title: Treatment of experimental arthritis with M2000, a novel designed non-steroidal anti-inflammatory drug.
abstract: The current study was planned to explore the therapeutic potency of M2000 (beta-D-mannuronic acid), a novel designed non-steroidal anti-inflammatory drug (NSAID) in adjuvant-induced arthritis model. Arthritis was induced in Lewis rats by a single intradermal injection (0.1 ml) of heat-killed Mycobacterium tuberculosis (0.3 mg) in Freund's incomplete adjuvant into the right footpad. Fourteen days after injection of adjuvant, the contralateral left footpad volume was measured. The animals with paw volumes 0.37 ml greater than normal paws were then randomized into treatment groups. Orally and intraperitoneally administrations of test drugs (M2000, 40/mg/kg/day and indomethacin, 2/mg/kg/day) were started on day 15 post-adjuvant injection and continued until final assessment on day 25. The left hind limb was removed for histological evaluation. The WEHI-164 cell line was used for assaying tolerability and matrix metalloproteinase type 2 (MMP-2) activity. MMP-2 activity was assessed using zymography. Pharmacotoxicology study was carried out on animal models based on the evaluation of serum and urine determinants, histology of kidney, gastrointestinal tolerability and body temperature. Results showed that the orally administration as well as intraperitoneally injection of M2000 to arthritic rats induced a significant reduction in paw oedema. Histopathological assessment showed a reduced inflammatory cells infiltrate in joints of treated rats, as well as the number of osteoclasts present in the subchondral bone, tissue oedema and bone erosion in the paws were markedly reduced following M2000 therapy. Cytotoxicity analysis of M2000 showed a much higher tolerability compared with other tested drugs (diclofenac, piroxicam and dexamethasone). The inhibitory effect of M2000 in MMP-2 activity was significantly greater than that of dexamethasone and of piroxicam at a concentration of 200 microg/ml. Moreover, the toxicological study revealed that M2000 had no influence on serum (blood urea nitrogen, creatinine, triglyceride and cholesterol) and urine (urea and urinary protein excretion) determinants, glomerular histology and body temperature in normothermic rats and had no ulcerogenic effects on rats' stomach. Our data show that M2000, as a novel NSAID, could be strongly suggested as the safest anti-inflammatory drug for long-term administration.
authors.affiliation: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. a_mirshafiey@yahoo.com
authors.forename: A
authors.initials: A
authors.lastname: Mirshafiey
authors.forename: S
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: B
authors.initials: B
authors.lastname: Rehm
authors.forename: E
authors.initials: E
authors.lastname: Mazzon
authors.forename: F
authors.initials: F
authors.lastname: Saadat
authors.forename: M
authors.initials: M
authors.lastname: Sotoude
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000473:pathology; D005121:Extremities / Q000473:pathology; D006603:Hexuronic Acids / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009169:Mycobacterium tuberculosis; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
chemical_list: D006603:Hexuronic Acids; C008324:mannuronic acid; D020778:Matrix Metalloproteinase 2