4 h post-carrageenan, respectively. It is suggested that fluoxetine alone or co-administered with either imipramine or melatonin would be of benefit in the sitting of neuropathic or inflammatory pain conditions. Both the serotonergic and the opioid systems are likely to be involved in the modulating action of fluoxetine on peripheral inflammation.     

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat.

The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg(-1), melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg(-1), i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg(-1), i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg(-1), i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg(-1), i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg(-1), i.p.) was only slightly increased by melatonin administration at 0.5 mg kg(-1). Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg(-1), s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 microg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.     

Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat.

Ginkgo biloba extract (GbE) was assessed in models of acute inflammation induced by carrageenan, formalin or capsaicin in the rat, in models of nociceptive pain, such as hot-plate (55 degrees C) latency, tail-electric stimulation assay and capsaicin-induced paw licking and in the model of acute gastric damage induced by indomethacin. The agent showed marked anti-inflammatory activity in the carrageenan model of paw oedema. When given subcutaneously (s.c.) (25 and 50 mg kg(-1)) 30 min before challenge, GbE inhibited paw oedema with a maximal effect of 43.7 and 56.9%, respectively, at 2h post-carrageenan. Significant inhibition of oedema was also observed when GbE (50 mg kg(-1), s.c.) was given 30 min after carrageenan challenge. The agent was also active p.o. in acute inflammation caused by carrageenan. The administration of GbE with indomethacin, rofecoxib, celecoxib, dexamethasone or melatonin resulted in an additive effect. GbE (50 mg kg(-1), s.c.) caused significant inhibition of formalin-induced paw oedema, but did not reduce the capsaicin-induced paw oedema. In tests of nociception, GbE (25, 50 or 100 mg kg(-1)) decreased in dose-dependent manner the capsaicin-induced hind paw licking time and was similarly effective in the hot-plate assay of nociception. In contrast, when assessed in the tail-electric stimulation test, GbE was only effective in the highest dose (100 mg kg(-1)). In pylorus-ligated rats, GbE (25 or 50 mg kg(-1)) increased gastric acid secretion, but reduced gastric mucosal damage caused by IND. Results suggest that GbE may be of clinical value as an anti-inflammatory and analgesic drug alone or in conjunction with NSAIDs.     

Modulation of inflammatory paw oedema by cysteamine in the rat.

Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Given subcutaneously (s.c.) 1 h before carrageenan, cysteamine caused significant, dose-dependent and long-lasting inhibition of rat paw oedema induced by carrageenan. At doses of 12.5, 25, 50 or 100 mg kg (-1), cysteamine significantly inhibited the carrageenan-induced paw oedema at 4 h by 52.3, 40, 40.7 or 26.3%. Cysteamine given at 300 mg kg (-1), a dose well known to deplete tissue somatostatin, reduced oedema by only 16.2% vs control values. Significant inhibition of the carrageenan-induced rat paw oedema was still evident 24 h post-injection at cysteamine doses of 12.5, 25, 50 or 100 mg kg (-1). Given s.c. at 300 mg kg (-1), 4 h prior to carrageenan, cysteamine decreased rat paw oedema at 4 h by 14.9%. Cysteamine (300 mg kg (-1)), 4 h beforehand, had little modulatory effect on the oedema induced by formalin (2.5%) but reduced that caused by intraplantar histamine (5 micromol). The anti-oedematogenic effect of indomethacin, but not that of the selective COX-2 inhibitor celecoxib, was less marked in rats pre-treated with cysteamine at 300 mg kg (-1). Cysteamine (0.3 microg- 0.3 mg paw (-1)) co-administered with carrageenan was devoid of anti-inflammatory effect and even promoted inflammation at low concentrations. Cysteamine given locally alone induced slight paw oedema. These data indicate that systemic cysteamine possesses potent and long-lasting anti-inflammatory effects and modulates the anti-inflammatory effect of cyclooxygenase inhibitors in a model of peripheral inflammation in the rat. The effect of cysteamine is likely to be mediated via central action.     

Effect of Ginkgo biloba extract on carrageenan-induced acute local inflammation in gamma irradiated rats

The effect of low dose whole-body gamma irradiation on inflammation and its possible modulation by Ginkgo biloba extract (GbE) was studied in the carrageenan-induced paw oedema model. Rats were subjected to two doses of gamma radiation (2 Gy or intermittent radiation at 2 Gy increment delivered daily up to cumulative dose of 4 Gy), 4 h before unilateral subplantar injection of carrageenan. The effect of GbE (25 or 50 mg/kg) administered subcutaneously daily for 3 days was also studied. Local oedema (days 1-3), the content of gamma glutamyl transpeptidase (GTT), malondialdehyde (MDA) and glutathione (GSH) in paw (72 h), were determined. In rats subjected to 4 Gy fraction, paw oedema was significantly reduced 1-4 h post-carrageenan injection (-26.2 to -16.2% vs control group). Moreover, at 24, 48 and 72 h after carrageenan, paw oedema was much reduced in the 2 Gy (-33.6, -46.4, -40%) or 4 Gy (-55, -56, -71.8%) irradiated groups compared to carrageenan unirradiated control. In addition, in irradiated rats, the carrageenan oedema was further significantly reduced by the administration of GbE, the effect of the agent being more marked in those irradiated with 2 Gy fraction. Changes in paw oedema were matched by a reduction in GGT and MDA paw tissue levels, while GSH content decreased in inflamed paw tissue 72 h post-treatment. These results indicate that exposure to 4 Gy fraction decreased the carrageenan-induced paw oedema and that the administration of GbE further lessened the severity of this inflammatory response in irradiated rats. The effects observed may be related in part to the inhibition of GGT activity and MDA production, and partly to augmentation of GSH content in the inflamed paw tissue.     

Anti-inflammatory effects of peripheral benzodiazepine receptor ligands in two mouse models of inflammation

In vivo treatment of mice with peripheral benzodiazepine receptor ligands exerts an inhibitory effect on the inflammatory response in two models of acute inflammation. In the first model, pretreatment of the animals (24 h) with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) and 7-chloro-5-(4-Chlorophenyl)-1, 3-dihydro-1-methyl-2-H-1,4-benzodiazepin-2 (Ro5-4864), at different doses (0.00001-10 mg/kg, i.p.) dose dependently inhibited the formation of mouse paw oedema induced by carrageenan with mean ID(50s) of 0.009 (95% confidence limits=0.0076-0.013) and 0.04 (95% confidence limits=0.025-0.0086) mg/kg, respectively. Both ligands (0. 1 mg/kg, i.p.) inhibited in the same way the mouse paw oedema induced by carrageenan in animals with and without adrenal glands. PK11195 and Ro5-4864 (0.1 mg/kg, i.p.) inhibited the mouse paw oedema induced by several inflammatory mediators. In the second model, the pretreatment (24 h) with peripheral benzodiazepine receptor ligands (0.1 mg/kg, i.p.) exerted an inhibitory effect on neutrophil influx and produce a marked inhibition of carrageenan-produced interleukin-13 and interleukin-6 in pleural exudation. Our results extend previous findings that peripheral benzodiazepine receptor is involved in the inflammatory response, and suggest that this action may be linked to the action of different inflammatory mediators, probably mainly by the inhibition of the release of pro-inflammatory cytokines.     

Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain

BACKGROUND AND PURPOSE: Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb-761 has anti-inflammatory properties and modulatory effects on key pain-related molecules. This study investigated the analgesic and anti-inflammatory effects of EGb-761 on carrageenan-induced inflammatory and hindpaw incisional pain. EXPERIMENTAL APPROACH: Adult male Wistar rats (n=6-10/group; 250-420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. EGb-761 (3, 10, 30, 100 or 300 mg kg(-1)), diclofenac (5 mg kg(-1)) or drug-vehicle was administered 3 h post-carrageenan/post-surgery. Hindpaw withdrawal latency (in seconds) to thermal stimulation, response threshold (in grams) to mechanical stimulation and paw volume were measured. KEY RESULTS: Carrageenan induced significant mechanical allodynia, thermal hyperalgesia and paw oedema at 6 h post-carrageenan, while paw incision surgery induced significant mechanical allodynia and thermal hyperalgesia at 6 and 24 h post-surgery. Administration of EGb-761 dose-dependently inhibited thermal hyperalgesia and was equally effective as diclofenac (5 mg kg(-1)) in both the carrageenan and hindpaw incision model. EGb-761 had no effect on carrageenan- or incision-induced mechanical allodynia or paw oedema. Diclofenac significantly reduced mechanical allodynia in both models and carrageenan-induced paw oedema. CONCLUSIONS AND IMPLICATIONS: EGb-761 dose-dependently alleviates acute inflammatory and surgically induced thermal hyperalgesia and is comparable to diclofenac, a commonly prescribed non-steroidal anti-inflammatory drug. This indicates that EGb-761 has analgesic potential in acute inflammatory pain.     

Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors

The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4 h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3 mg kg(-1)) 30 min prior to carrageenan administration, dose-dependently reduced oedema formation. At the 4 h time point, the ED(50) for URB597 was approximately 0.3 mg kg(-1). Indomethacin (5 mg kg(-1) i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3 mg kg(-1) i.p. of the CB(2) receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator-activated receptor gamma antagonist bisphenol A diglycidyl ether (30 mg kg(-1) i.p.) or the TRPV1 antagonist capsazepine (10 mg kg(-1) i.p.), when oedema was assessed 4 h after carrageenan administration. The CB(1) receptor antagonists AM251 (3 mg kg(-1) i.p.) and rimonabant (0.5 mg kg(-1) i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3 mg kg(-1)) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528-sensitive anti-inflammatory effects in the carrageenan model of acute inflammation.     

Apoptotic mimicry: phosphatidylserine liposomes reduce inflammation through activation of peroxisome proliferator-activated receptors (PPARs) in vivo

BACKGROUND AND PURPOSE: Recently, there has been much attention paid to understanding the molecular mechanisms underlying apoptosis and the functional consequences of apoptotic body clearance by phagocytes. In an attempt to investigate this latter aspect, the present study evaluated the anti-inflammatory effects of in vivo administration of phosphatidylserine (PS) liposomes, a well-characterised membrane component expressed during apoptosis. The participation of peroxisome proliferator-activated receptors (PPARs) in PS-mediated effects was also investigated. EXPERIMENTAL APPROACH: The anti-inflammatory effect of PS liposomes on the delayed phase of carrageenan mouse paw oedema was studied. PS liposomes were injected at different doses and times, after carrageenan. Hind paws were collected for evaluation of interleukin-1beta (IL-1beta) levels, myeloperoxidase (MPO) and N-acetyl-glucosaminidase (NAG) activities and Evans blue dye leakage. Participation of PPAR pathways was explored by using PPAR antagonists (BADGE and GW9662). KEY RESULTS: Administration of PS, but not phosphatidylcholine (PC), liposomes (20-200 mg kg(-1), i.p., 8 h after carrageenan) reduced the paw oedema in a dose-dependent manner. PS liposomes were effective even when administered 24 and 48 h after carrageenan, a time at which indomethacin (1 mg kg(-1), i.p.) had no significant effects. Carrageenan-induced Evans blue leakage and IL-1beta production was decreased in PS-treated paws. The PPAR antagonists (BADGE and GW9662) partially prevented the anti-inflammatory effects of PS administration. CONCLUSIONS AND IMPLICATIONS: PS liposomes have anti-inflammatory effects in vivo that are at least partly dependent on PPAR activation. Therapeutic strategies mimicking apoptosis may be useful for the treatment of inflammatory disorders.     

Antinociceptive and anti-inflammatory properties of the hydroalcoholic extract of stems from Equisetum arvense L. in mice.

In this study, antinociceptive and anti-inflammatory effects of hydroalcoholic extract of stem from Equisetum arvense in mice were evaluated. The extract (10, 25, 50 and 100mgkg(-1), i.p.), reduced the writhing induced by acetic acid in 49, 57, 93 and 98%, respectively. In the formalin test, 50 and 100mgkg(-1) (i.p.) extract, reduced in 80 and 95% the licking activity in the first phase, but in the second phase only the latter dose diminished the licking time (35%). In both phases, naloxone failed to revert the analgesic effect of the extract. In the hot-plate test, the extract at 100 and 200mgkg(-1) does not change the latency to licking or jumping. In the carrageenan-induced paw oedema, the extract at 50mgkg(-1), reduced the paw oedema 2h (25%) and 4h (30%) after carrageenan administration. The dose of 100mgkg(-1) caused reduction of the paw oedema (29%) only 4h after carrageenan administration. These results indicate that this extract exhibits an antinociceptive effect in chemical models of nociception which is not related to the opioid system, as well as anti-inflammatory properties.     

Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.

The present study was designed to compare the anti-inflammatory and anti-nociceptive effects of different classes of antidepressant drugs on the carrageenan paw oedema and tail-electric stimulation assays in the rat. Drugs were intraperitoneally administered 30 min prior to carrageenan or nociceptive testing. The non-selective noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors imipramine, amitriptyline and clomipramine displayed anti-inflammatory activity in the carrageenan model of paw inflammation. The maximal degree of oedema inhibitions seen with these agents were 28.8, 41.5 and 46.8% for 5, 10 and 20 mg kg(-1) amitriptyline, 26.2, 38.2 and 51.4% for 3.75, 7.5 and 15 mg kg(-1) imipramine and 51.2 and 54.1% for 16 and 32 mg kg(-1) clomipramine, respectively. The heterocyclic agent trazodone significantly inhibited paw oedema by 46 and 41% at 1 and 2h after dosing at the highest dose (40 mg kg(-1)) examined. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) caused dose-related reduction of paw oedema, with 20.7% inhibition at the dose of 10 mg kg(-1). In contrast, sertraline, another SSRI caused dose-dependent enhancement of paw oedema. All antidepressant drugs in the study showed anti-nociceptive properties in the tail-electric stimulation assay with amitriptyline and trazodone being the most effective in this respect. Taken together, data in the present study confirm anti-inflammatory and anti-nociceptive effect for some antidepressant drugs and indicate that SSRIs differently affects inflammation.     

A comparison of the anti-inflammatory and anti-nociceptive activity of nitroaspirin and aspirin

1. Nitroaspirin (2.5 - 50 mg kg(-1), i.p. or 2.5 - 100 mg kg(-1), p.o.) and aspirin (2.5 - 100 mg kg(-1), i.p. or p.o.) exhibit anti-inflammatory activity in the carrageenan-induced hindpaw oedema model in the rat. When administered i.p., nitroaspirin was a more effective anti-oedema agent than aspirin particularly in the 'early' phase (i.e. up to 60 min) of the response. The ED(50) values for nitroaspirin and aspirin as inhibitors of the 'late' phase response (measured at 180 min) were 64.3 micromol kg(-1) and >555 micromol kg(-1), respectively. When administered p.o., neither nitroaspirin nor aspirin exhibited significant anti-inflammatory activity in the 'early' phase and were of similar potency in the 'late' phase. Thus, at the highest dose used (100 mg kg(-1), 360 min) orally administered nitroaspirin (aspirin in parenthesis) inhibited oedema formation by 46.9+/-1.6% (47.2+/-3.8%, both n=6, P<0.05). 2. Nitroaspirin and aspirin (25 - 200 mg kg(-1), p.o.) caused dose-related inhibition of the hyperalgesia to mechanical stimulation following intraplantar injection of carrageenan in the rat. ED(50) values were 365 micromol kg(-1) and 784 micromol kg(-1), respectively. Neither drug influenced the threshold for mechanical stimulation in the contralateral (i.e. untreated) hindpaw. 3. Nitroaspirin and aspirin (2.5 - 100 mg kg(-1), p.o.) caused dose-related inhibition of acetic acid induced abdominal constrictions in the mouse (ED(50) values of 154.7 micromol kg(-1) and 242.8 micromol kg(-1), respectively). 4. Nitroaspirin and aspirin (>200 mg kg(-1), p.o.) reduced the 'late' phase (but not the 'early' phase) of the formalin-induced hindpaw licking assay in the mouse. Similarly, nitroaspirin and aspirin (>50 mg kg(-1), p.o.) prolonged tail withdrawal latency following application of a noxious heat stimulus in the mouse.     

Synergistic effect of nitric oxide synthase and cyclooxygenase inhibitors on carrageenan-induced paw edema in rats

The present study examined the effects of L-nitroarginine methylester (L-NAME, CAS 50903-99-6), a non-selective nitric oxide synthase (NOS) inhibitor, indometacin (IND, CAS 3305-29-1), a non-selective cyclooxygenase (COX) inhibitor, and a combination of these agents (L-NAME + IND) on carrageenan-induced paw edema for 4 h after the injection of carrageenan in rats. L-NAME at 10 and 30 mg/ kg but not 3 mg/kg (i.p.) decreased paw volume slightly but significantly only at 1 h after the carrageenan injection. IND reduced paw volume slightly at 1 and 3 mg/kg, and markedly at 10 mg/kg (p.o.). A combination of L-NAME and IND at a subthreshold dose (3 mg/kg, i.p. and 1 mg/kg, p.o., respectively) caused a marked reduction of paw edema, which was also confirmed by histopathological examinations. A combination of N-(3-(aminomethyl)benzyl)acetamidine (1400W, CAS 180001-34-7), a selective inhibitor of inducible NOS, and IND at 3 mg/kg, i.p., and 1 mg/kg, p.o., respectively, did not show synergistic anti-inflammatory effects. In conclusion, the combination of non-selective NOS and COX inhibitors had synergistic anti-inflammatory effects on carrageenan-induced paw edema at an early stage, suggesting negative crosstalk between the endogenous NOS-NO and COX-PG pathways in the early stages of acute inflammation.     

Grapefruit juice potentiates the anti-inflammatory effects of diclofenac on the carrageenan-induced rat's paw oedema.

The anti-inflammatory effect of diclofenac alone or in combination with double strength grapefruit juice was investigated on carrageenan-induced rat's paw oedema. Paw was measured by using a plethysmometer 3 h after injecting the phlogestic agent. There was significant inhibition (P< 0.05) of the oedematous response after oral administration of diclofenac alone (1, 2.5, 5 mg kg(-1)p.o.) in a dose-dependent manner. Coadministration of grapefruit juice (10 ml kg(-1)p.o.) orally with all doses of diclofenac, enhanced the inhibitory effect of diclofenac on rat's paw oedema. Double-strength grapefruit juice has synergistic inhibitory effect on rat's paw oedema when administered in combination with diclofenac.     

Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat.

1. The antiinflammatory activity of synthetic cannabinoid nabilone in the rat model of carrageenan-induced acute hindpaw inflammation was compared with that of the endocannabinoid palmitoylethanolamide and the nonsteroidal antiinflammatory drug indomethacin. 2. Preliminary experiments in rats used a tetrad of behavioural tests, specific for tetrahydrocannabinol-type activity in the CNS. These showed that the oral dose of nabilone 2.5 mg kg(-1) had no cannabinoid psychoactivity. 3. Intraplantar injection of carrageenan (1% w v(-1)) elicited a time-dependent increase in paw volume and thermal hyperalgesia. 4. Nabilone (0.75, 1.5, 2.5 mg kg(-1), p.o.), given 1 h before carrageenan, reduced the development of oedema and the associated hyperalgesia in a dose-related manner. Nabilone 2.5 mg kg(-1), palmitoylethanolamide 10 mg kg(-1) and indomethacin 5 mg kg(-1), given p.o. 1 h before carrageenan, also reduced the inflammatory parameters in a time-dependent manner. 5. The selective CB(2) cannabinoid receptor antagonist [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide] (SR 144528), 3 mg kg(-1) p.o. 1 h before nabilone and palmitoylethanolamide, prevented the anti-oedema and antihyperalgesic effects of the two cannabinoid agonists 3 h after carrageenan. 6. Our findings show the antiinflammatory effect of nabilone and confirm that of palmitoylethanolamide indicating that these actions are mediated by an uncharacterized CB(2)-like cannabinoid receptor.     

Effects of calcium channel blockers on hyaluronidase-induced capillary vascular permeability

Inflammation and increased capillary permeability is a significant aspect of the pathogenesis of many diseases including atherosclerosis. L-type calcium channel blockers (CCB) are commonly used as cardiovascular drugs. Amlodipine, lacidipine, and nicardipine were evaluated for anti-inflammatory activity on the paw oedema produced by carrageenan. The effect of these drugs was compared with the activity of indomethacin. Their effects on vascular permeability were also tested by hyaluronidase-induced capillary permeability. In our animal experiments, amlodipine decreased the carrageenan-induced paw oedema at doses of 1, 3, and 6 mg kg(-1) by 27.3%, 43.7%, and 67.3% four hour after carrageenan administration; the same doses of lacidipine and nicardipine decreased paw oedema by 37.1%, 55.6%, 76.4%, 11.2%, 31.0%, 91%; and indomethacin decreased oedema by 38.2% at a dose of 6 mg kg(-1). Lacidipine significantly inhibited the hyaluronidase-induced increase in capillary permeability at doses of 1, 3, and 6 mg kg(-1) compared with the control group. However, amlodipine and nicardipine significantly inhibited the hyaluronidase-induced increase in capillary permeability at 3 and 6 mg kg(-1) doses. A 6 mg kg(-1) dose of indomethacin significantly decreased the capillary permeability which was increased by hyaluronidase. These results suggest that CCBs can be efficient anti-inflammatories, and can also significantly decrease capillary permeability.     

Effects of valeryl salicylate, a COX-1 inhibitor, on models of acute inflammation in mice.

The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2mg per ear; 20 microliters) or croton oil (1mg per ear; 20 microliters) to the inner surface of the left ear and the change in the ear's thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after lh at doses of 1.5-45 micrograms per ear; however, only at the dose of 45 micrograms per ear was it able to significantly reduce the croton oil-induced oedema at 6h. Paw oedema was induced by the injection of 25 microliters of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2h, in the early phase (0-4h), and the other, occurring at 48h after carrageenan injection, in the late phase (24-72h). The pre-treatment with VS significantly reduced the paw oedema at 2h, the same effect observed with celecoxib and indomethacin treatments. At 24h, VS did not inhibit oedema but significantly increased it mainly at 48h after carrageenan injection. These results showed that VS was pharmacologically active in these models and suggest that COX-1 may participate in the early and late phases of inflammation in the models studied.     

Antinociceptive and anti-inflammatory activity of a novel quipazine derivative (AAL-13): a selective inhibitor of 5-hydroxytryptamine reuptake

The anti-inflammatory and antinociceptive activities of a novel quipazine derivative 2(4-(3-chloropropyl)piperazinyl) quinoline (AAL-13), a selective inhibitor of 5-hydroxytryptamine (5-HT) reuptake, has been examined. Anti-inflammatory activity was assessed by mesuring the inhibition of a cotton pellet granuloma and of carrageenan-induced paw oedema in rats, and of cantharidin-induced topical inflammation in the mouse ear. Antinociceptive activity was studied by using the modified Randall-Selitto method. Indomethacin was used as a reference. AAL-13 slightly inhibited granuloma formation (13%, P less than 0.02) at 100 mg kg-1 day-1 for 7 days, whereas half that dose had no significant effect. There was significant inhibition of carrageenan-induced rat paw oedema (35%, P less than 0.05 and 103%, P less than 0.001) 3 h after single doses of AAL-13 (50 and 100 mg kg-1 p.o., respectively). Three hours after i.p. injection, the oedema inhibition was 58% (P less than 0.05) and 86% (P less than 0.001) for doses of 25 and 50 mg kg-1, respectively. In comparison, indomethacin (3, 6 and 12 mg kg-1 p.o.) inhibited oedema by 59% (P less than 0.02), 65% (P less than 0.01) and 63% (P less than 0.02), respectively. Intraperitoneally, only the 12 mg kg-1 dose produced significant inhibition (82%, 3 h after carrageenan injection, P less than 0.05). AAL-13 (1.5 mg/ear) had a significant anti-inflammatory effect on the mouse ear (52%, inhibition, P less than 0.05), while indomethacin (3 mg/ear) gave 43% inhibition (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapeutic effect of the endogenous fatty acid amide,palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems

1. The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. 2. Palmitoylethanolamide (1, 3, 5, 10 mg kg(-1); p.o.) and indomethacin (5 mg kg(-1); p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. 3. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg(-1) p.o. On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg(-1)) and indomethacin markedly reduced these increases. 4. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity.     

Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo

Histamine, vascular endothelial growth factor, acetylcholine, oestrogen as well as fluid shear stress activates a mechanism that recruits heat shock protein 90 to the endothelial nitric oxide synthase. The interaction between Hsp90 and eNOS enhances the activation of the enzyme in cells and in intact blood vessels leading to NO production. Intraplantar administration of carrageenan (50 microl paw(-1)) to mice causes an oedema lasting 72 h. Geldanamycin (0.1, 0.3, 1 mg kg(-1)), a specific inhibitor of Hsp-90, that inhibits endothelium-dependent relaxations of the rat aorta, mesentery and middle artery inhibits carrageenan-induced mouse paw oedema in a dose dependent manner. Co-administration to mice of dexamethasone (1 mg kg(-1)) with geldanamycin (0.3 mg kg(-1)) at anti-inflammatory dose causes a loss of the total anti-inflammatory effect of each agent alone. RU 486 (10 mg kg(-1)), a well known glucocorticoid receptorial antagonist, does not inhibit oedema formation but prevents the anti-inflammatory action of dexamethasone (1 mg kg(-1)). Similarly, RU 486 prevents the anti-inflammatory action of geldanamycin (0.3 mg kg(-1)). In conclusion we have described for the first time that geldanamycin, an inhibitor of Hsp90 dependent signal transduction, is anti-inflammatory in vivo implying that Hsp90 is critical for pathways involved in carrageenan-induced paw oedema. In addition the ability of GA to block NO release and reduce oedema formation suggests a therapeutic rationale for specific inhibitors of Hsp90 as potential anti-inflammatory drugs.