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Salvatore Cuzzocrea

Publications and source records attributed to Salvatore Cuzzocrea.

At least 55 records · Page 3Linked to original sources
PubMed2006

Neuroprotection and enhanced recovery with hypericum perforatum extract after experimental spinal cord injury in mice.

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants, and/or a depletion of antioxidants. A considerable body of recent evidence suggests that oxidative stress and exaggerated production of reactive oxygen species play a major role in several aspects of inflammation. Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely, flavonoids and phenolic acids. Because polyphenolic compounds have high antioxidant potential, in this study, we evaluated the effect of H. perforatum (given at 30 mg . kg (-1)) in an experimental animal model of spinal cord injury, which was induced by the application of vascular clips to the dura via a four-level T5 through T8 laminectomy. The degree of (a) spinal cord inflammation and tissue injury (histological score), (b) nitrotyrosine, (c) poly(adenosine diphosphate-ribose), (d) neutrophils infiltration, and (e) the activation of signal transducer and activator transcription 3 was markedly reduced in spinal cord tissue obtained from H. perforatum extract-treated mice. We have also demonstrated that H. perforatum extract significantly ameliorated the recovery of limb function.

Animals↗
PubMed2006

Absence of peroxisome proliferators-activated receptors (PPAR)alpha enhanced the multiple organ failure induced by zymosan.

The peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study is to evaluate the role of PPAR-alpha receptor on the development of multiple-organ dysfunction syndrome (MODS) induced by zymosan. MODS was induced by peritoneal injection of zymosan (dose, 500 mg/kg i.p. as a suspension in saline) in PPAR-alpha wild-type (PPAR-alphaWT) and PPAR-alpha knockout (PPAR-alphaKO) mice, was assessed 18 h after the administration of zymosan, and was monitored for 12 days (for loss of body weight and mortality). A severe inflammatory process, induced by zymosan administration in wild-type mice, coincided with the damage of liver, kidney, pancreas, and small intestine. Myeloperoxidase activity, indicative of neutrophil infiltration, and lipid peroxidation were significantly increased in zymosan-treated wild-type mice. Zymosan in the wild-type mice also induced a significant increase in the plasma levels of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine and Fas ligand in the intestine of zymosan-treated wild-type mice. In contrast, the degree of (1) peritoneal inflammation and tissue injury, (2) nitrotyrosine formation and Fas ligand expression, and (3) neutrophil infiltration were markedly enhanced in intestinal tissue obtained from zymosan-treated PPAR-alphaKO mice. Zymosan-treated PPAR-alphaKO mice also showed a significantly increased mortality. Taken together, the present study clearly demonstrates that PPAR-alpha pathway modulates the degree of MODS associated with zymosan-induced nonseptic shock.

Animals↗
PubMed2006

Oxidative stress as the leading cause of acute myocardial infarction in diabetics.

The risk factors, such as hypertension and metabolic syndrome, tend to promote heart pathology. These risk factors can aggravate concomitant heart insults as well. Diabetes mellitus represents one of the most important risk factors for the development of heart pathology. By itself it represents a source of vascular and heart dysfunction through formation of reactive oxygen species (ROS) and can compromise the recovery from cardiovascular diseases. This review focuses on the evidence that cellular oxidative stress is the leading cause of the worst outcome of myocardial infarction (MI) in diabetics. Hyperglycemia is viewed in this article as the primary mediator of a cascade of heart damaging events, starting from ROS formation and leading to myocardial ischemia, inflammation and death of myocytes. This article also provides insights into why diverse therapeutic interventions, which have in common the ability to reduce oxidative stress and inflammation, can impede or delay the onset of complications of myocardial infarction in diabetic patients.

Diabetes Complications↗
PubMed2006

Effects of combination of melatonin and dexamethasone on acute lung injury in a mice model of carrageenan-induced pleurisy.

The aim of this study was to investigate the effects of combination therapy with melatonin and dexamethasone (DEX) on acute lung injury. In particular, we investigated the effects of combination therapy in animal models of acute lung inflammation (carrageenan-induced pleurisy). Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of neutrophils [polymorphonuclear leukocyte (PMN)] as well as an infiltration of PMN in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), and prostaglandin E2 (PGE2). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, inducible nitric oxide synthase, cycloxygenase-2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. No anti-inflammatory effect was observed in animals treated with melatonin (10 mg/kg) or with DEX (0.01 mg/kg) alone. This study shows that the combination therapy with melatonin and DEX reduced the degree of acute lung inflammation and tissue damage associated with carrageenan-induced pleurisy in mice and supports the possible use of melatonin in combination with steroids in order to reduce the dose and the side effects related with the use of steroids for the management of inflammatory disease.

Acute Disease↗
PubMed2006

Melatonin modulates signal transduction pathways and apoptosis in experimental colitis.

Various evidences have documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. The aim of the present study was to evaluate whether melatonin regulates the inflammatory response of experimental colitis in rats at the level of signal transduction pathway. Colitis was induced by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Four days after DNBS administration, a substantial increase of colon TNF-alpha production was associated with the colon damage. In DNBS-treated rats, the colon injury correlated with a significant rise of apoptosis (evaluated by TUNEL coloration) which was associated with a significant increased expression of proapoptotic Bax and decreased colon content of antiapoptotic Bcl-2. This inflammatory response was also related to activation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun as well as FAS ligand expression in the colon. Treatment with melatonin (15 mg/kg daily i.p.) was associated with a remarkable amelioration of colonic disrupted architecture as well as a significant reduction of TNF-alpha. Melatonin also reduced the NF-kappaB activation and phosphorylation of c-Jun as well as the Fas ligand expression in the colon. Furthermore, melatonin reduced the expression of Bax and prevented the loss of Bcl-2 proteins as well as the presence of apoptotic cells caused by DNBS. The results of this study show that melatonin administration exerts beneficial effects in inflammatory bowel disease by modulating signal transduction pathways.

Animals↗
PubMed2006

Anti-allergic properties of Mangifera indica L. extract (Vimang) and contribution of its glucosylxanthone mangiferin.

Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract.

Anaphylaxis↗
PubMed2006

Role of nitric oxide and reactive oxygen species in arthritis.

A vast amount of circumstantial evidence implicates oxygen-derived free radicals, especially reactive oxygen species and nitric oxide as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. The aim of the current article is to overview the recent developments in this field, as it relates to the roles of nitric oxide (NO) and reactive oxygen species in the pathogenesis of this condition. The first part of the review focuses on the biochemical impact of NO and reactive oxygen species. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible isoform of nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in inflammation. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of inflammation. Reactive oxygen species are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently it has been demonstrated that iNOS inhibitor prevents the activation of poly (ADP ribose) synthetase, and prevents the organ injury associated with inflammation. Although the severity and duration of inflammation may dictate the timing and extent of NOS expression, it is now evident that the up-regulation of NOS can take place during sustained inflammation. Thus, induced nitric oxide, in addition to being a "final common mediator" of inflammation, is essential for the up-regulation of the inflammatory response. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of reactive oxygen species, with them associated toxicities, and indirectly through the amplification of the inflammatory response.

Animals↗
PubMed2006

Modulation of nitric oxide homeostasis in a mouse model of spinal cord injury.

OBJECT: A traumatic spinal cord injury (SCI) immediately induces primary damage, and this is followed by secondary damage characterized by a series of events among which is a progressive extension of cell death within the damaged tissue. In this study, the authors investigated the role of inducible nitric oxide synthase (iNOS) in an experimental model of SCI in mice. METHODS: In wild-type (iNOS+/+) mice, SCI rapidly induced an inflammatory response as shown by nitrotyrosine formation, activation of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase (PARP), neutrophil infiltration, and spinal cord tissue histopathological changes, indicating the involvement of iNOS-derived massive amounts of NO in SCI. CONCLUSIONS: Genetic inhibition of iNOS, however, resulted in a significant reduction in secondary damage, and this therapeutic efficacy was associated with the prevention of an SCI-induced drop in neuronal and endothelial NOS activity.

Animals↗
PubMed2005

Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock.

Poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme activated by DNA strand breaks, plays a detrimental role during inflammation. As inflammation is important in the development of colitis and ischemia/reperfusion (I/R) injury of the intestine, we investigated the effects of 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI 15427) and 2-(4-methyl-piperazin-1-yl)-5H-benzo[c][1,5]naphthyridin-6-one (GPI 16539), two novel and potent inhibitors of PARP-1, in a rat model of gut injury and inflammation, splanchnic artery occlusion (SAO)shock and dinitrobenzene sulfonic acid (DNBS)-induced colitis. We report here for the first time that post-injury administration of GPI 15427 and GPI 16539 exerts potent anti-inflammatory effects by reducing inflammatory cell infiltration and histological injury, and delaying the development of clinical signs in both in vivo models. Furthermore, GPI 15427 and GPI 16539 treatment diminished the accumulation of poly(ADP-ribose) in the ileum of splanchnic artery occlusion-shocked rats and in the colons of dinitrobenzene sulfonic acid-treated rats. Thus, GPI 15427 and GPI 16539 exhibited anti-inflammation activity against damage caused by intestinal ischemia/reperfusion and colitis. GPI 15427 and GPI 16539 may be useful for treating gut ischemia and inflammation.

Animals↗
PubMed2005

Immunomodulatory effects of etanercept in an experimental model of spinal cord injury.

Etanercept is a tumor necrosis factor antagonist with anti-inflammatory effects. The aim of our study was to evaluate for the first time the therapeutic efficacy of in vivo inhibition of tumor necrosis factor-alpha (TNF-alpha) in experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production that it is followed by recruitment of other inflammatory cells, such as production of a range of inflammation mediators, tissue damage, apoptosis, and disease. Treatment of the mice with etanercept significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase evaluation); 3) inducible nitric-oxide synthase, nitrotyrosine, cyclooxygenase-2, and cytokines expression (TNF-alpha and interleukin-1beta); and 4) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Bax and Bcl-2 expression). In a separate set of experiment, we have also clearly demonstrated that TNF-alpha inhibitor significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

Animals↗
PubMed2005

A protective role for proteinase activated receptor 2 in airways of lipopolysaccharide-treated rats.

Proteinase activated receptor-2 (PAR2), a seven transmembrane domain G protein coupled receptor, is expressed on airway epithelium and smooth muscle cells and over-expressed in human airways under pathological conditions, such as asthma and chronic obstructive pulmonary disease (COPD). However, the role of PAR2 in airways has not yet been defined. Aim of the present study, was to evaluate the in vitro rat bronchial response to a synthetic peptide activating PAR2 (PAR2-AP; SLIGRL), following an in vivo treatment with bacterial lipopolysaccharide (LPS). Bronchi from LPS-treated animals showed an increased relaxant response to PAR2-AP, compared to naïve animals, the effect was maximum after 20-h pre-treatment and reduced by epithelium removal. Western blot analysis showed an increased PAR2 protein expression on bronchi removed 20h after LPS treatment. PAR2-AP-induced bronchorelaxation was inhibited by ibuprofen, by the selective cyclooxygenase2 (COX-2) inhibitor, diisopropyl fluorophosphate (DFP) and partially by the calcitonin gene related peptide (CGRP) antagonist, rat-CGRP([8-37]). Furthermore, there was a strong immunoreactivity for COX-2 on bronchial epithelium of LPS-treated rats. Prostaglandin E2 (PGE2) tissue release and CGRP tissue content were significantly increased following tissue incubation with PAR2-AP. The in vivo LPS treatment in rats strongly increases the bronchorelaxant effect of PAR2-AP, this effect correlates with an increased tissue protein receptor expression and the COX-2 localization on bronchial epithelium. Our work supports a role for PAR2 as a defence mechanism aimed to preserve bronchial functionality under systemic inflammatory conditions; both COX-2-derived PGE2 and CGRP are involved in this effect.

Animals↗
PubMed2005

Hypericum perforatum attenuates the development of carrageenan-induced lung injury in mice.

Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. Since polyphenolic compounds have a high antioxidant potential, in this study we evaluated the effect of H. perforatum in an animal model of acute inflammation, carrageenan-induced pleurisy. We report here that H. perforatum extract (given at 30 mg/kg orally, bolus prior to carrageenan) exerts potent anti-inflammatory effects in an animal model of acute inflammation. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of neutrophils (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation (as determined by thiobarbituric acid-reactant substance measurement) and increased production of tumor necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1 beta). All parameters of inflammation were attenuated by H. perforatum extract. Furthermore, carrageenan induced an upregulation of the expression of adhesion molecules ICAM-1, as well as an increase in the amounts of nitrotyrosine and poly(ADP-ribose) (PAR), as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, nitrotyrosine, and PAR was significantly reduced by H. perforatum extract. Additionally, we demonstrate that these inflammatory events were associated with the activation of nuclear factor-kappaB (NF-kappaB) and signal transducer and activator transcription-3 (STAT-31) activation in the lung. NF-kappaB and STAT-3 activation were significantly inhibited by H. perforatum extract treatment. Taken together, our results indicate that prevention of the activation of NF-kappaB and STAT-3 by H. perforatum extract reduces the development of acute inflammation.

Animals↗
PubMed2005

Increased oxidative-related mechanisms in the spinal cord injury in old rats.

In the present study, we evaluated the effect of age, in a model of spinal cord injury that was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in old rats resulted in severe trauma characterized by edema and neutrophil infiltration. Immunohistochemical examination demonstrated an increase in immunoreactivity for nitrotyrosine. In contrast, the degree of: (a) spinal cord inflammation and tissue injury (histological score), (b) nitrotyrosine, (c) PARS, and (d) neutrophils infiltration was markedly reduced in spinal cord tissue obtained from young rats. We have also demonstrated that ageing significantly worsened the recovery of limb function and caused an increase in mortality rate when compared with young rats.

Age Factors↗
PubMed2005

Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines.

GILZ (glucocorticoid-induced leucine zipper), a gene induced by dexamethasone, is involved in control of T lymphocyte activation and apoptosis. In the present study, using Gilz transgenic mice (TG), which overexpress GILZ in the T-cell lineage, we demonstrate that Gilz is implicated in T helper-2 (Th-2) response development. After in vitro stimulation by CD3/CD28 antibodies, peripheral naive CD4+ T cells from TG mice secrete more Th-2 cytokines such as interleukin-4 (IL-4), IL-5, IL-13, and IL-10, and produce less Th-1 cytokines such as interferon-gamma (IFN-gamma) than wild-type mice (WT). CD4+ TG lymphocytes up-regulated Th-2 cytokine expression in the specific response to ovalbumin chicken egg (OVA) antigen immunization. Up-regulation correlated with increased expression of GATA-3 and signal transducer and activator of transcription 6 (Stat6), Th-2-specific transcription factors and decreased expression of T-bet, a transcription factor involved in Th-1 differentiation. Finally, in TG mice delayed-type hypersensitivity, a Th-1 response, was inhibited and bleomycin-induced pulmonary fibrosis, a Th-2 mediated disease, was more severe. These results indicate that Gilz contributes to CD4+ commitment toward a Th-2 phenotype and suggest this contribution may be another mechanism accounting for glucocorticoid immunomodulation.

Animals↗
PubMed2005

Up-regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-{gamma}.

Leukotrienes (LT) and prostaglandins (PG) are proinflammatory mediators generated by the conversion of arachidonic acid via 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways. It has long been proposed that the inhibition of the 5-LO could enhance the COX pathway leading to an increased PG generation. We have found that in in vitro models of inflammation, such as mice-elicited peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma), the deletion of the gene encoding for 5-LO or the enzyme activity inhibition corresponded to a negative modulation of the COX pathway. Moreover, exogenously added LTC(4), but not LTD(4), LTE(4), and LTB(4), was able to increase PG production in stimulated cells from 5-LO wild-type and knockout mice. LTC(4) was not able to induce COX-2 expression by itself but rather potentiated the action of LPS/IFN-gamma through the extracellular signal-regulated kinase-1/2 activation, as demonstrated by the use of a specific mitogen-activated protein kinase (MAPK) kinase inhibitor. The LT-induced increase in PG generation, as well as MAPK activation, was dependent by a specific ligand-receptor interaction, as demonstrated by the use of a cys-LT1 receptor antagonist, although also a direct action of the antagonist used, on PG generation, cannot be excluded. Thus, the balance between COX and 5-LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion.

Animals↗
PubMed2005

Effect of pyrimethamine in experimental rheumatoid arthritis.

BACKGROUND: Recent evidence has shown that the antimalarials are useful drugs in the treatment of various rheumatic diseases. The present study was designed to test the therapeutic effect of pyrimethamine (PYR) in collagen-induced arthritis (CIA). MATERIAL/METHODS: CIA was induced in Lewis rats. The intraperitoneal administration of PYR and methotrexate (MTX) were started on day 25 post-immunization and continued until final assessment on day 35. During this period, clinical examination was performed intermittently. Anti-C II Ab and nitric oxide (NO) synthesis were measured. The paws and knees were then removed for histopathology and radiography assay. The biocompatibility of PYR and MTX were assessed using a fibrosarcoma cell line. RESULTS: Data showed that i.p. injection of pyrimethamine to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cell infiltrate in the joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following PYR therapy. Moreover, our radiography results paralleled our histological findings. Cytotoxicity analysis of PYR showed greater tolerability compared with MTX. Treatment with PYR significantly diminished nitric oxide formation in treated rats compared with untreated controls. CONCLUSIONS: Our findings shed light on the therapeutic efficacy of pyrimethamine in experimental rheumatoid arthritis compared with a choice drug (methotrexate), which may recommended it as a second-line drug in the treatment of rheumatoid arthritis.

Animals↗
PubMed2005

M2000: a revolution in pharmacology.

BACKGROUND: The tolerability and the anti-inflammatory and immunosuppressive properties of a novel designed non-steroidal anti-inflammatory drug, M2000 (beta-D-mannuronic acid), were investigated in various experimental models. MATERIAL/METHODS: The anti-inflammatory and immunosuppressive properties of M2000 were tested in experimental models of rheumatoid arthritis (AIA) and multiple sclerosis (EAE). Its therapeutic potency on kidney diseases was studied using experimental models of nephrosis and immune complex glomerulonephritis (ICG). Biocompatibility and pharmacotoxicology assessment of M2000 was carried out using a fibrosarcoma cell line, zymography, and serum and urine determinants. RESULTS: Data showed that oral and/or i.p. administration of M2000 significantly reduces paw edema and histopathological parameters in arthritic rats. The immunosuppressive property of M2000 could significantly diminish clinical signs and histological erosions in the EAE model. Lymph node cell proliferation assay in EAE confirmed the immunosuppressive efficacy of the tested drug. Our findings in ICG and experimental nephrosis showed that M2000 enables a significant decrease in proteinuria, BUN, serum creatinine and cholesterol, as well as glomerular lesion in M2000-treated rats. Moreover, this drug inhibited MMP-2 activity. The pharmacotoxicology study showed that M2000 is the safest anti-inflammatory and immunosuppressive drug in comparison with dexamethasone and conventional NSAIDs tested. Additionally, M2000 had no ulcerogenic effect on the rat stomach. CONCLUSIONS: M2000 is the first novel designed NSAID with the lowest molecular weight, no gastro-nephrotoxicity, and therapeutic effects in glomerulonephritis and nephrosis and could be strongly recommended on an extensive scale as the safest drug for decreasing anti-inflammatory reactions.

Animals↗