Abstract
This investigation was planned to assess the therapeutic efficacy of a novel designed nonsteroidal anti-inflammatory drug, M2000 (ß- D- mannuronic acid) in experimental models of rheumatoid arthritis, multiple sclerosis, glomerulonephritis, and nephrotic syndrome. The anti-inflammatory property of M2000 was tested in Adjuvant-induced arthritis (AIA) by intraperitoneal (i.p.) administration of 40 mg/Kg/day M2000 and compared with indomethacin. The immunosuppressive effect of M2000 was evaluated using experimental model of multiple sclerosis, (Experimental autoimmune encephalomyelitis “EAE”). Its therapeutic potency on kidney diseases was studied using experimental models of nephrosis ( Adriamycin-induced nephropathy) and immune complex glomerulonephritis ( bovine serum albumin nephritis) by i.p. injection of M2000( 30mg/Kg/day) and compared with Piroxicam. Biocompatibility and pharmacotoxicology assessment of M2000 was carried out using WEHI-164 cell line, zymography method and determining the serum and urine parameters in healthy controls receiving M2000. Results showed that i.p. administration of M2000 to arthritic rats significantly reduced paw edema, and anti-inflammatory effect of tested drug was equivalent to that observed after treatment by Indomethacin. Immunosuppressive property of M2000 could significantly reduce clinical signs and histological erosions in treated Lewis rats compared with nontreated controls in EAE model, as well as lymph node cells proliferative assay in EAE confirmed immunosuppressive efficacy of tested drug. Our data in experimental model of immune complex glomerulonephritis and experimental nephrosis using Sprague-Dawley rats showed that i.p. administration of M2000 could significantly decrease the urinary protein excretion, blood urea nitrogen (BUN), serum creatinine and plasma concentration of cholesterol, as well as glomerular hypercellularity, PMN infiltration and cast formation in histological assessment of kidney in treated rats by M2000 compared with non-treated animals. Our findings using Fibrosarcoma (WEHI, 164) cell line revealed that tested drug has an inhibitory effect on Matrix Metalloproteinase 2 activity compared to Dexamethasone, Piroxicam and Diclofenac. Pharmacotoxicology study using animal models and in vitro examination showed that M2000 is the safest antiinflammatory and immunosuppressive drug with the greatest tolerability in comparison with Dexamethasone and tested conventional NSAIDs. Additionally, M2000 had no ulcerogenic effect on rat stomach and had no influence on the body temperature of normothermic rats at its anti-inflammatory dose range. Our data indicate that M2000 as a new anti-inflammatory drug with immunosuppressive property and greatest tolerability not only has no gastro-nephrotoxicity, but it is the first novel designed NSAID with lowest molecular weight and therapeutic effects on glomerulonephritis and nephrosis due to which it could be strongly recommended in an extensive scale as a safest drug for decreasing the anti-inflammatory reactions.
Keywords: anti-inflammatory, nsaids, rheumatoid arthritis, matrix metalloproteinase, multiple sclerosis, eae, glomerulonephritis, nephrosis, immunosuppressive
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