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Introduction The liver is the main metabolic organ of the human body, and it also metabolizes drugs and poisons. In most situations metabolism is accomplished without damage to the liver [...], Rosiglitazone, which is mainly used in the treatment of diabetes mellitus, is also involved in the regulation of inflammation. The peroxisome proliferator-activated receptor (PPAR)-γ receptor subtype appears to play a pivotal role in the regulation of inflammation. However, the exact mechanism for the protective effects of rosiglitazone against inflammation such as liver injury remains unclear. The aim of this study was to investigate the effects of rosiglitazone on inflammation in the liver of rats treated with D-GaIN/LPS. Male Sprague -Dawley rats were injected with D-GaIN/LPS with or without pre-administration of rosiglitazone (3, 10, or 30 mg/kg, intraperitoneal injection). Our data showed that rosiglitazone significantly inhibited D-GaIN/ LPS-induced hepatotoxicity in a dose-dependent manner, as indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Western blot analysis showed that rosiglitazone significantly decreased protein expression levels of COX-2 and production of pro-inflammatory markers, including TNF-α and IL-6, in DGaIN/ LPS-treated rat liver. The results indicated that the inhibition of D-GaIN/LPS-induced inflammation by rosiglitazone can be attributed, at least partially, to its capacity to regulate the the immunoregulatory transcription factor nuclear factor kappa B (NF-κB) signaling pathway. Key words: rosiglitazone, liver injury, inflammation, D-GaIN/LPS, NF-κB, TNF-α, IL-6, COX-2. On rapporte que le rosiglitazone, principalement utilise dans le traitement du diabete sucre, est aussi implique dans la regulation de l'inflammation. Le recepteur PPAR-γ semble jouer un role pivot dans la regulation de l'inflammation. Cependant, le mecanisme exact de ses effets protecteurs envers l'inflammation comme le dommage hepatique demeure flou. Le but de la presente etude etait d'examiner les effets du rosiglitazone dans l'inflammation hepatique de rats traites au DGalN/LPS. Des rats males Sprague-Dawley ont recu une injection de D-GalN/LPS avec ou sans une administration prealable de rosiglitazone (3, 10 ou 30 mg/kg par voie intraperitoneale). Les donnees des auteurs ont montre que le rosiglitazone inhibait significativement l'hepatotoxicite induite par le D-GalN/LPS en fonction de sa concentration, comme l'indiquaient les indicateurs diagnostiques du dommage hepatique (activite des aminotransferases de serum) et l'analyse histopathologique. L'analyse par buvardage Western a montre que le rosiglitazone diminuait significativement les niveaux d'expression de COX-2 et la production de marqueurs pro-inflammatoires incluant le TNF-α et l'IL-6 dans le foie des rats traites au D-GalN/LPS. Les auteurs concluent que l'inhibition par le rosiglitazone de l'inflammation induite par le D-GalN/LPS est attribuable au moins en partie a sa capacite de reguler la voie de signalisation du facteur de transcription immuno-regulateur NF-κB. [Traduit par la Redaction] Mots-cles: rosiglitazone, dommage hepatique, inflammation, D-GalN/LPS, NF-κB, TNF-α, IL-6, COX-2.

The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) by the interstitial lipofibroblast. We have recently shown (Dasgupta C et al., Am J Physiol Lung Cell Mol Physiol 296: L103l-L1041, 2009.) that PPAR-[gamma] agonists administered postnatally accelerate lung maturation and prevent hyperoxia-induced lung injury. However, whether the same occurs antenatally is not known. The objective of this study was to test the hypothesis that the potent PPAR-[gamma] agonist rosiglitazone (RGZ), administered antenatally, enhances fetal lung maturation and protects against hyperoxia-induced neonatal lung injury. Sprague-Dawley rat dams were administered either diluent or RGZ (3 mg/kg), at late gestation, to determine its effect on lung maturation and on hyperoxia (95% [O.sub.2] exposure for 24 h)-induced neonatal lung injury. The lungs were examined for the expression of specific markers of alveolar development (surfactant proteins A and B, cholinephosphate cytidylyltransferase-[alpha], leptin receptor, triglyceride uptake, and [[sup.3]H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-[beta] signaling (activin receptor-like kinase-5, SMAD3, lymphoid enhancer factor-1, fibronectin, and calponin). Overall, antenatal RGZ accelerated lung maturation and blocked the inhibition of alveolar sacculation and septal wall thinning by hyperoxia. RGZ specifically stimulated the development of the alveolar epithelial type II cell, the lipofibroblast, and the vasculature. The increased expression of the transforming growth factor-[beta] intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-[gamma] agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury. lung development; peroxisome proliferator-activated receptor-[gamma]; surfactant; lipofibroblast; hyperoxia doi: 10.1152/ajplung.00240.2010.

We investigated the involvement of basal sympathetic tone in brown adipose tissue (BAT) recruitment and gene expression profile induced by peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) activation. Innervated and surgically denervated BAT pads of rats treated or not with rosiglitazone (15 mg x [kg.sup.-1] x [day.sup.-1], 7 days) were evaluated for weight, triacylglycerol (TAG) and DNA content, mitochondrial mass, and gene expression. Rosiglitazone induced BAT recruitment (increased mass, TAG and DNA content) and mRNA levels of lipolytic (adipose tissue triglyceride lipase and CGI58) and lipogenic (lipoprotein lipase, phosphoenolpyruvate carboxykinase, fatty acid binding protein 4, and diacylglycerol acyltransferase 1) proteins independently of tissue innervation status. Mitochondrial mass and mRNA levels of its regulators peroxisome proliferator-activated receptor coactivator-[alpha] and CCAAT/enhancer binding protein-[beta] were not affected by rosiglitazone, while being significantly reduced by denervation. By contrast, maximal stimulation of uncoupling protein 1 (UCP1) (thermogenesis), cell death-inducing DNA fragmentation factor-45-1ike effector A (inhibitor of UCP1 activity), monoacylglycerol lipase (lipolysis), small heterodimer partner (transcription), and glycerokinase (TAG synthesis) by rosiglitazone depended on the presence of intact BAT innervation. Cold exposure (5 [degrees]C, 24 h) significantly increased UCPI mRNA levels in innervated BAT pads of untreated rats, without affecting the already high BAT UCPI levels of rosiglitazone-treated animals. A similar pattern of response was found in denervated pads, but with markedly lower UCP1 expression than that in innervated BAT. In conclusion, whereas the mass (hyperplasia and hypertrophy), lipogenic, and lipolytic components of BAT recruitment induced by rosiglitazone occur independently of tissue sympathetic innervation, maximal UCP1 expression induced by PPAR-[gamma] in vivo depends on the presence of basal BAT adrenergic tone. The residual sympathetic tone found under rosiglitazone treatment is, therefore, involved in the modulation of a subset of major components of PPAR-[gamma]-mediated BAT recruitment. thermogenesis; sympathetic innervation; mitochondria; peroxisome proliferator-activated receptor coactivator-[alpha]; rosiglitazone doi: 10.1152/ajpregu.00821.2009.

Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor [gamma] agonists was examined in the metabolically maladapted [F.sub.1] pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate [RG; 11 [micro]mol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old [F.sub.1] female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre- and postnatal (IUGR + PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a l:1 mixture of [[2-.sup.2][H.sub.2]]- and [6,[6-.sup.2][H.sub.2]]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR + PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR + PNGR. glucose tolerance test; hepatic glucose production; stable isotopes doi:10.1152/ajpendo.00361.2009.

Increased glomerular permeability to proteins is a characteristic feature of diabetic nephropathy (DN). The slit diaphragm is the major restriction site to protein filtration, and the loss of nephrin, a key component of the slit diaphragm, has been demonstrated in both human and experimental DN. Both systemic and glomerular hypertension are believed to be important in the pathogenesis of DN. Human immortalized podocytes were subjected to repeated stretch-relaxation cycles by mechanical deformation with the use of a stress unit (10% elongation, 60 cycles/ rain) in the presence or absence of candesartan (1 [mu]M), PD-123319 (1 [mu]M), and rosiglitazone (0.1 [mu]M). Nephrin mRNA and protein expression were assessed using quantitative real-time PCR, immunoblotting, and immunofluorescence, and the protein expression of ATI receptor and angiotensin II secretion were evaluated. Exposure to stretch induced a significant -50% decrease in both nephrin mRNA and protein expression. This effect was mediated by an angiotensin II-[AT.sub.1] mechanism. Indeed, podocyte stretching induced both angiotensin II secretion and [AT.sub.1] receptor overexpression, podocyte exposure to angiotensin II reduced nephrin protein expression, and both the AT-1 receptor antagonist candesartan and a specific anti-angiotensin II antibody completely abolished stretch-induced nephrin downregulation. Similar to candesartan, the peroxisome proliferator-activated receptor (PPAR)-[gamma] agonist, rosiglitazone, also inhibited stretch-induced nephrin downregulation, suggesting interference with stretchinduced activation of the angiotensin II-[AT.sub.1] receptor system. Accordingly, rosiglitazone did not alter stretch-induced angiotensin II secretion, but it prevented [AT.sub.1] upregulation in response to stretch. These results suggest a role for hemodynamic stress in loss of nephrin expression and allude to a role of PPAR-[gamma] agonists in the prevention of this loss. diabetic nephropathy; proteinuria; [AT.sub.1] receptor doi: 10.1152/ajprenal.90423.2008.

Peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) agonists have been shown to protect the cerebral vasculature, including the blood-brain barrier. In the present study, we investigated the effect of the PPAR-[gamma] agonist rosiglitazone on changes in venous permeability during chronic hypertension induced by nitric oxide synthase inhibition. Female Sprague-Dawley rats were either treated with [N.sup.G]-nitro-L-arginine methyl ester (L-NAME; 0.5 g/l in drinking water) for 5 wk (HTN; n = 8), L-NAME for 5 wk plus the PPAR-[gamma] agonist rosiglitazone (20 mg/kg in food) for the last 3 wk (HTN + Rosi; n = 5), L-NAME for 5 wk plus the superoxide dismutase mimetic Tempol (1 mmol/l in drinking water) for the last 3 wk (HTN + Tempol; n = 8), or were untreated controls (n = 9). Fluid filtration ([J.sub.v]/S) and hydraulic conductivity ([L.sub.p]) of cerebral veins were compared in vitro between groups after a step increase in pressure from 10 to 25 mmHg to mimic the change in hydrostatic pressure during acute hypertension. Hypertension increased [J.sub.v]/S by 2.2-fold and [L.sub.p] by 3.2-fold. Rosiglitazone treatment after 2 wk of hypertension completely reversed the increased [J.sub.v]/S and [L.sub.p] that occurred during hypertension, whereas Tempol had no effect. These results demonstrate that rosiglitazone was effective at reversing changes in venous permeability that occurred during chronic hypertension, an effect that does not appear to be related to its antioxidant properties. Our findings suggest that PPAR-[gamma] may be a key regulator of blood-brain barrier permeability and a potential therapeutic target during hypertension. cerebral veins; acute hypertension; hydraulic conductivity doi: 10.1152/ajpheart.00630.2009

Endocrine effects of adipose-derived adiponectin on skeletal muscle have been shown to account, at least in part, for the anti-diabetic effects of this adipokine. Recently, the concept of myokines has gained credence, and the potential for skeletal muscle to produce adiponectin has been suggested. Here we demonstrated an increased level of adiponectin mRNA and protein expression as well as protein secretion in response to rosiglitazone treatment in L6 muscle cells. This correlated with the ability of rosiglitazone to enhance insulin sensitivity for stimulation of protein kinase B (Akt) phosphorylation and glucose transport; rosiglitazone also corrected high-glucose-induced insulin resistance in L6 cells. Overexpression of adiponectin confirmed the functional significance of local production of adiponectin in muscle cells via elevated glucose uptake and increased insulin sensitivity. In obese diabetic db/db mice, there was a change in the adiponectin expression profile in soleus and extensor digitorum longus (EDL) muscle with less high molecular weight (HMW) and more medium (MMW)/low (LMW) molecular weight species detected. Induction of obesity and insulin resistance in rats by feeding a high-fat high-sucrose diet also led to decreased muscle HMW adiponectin content that could be corrected by rosiglitazone treatment. In summary, we show the ability of skeletal muscle cells to produce adiponectin, which can mediate autocrine metabolic effects, thus establishing adiponectin as a bona fide myokine. We also demonstrate that skeletal muscle adiponectin production is altered in animal models of obesity and diabetes and that these changes can be corrected by rosiglitazone. adiponectin; myokine; glucose uptake; obesity; insulin sensitivity

Introduction Endothelial dysfunction plays a key role in the development of diabetic vascular complications (King 1996). It has been reported that high glucose triggers endothelial cell apoptosis (Zhang et al. [...], Previous studies have shown that the phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase/NO (PI3K/Akt/eNOS/NO) pathway is involved in high glucose-induced endothelial cell apoptosis and rosiglitazone has a protective effect on endothelium. In the present study, we investigated the antiapoptotic effect of rosiglitazone on human umbilical vein endothelial cells (HUVECs) exposed to high glucose and explored its possible mechanism. Treatment of high glucose (33 mmol/L) for 48 h significantly induced the apoptosis of HUVECs, concomitantly with increased caspase-3 activity. High glucose treatment also decreased Akt and eNOS phosphorylation levels with subsequent NO production. All these alterations induced by high glucose were attenuated by rosiglitazone (1 mmol/L). Interestingly, the antiapoptotic effect of rosiglitazone was inhibited by PI3K inhibitor (LY294002, wortmannin) or eNOS inhibitor [N.sup.G]-L-nitro-arginine methyl ester (L-NAME). The reverse effects of rosiglitazone on phosphorylation of Akt and eNOS with subsequent NO production were also inhibited by LY294002, wortmannin or L-NAME, respectively. These findings suggest that rosiglitazone inhibits high glucose-induced apoptosis in HUVECs through the PI3K/Akt/eNOS pathway. Key words: rosiglitazone, PI3K, Akt, eNOS, NO, caspase-3. Des etudes arterieures ont montre; que la voie phosphatidylinositol 3-kinase (PI3K)/Akt/monoxyde d'azote synthase (NO) endotheliale (eNOS)/NO joue un role dans l'apoptose des cellules endotheeliales induite par le glucose; ces etudes ont aussi indique: que le rosiglitazone a un effet protecteur sur l'endothelium. Dans la presente etude, nous avons etudiee l'effet antiapoptotique du rosiglitazone sur les cellules endotheliales de la veine ombilicale humaine (HUVEC) exposees a une forte concentration de glucose, et examinee son meecanisme potentiel. Un traitement dans un milieu a forte teneur en glucose (33 mmol/L) pendant 48 h a provoque une forte apoptose des HUVEC et augmente; l'activitee de la caspase-3. Le traitement a de plus induit une diminution des taux de phosphorylation de l'Akt et de eNOS, et la production subsequente de NO. Le rosiglitazone (1 [micron]mol/L) a atteenue toutes ces modifications. Fait interessant, l'effet antiapoptotique du rosiglitazone a ete bloque par un inhibiteur de la PI3K (LY294002, wortmannine) ou l'inhibiteur de eNOS, [N.sup.G]-L-nitroarginine methylester (L-NAME). Les effets du rosiglitazone sur la phosphorylation de l'Akt et de eNOS, et la production subsequence de NO ont aussi ete inhibes par LY294002, la wortmannine ou L-NAME, respectivement. Ces resultats donnent a penser que le rosiglitazone inhibe par la voie PI3K/Akt/eNOS l'apoptose des HUVEC induite par une forte concentration de glucose. Mots-cles: rosiglitazone, PI3K, Akt, eNOS, NO, caspase-3. [Traduit par la Redaction]

Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize I) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-[beta] signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and [beta]-catenin and TGF-[beta] pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins [alpha]-smooth muscle actin ([alpha]-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-[beta] signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPAR[gamma] agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD. bronchopulrnonary dysplasia; peroxisome proliferator-activated receptor-[gamma]; lung development; lung fibroblast

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma ([PPAR.sub.[gamma]]) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n [greater than or equal to] 6/group) were fed Rosi (5 mg x [kg.sup.-1] x [day.sup.-1] in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 [+ or -] 4 vs. 111 [+ or -] 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 [+ or -] 4, P < 0.05) but not in controls (111 [+ or -] 4). Urinary albumin ([micro]g/mg creatinine) was increased in SLE mice compared with controls (12,396 [+ or -] 6,525 vs. 50 [+ or -] 6) and reduced with Rosi treatment (148 [+ or -] 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 [+ or -] 1.6 vs. 0.4 [+ or -] 0.3, P < 0.05). Renal monocyte/ macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 [+ or -] 11.0 vs. 10.6 [+ or -] 3.6, P < 0.05) but unchanged in controls (3.7 [+ or -] 1.6 vs. 3.7 [+ or -] 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 [+ or -] 0.59 vs. 0.6 [+ or -] 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 [+ or -] 0.11, P < 0.05). [PPAR.sup.[gamma]]/protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury. lupus; inflammation; endothelin; glomerulosclerosis; proliferator activated receptor gamma

Asian ginseng (Panax ginseng) and its close relative North American ginseng (Panax quinquefolius) are perennial aromatic herbs that are widely used in Oriental medicine and have been acclaimed to have [...]

The treatment of type 2 diabetes with Rosiglitazone and its resulting long-term effect on cardio-vascular system is outlined.

Byline: Salvatore Cuzzocrea (1), Barbara Pisano (2), Laura Dugo (1), Angela Ianaro (2), Domenico Britti (3), Nimesh S. A. Patel (4), Rosanna Di Paola (1), Tiziana Genovese (1), Massimo Di Rosa (2), Achille P. Caputi (1), Christoph Thiemermann (3) Keywords: PPAR- ; Pancreatitis; Adhesion molecules; Inflammation; Neutrophil infiltration Abstract: Objective In the present study, we investigated the effects of rosiglitazone (10 mg/kg, i.p.), a PPAR-I3 agonist, on the development of acute pancreatitis. Design Intraperitoneal injection of cerulein in mice induced an acute pancreatitis characterized by edema, neutrophil infiltration elevated serum levels of amylase and lipase. This experimental model was performed to test the anti-inflammatory activity of rosiglitazone. Setting University research laboratory. Interventions Male CD mice (20--22 g) were allocated into four groups (n=10 for each group): (a) Cerulein+vehicle group. Mice were treated hourly (x5) with cerulein (50 ug/kg, in saline solution, i.p.) (b) Rosiglitazone group (same as the Cerulein+vehicle group but were administered rosiglitazone, 10 mg/kg bolus, 30 min prior to cerulein) (c) Sham+saline group. Mice were treated with saline instead of cerulein (d) Sham+Rosiglitazone. Identical to Rosiglitazone group except that the saline was administered instead of cerulein. Mice were killed at 6 h after the induction of pancreatitis. Blood samples, pancreas, and lungs were collected. Measurements and results Infiltration of pancreatic and lung tissue with neutrophils was associated with enhanced lipid peroxidation. Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and for ICAM-1 in the pancreas of cerulein-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury, (b) upregulation/formation of ICAM-1 and nitrotyrosine, and (c) neutrophils infiltration was markedly reduced in pancreatic tissue obtained from rosiglitazone-treated mice. Conclusion These findings support the view that rosiglitazone and other potent PPAR-I3 agonists may be useful in the therapy of acute pancreatitis. Author Affiliation: (1) Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123, Messina, Italy (2) Department of Experimental Pharmacology, Universita 'Federico II', Napoli, Italy (3) Department of Clinical Veterinary Science, University of Teramo, Teramo, Italy (4) The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK Article History: Registration Date: 09/01/2004 Received Date: 01/10/2003 Accepted Date: 06/01/2004 Online Date: 24/02/2004