Rheumatoid Arthritis: Di Paola R

Di Paola R, Cuzzocrea S. · IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. · Autoimmun Rev. · Pubmed #18708167 No free full text.

Abstract: Arthritis literally means joint inflammation. Arthritis is not a single disease. Arthritis refers to a group of rheumatic diseases and other conditions that can cause pain, stiffness and swelling in the joints. The forms range from those related to wear and tear of cartilage (such as osteoarthritis) to those associated with inflammation resulting from an overactive immune system (such as rheumatoid arthritis). Arthritis is more heterogeneous and this is an important starting point when discussing animal models for arthritis. Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of rheumatoid arthritis. Several new mouse models have either been produced. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA.

Mirshafiey A, Saadat F, Attar M, Di Paola R, Sedaghat R, Cuzzocrea S. · Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. · Immunopharmacol Immunotoxicol. · Pubmed #16997789 No free full text.

Abstract: This study was aimed to evaluate the therapeutic potency of a new antimalarial drug, artesunate, in an experimental model of rheumatoid arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats.The intraperitoneally administration of artesunate (ARS) and methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was intermittent. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ARS and MTX were assessed using fibrosarcoma cell line. Our results showed that i.p. injection of artesunate 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 cells infiltrate in joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following ARS therapy. Moreover, our radiographic results paralleled histological findings. Cytotoxicity analysis of ARS showed greater tolerability compared with MTX. Treatment with ARS significantly diminished nitric oxide formation in treated rats compared with untreated controls. Our findings revealed the therapeutic efficacy of artesunate in experimental rheumatoid arthritis compared with a choice drug (methotrexate). This result may recommend it as a second-line drug in the treatment of rheumatoid arthritis.

Cuzzocrea S, Mazzon E, Di Paola R, Muià C, Crisafulli C, Dugo L, Collin M, Britti D, Caputi AP, Thiemermann C. · Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi-98100 Messina, Italy. · Clin Immunol. · Pubmed #16631408 No free full text.

Abstract: Recently, glycogen synthase kinase-3 (GSK-3) has being identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of arthritis caused by type II collagen (CII) in the mouse (collagen-induced arthritis; CIA). Mice developed erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund's adjuvant (CFA). The incidence of CIA was 100% by day 28 in the CII-challenged mice and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of mice with the GSK-3beta inhibitor TDZD-8 (1 mg/kg/day i.p.) starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26-35 and improved histological status in the joint and paw. Immunohistochemical analysis for nitrotyrosine, poly(ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) revealed a positive staining in inflamed joints from mice subjected to CIA. The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 was significantly reduced in CII-challenged mice treated with the GSK-3beta inhibitor. Plasma levels of tumor necrosis factor (TNF)-alpha and the joint tissue levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 were also significantly reduced by GSK-3beta inhibition. These data demonstrate that GSK-3beta inhibition exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.

Cuzzocrea S, Saadat F, Di Paola R, Mirshafiey A. · Institute of Pharmacology, School of Medicine, University of Messina, Italy. · Immunopharmacol Immunotoxicol. · Pubmed #16435580 No free full text.

Abstract: The current research was designed to determine the effect of artemether in treatment of experimental rheumatoid arthritis. Collagen-induced arthritis was induced in Lewis rats. The intramusculary administration of artemether (ART) and intraperitoneally injection of methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was taken intermittently. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ART and MTX were assessed using fibrosarcoma cell line. Data showed that i.m. injection of ART 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 a reduced inflammatory cell infiltrate in joints of treated rats; tissue edema, and bone erosion in the paws were markedly reduced following ART therapy. Furthermore, our radiography results paralleled our histological findings. Cytotoxicity analysis of ART showed greater tolerability compared with MTX. Treatment with ART significantly diminished NO formation in treated rats compared with nontreated controls. Our data shed light on the therapeutic efficacy of artemether in experimental rheumatoid arthritis compared with a choice drug (methotrexate), and it may be offered as a second-line drug in treatment of rheumatoid arthritis.

Cuzzocrea S, Ayroldi E, Di Paola R, Agostini M, Mazzon E, Bruscoli S, Genovese T, Ronchetti S, Caputi AP, Riccardi C. · Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, Messina, Italy. · FASEB J. · Pubmed #16051692 links to  free full text

Abstract: In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNgamma, IL-6, TNFalpha, MIP-1alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.

Saadat F, Cuzzocrea S, Di Paola R, Pezeshki M, Khorramizadeh MR, Sedaghat M, Razavi A, Mirshafiey A. · Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. · Med Sci Monit. · Pubmed #16049375 No free full text.

Abstract: 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.