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 (b-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 mg/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.

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation

“…Of course, while ankle swelling does not reflect the full complement of peripheral inflammatory processes, it underscores the potential independence of pain and swelling in peripheral inflammatory pain states. Indeed, while both swelling and hypersensitivity can be dose-dependently reduced with non-steroidal anti-inflammatory drugs (NSAIDs; [49; 91]), hypersensitivity can also be attenuated independently from swelling [14; 37; 125]. Therefore, while ankle swelling alone should not be considered to be a definitive measure of the state of peripheral inflammation, it suggests that the processes underlying ongoing swelling may be unaffected by voluntary exercise, in contrast to pain- and stress-related behaviors.…”

Models of Inflammation: Carrageenan‐ or Complete Freund's Adjuvant (CFA)–Induced Edema and Hypersensitivity in the Rat

“…The behaviors used to determine hypersensitivity include unlearned behaviors such as flinching, vocalization, and grooming (D'Amour and Smith, 1941; Woolfe and MacDonald, 1944; Randall and Selitto, 1957) or segmental withdrawal reflexes in response to thermal or mechanical stimulation (Hargreaves et al , 1988; Chaplan et al , 1994). Using models of inflammation induced by either carrageenan or CFA, researchers have demonstrated that the NSAID, indomethacin, reduces paw swelling in a dose-dependent manner by at least 60% (1–9 mg/kg, ip; Winter et al , 1962; Winter et al , 1968; Mirshafiey et al , 2005) and attenuates hyperalgesia and allodynia (2–4 mg/kg, ip; Hargreaves et al , 1988; Tall et al , 2004; Zhang et al , 2004). Interestingly, these components of inflammation (edema and hypersensitivity) do not necessarily go hand in hand.…”

Targeting of crosstalk between tumor and tumor microenvironment by β‐D mannuronic acid (M2000) in murine breast cancer model

“…The β‐D mannuronic acid (BDM) extracted from alginic acid sodium salt is a novel antiinflammatory agent with no evidence of toxicity in our preclinical toxicology study . Our previous studies have shown therapeutic efficacy of BDM with the high tolerability in various animal models such as experimental autoimmune encephalomyelitis , adjuvant‐induced arthritis , nephrotic syndrome , and acute glomerulonephritis . Currently, we are analyzing the efficacy of BDM in clinical trials in patients with ankylosing spondylitis (IRCT: 2013062213739N1) and rheumatoid arthritis (IRCT: 2014011213739N2).…”