sc-236 and Inflammation

Little is known about the neuroimmune mechanisms responsible for the switch from fever to hypothermia observed in severe forms of systemic inflammation. We evaluated whether bacterial lipopolysaccharide (LPS) acting directly on the brain could promote a fever-hypothermia switch as well as the hypotension that is often associated with hypothermia in models of systemic inflammation. At an ambient temperature of 22°C, freely moving rats received intracerebroventricular (i.c.v.) injections of LPS at doses ranging from 0.5 to 25μg. Despite the use of such high doses, the prevailing thermal response was fever. To investigate if a hypothermic response could be hidden within the prevailing febrile response, rats were pretreated with a cyclooxygenase-2 inhibitor (SC-236, 3.5mg/kg i.v.) known to block fever, but this strategy also failed to reveal any consistent hypothermic response following i.c.v. LPS. At the doses tested, i.c.v. LPS was similarly ineffective at inducing hypotension. Additional doses of LPS did not need to be tested because the 25-μg dose was already sufficient to induce both hypothermia and hypotension when administered peripherally (intra-arterially). An empirical 3D model of the interplay among body temperature, arterial pressure and heart rate following intra-arterial LPS reinforced the strong association of hypothermia with hypotension and, at the same time, exposed a bell-shaped relationship between heart rate and body temperature. In summary, the present study demonstrates that hypothermia and hypotension are triggered exclusively by LPS acting outside the brain and provides an integrated model of the thermal and cardiovascular responses to peripheral LPS.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Fever; Hypotension; Hypothermia; Inflammation; Injections, Intraventricular; Lipopolysaccharides; Male; Motor Activity; Pyrazoles; Rats; Rats, Wistar; Sulfonamides

Inflammation is an important biological process that is activated after status epilepticus and could be implicated in the development of epilepsy. Here we tested whether an anti-inflammatory treatment with a selective cox-2 inhibitor (SC58236) could prevent the development of epilepsy or modify seizure activity during the chronic epileptic phase. SC58236 was orally administered (10mg/kg) during the latent period for 7 days, starting 4h after electrically induced SE. Seizures were monitored using EEG/video monitoring until 35 days after SE. Cell death and inflammation were investigated using immunocytochemistry (NeuN and Ox-42). Sprouting was studied using Timm's staining after 1 week and after 4-5 months when rats were chronic epileptic. SC58236 was also administered during 5 days in chronic epileptic rats. Hippocampal EEG seizures were continuously monitored before, during and after treatment. SC58236 effectively reduced PGE(2) production but did not modify seizure development or the extent of cell death or microglia activation in the hippocampus. SC58236 treatment in chronic epileptic rats did not show any significant change in seizure duration or frequency of daily seizures. The fact that cox-2 inhibition, which effectively reduced prostaglandin levels, did not modify epileptogenesis or chronic seizure activity suggests that this type of treatment (starting after SE) will not provide an effective anti-epileptogenic or anti-epileptic therapy.

Topics: Adolescent; Adult; Animals; Brain; CD11b Antigen; Cell Death; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Electroencephalography; Electroshock; Epilepsy, Temporal Lobe; Female; Gene Expression Regulation; Hippocampus; Humans; Inflammation; Male; Middle Aged; Phosphopyruvate Hydratase; Pyrazoles; Rats; Rats, Sprague-Dawley; Seizures; Sulfonamides; Time Factors; Young Adult

To investigate a possible role of 8-isoprostaglandin F2alpha in inflammation, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were determined by enzyme immunoassay (EIA) in carrageenan-induced air pouch model in rats. In this model, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were found to be increased significantly. To evaluate whether this increase was due to the development of inflammation or solely to cyclooxygenase-2 induction, a lipopolysaccharide-induced air pouch model, in which only cyclooxygenase-2 induction occurs without inflammation, was used. In this model, 8-isoprostaglandin F2alpha was also found to be increased parallel to the increase in prostaglandin E2 level. Cyclooxygenase-dependent formation of 8-isoprostaglandin F2alpha was investigated in carrageenan-induced air pouch model by administrating nonselective cyclooxygenase inhibitor indomethacin, selective cyclooxygenase-1 inhibitor valeryl salicylate or selective cyclooxygenase-2 inhibitor SC-582368 (4-(5-(4-chlorophenyl)-3-3-trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonanmide) 1 h before carrageenan injection. All these inhibitors significantly inhibited the production of 8-isoprostaglandin F2alpha and prostaglandin E2. These findings show that 8-isoprostaglandin F2alpha can be formed in carrageenan-induced air pouch model in rats. The formation of 8-isoprostaglandin F2alpha in lipopolysaccharide-induced air pouch model and the inhibition of its production by various cyclooxygenase inhibitors provide evidence for cyclooxygenase-dependent formation of isoprostanes in this model.

Topics: Air; alpha-Tocopherol; Animals; Carrageenan; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Exudates and Transudates; Female; Immunoenzyme Techniques; Inflammation; Lipopolysaccharides; Pyrazoles; Rats; Rats, Wistar; Sulfonamides

The aim of present study was to examine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold (1.5xT, the intensity threshold) electrical stimuli with different frequencies (3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced inflammation and central sensitization. During normal conditions, the responses of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli (3 Hz, wind-up) were depressed by systemic administration of SC-236 as well as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both the WDR neurons and the simultaneously recorded SMUs after electrical stimuli with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms underlying the generation of the C-fiber mediated late responses and the after-discharges may be different. The enhanced responsiveness of both WDR neurons and SMUs to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia) in the BV experiments was apparently depressed by SC-236, but not its vehicle. For electrical stimulation, the enhanced late responses and after-discharges, but not early responses, of both the WDR neurons and the simultaneously recorded SMUs were markedly depressed only by SC-236. This indicates that different central pharmacological mechanisms underlie the generation of these enhanced early, late responses, and after-discharges during BV-induced inflammation. The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities of both spinal cord dorsal horn neuron and spinal withdrawal reflex during BV-induced sensitization, indicating that COX-2 plays an important role in the maintenance of central sensitization.

Topics: Action Potentials; Anesthesia; Animals; Bee Venoms; Cyclooxygenase Inhibitors; Drug Interactions; Electric Stimulation; Electromyography; Electrophysiology; Hindlimb; Hyperalgesia; Inflammation; Male; Muscle, Skeletal; Nociceptors; Pain Measurement; Pain Threshold; Physical Stimulation; Posterior Horn Cells; Pyrazoles; Rats; Rats, Wistar; Reflex; Spinal Cord; Spinal Cord Injuries; Sulfonamides

1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non-inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4. In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

Topics: Animals; Carrageenan; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Hindlimb; Hyperalgesia; Indomethacin; Inflammation; Isoenzymes; Lactones; Male; Pain Threshold; Piroxicam; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Sulfonamides; Sulfones

Effects of misoprostol, a synthetic prostaglandin E1 (PGE1) analogue, on cyclooxygenase-2 (COX-2) protein level and exudate prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) level were investigated in acute carrageenan-induced air pouch inflammation in rats. Treatment with misoprostol (12.5, 25, and 50 microg/kg) has been started in separated groups, 30 min and 2 days before carrageenan injection and it was given twice a day (total of five doses) by orogastric route. Indomethacin, in doses of 0.5 and 5 mg/kg, and specific COX-2 inhibitor SC-58236, in doses of 5, 10, and 20 mg/kg were given 1 h before carrageenan injection by the orogastric route. Misoprostol increased the levels of PGE2 and COX-2 protein at all doses applied. Despite indomethacin and SC-58236 increased the level of COX-2 protein when they used alone, these drugs partially inhibited misoprostol-induced increase in the level of COX-2 protein. Partial inhibition of misoprostol-induced increase in the level of COX-2 protein by indomethacin or SC-58236 may indicate the modulatory roles of endogenous prostaglandins (PGs, especially, PGE2) on the COX-2 expression.

Topics: Animals; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Drug Combinations; Enzyme Induction; Exudates and Transudates; Female; Indomethacin; Inflammation; Isoenzymes; Leukocyte Count; Leukocytes; Misoprostol; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Thromboxane B2

Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.

Topics: Animals; Anorexia; Corticotropin-Releasing Hormone; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Energy Intake; Energy Metabolism; Hypothalamus; Immunity; Inflammation; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred C3H; Mice, Knockout; Neuropeptide Y; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; RNA, Messenger; Sulfonamides; Weight Loss

Both in experimental colitis and in inflammatory bowel disease, colonic eicosanoid generation is enhanced and may contribute to the pathogenesis of the inflammatory response.. To evaluate the effect of selective cyclo-oxygenase-2 (COX-2) inhibitors on the extent and severity of two models of experimental colitis.. Colitis was induced by intra-caecal administration of 2 ml 5% acetic acid or intra-colonic administration of 0.1 ml 3% iodoacetamide. Rats were treated intra-gastrically with nimesulide 2 x 10 mg/kg/day, or once with SC-236 6 mg/kg, and killed 1 or 3 days after damage induction. The colon was isolated, weighed, macroscopic damage was measured, and mucosal samples were obtained for histology and for determination of myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities and eicosanoid generation. The serum levels of thromboxane B2 (TXB2), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined.. Nimesulide significantly decreased the extent of colitis induced by acetic acid. Both nimesulide and SC-236 significantly decreased the extent of iodoacetamide-induced colonic damage. The decrease in the extent of colitis induced by nimesulide was accompanied by a significant decrease in mucosal MPO and NOS activities. Nimesulide and SC-236 decreased the enhanced colonic eicosanoid generation in acetic acid and iodoacetamide-induced colitis, and, in iodoacetamide-treated rats, nimesulide also decreased the elevated serum TNF-alpha and IL-1beta levels.. The effective nimesulide and SC-236-induced amelioration of the severity of the colitis in acetic acid and iodoacetamide-treated rats confirms the role of eicosanoids in their pathogenesis and suggests that COX-2 inhibitors may be of value in the treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Cyclooxygenase Inhibitors; Disease Models, Animal; Eicosanoids; Indomethacin; Inflammation; Interleukin-1; Male; Nitric Oxide Synthase; Peroxidase; Pyrazoles; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Sulfonamides; Tumor Necrosis Factor-alpha