methyl-3-methoxy-4-hydroxystyryl-ketone and Stomach-Ulcer

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1β by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration.

Topics: Administration, Oral; Animals; Arthritis; Cyclooxygenase Inhibitors; Cytokines; Enzyme Activation; Female; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Protective Agents; Protein Transport; Rats, Wistar; RAW 264.7 Cells; Spleen; Stomach; Stomach Ulcer; Styrenes; Weight Loss

Methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones (MHSK and PHSK, resp.) upon oral administration displayed marked antiinflammatory activity in a variety of acute tests viz. carrageenan, histamine, 5-hydroxytryptamine, dextran, bradykinin and prostaglandin (PG) induced oedema in rats and carrageenan evoked swelling in mice; the activity was not altered by adrenalectomy. In subacute test of formaldehyde arthritis, they showed significant reduction in paw swelling but were less effective in granuloma tests. In chronic tests, they produced marked antiarthritic effect both in developing and established adjuvant arthritis. The compounds prevented the inflammation induced increase in serum transaminase levels and leucocyte counts. They inhibited the passive cutaneous anaphylaxis and produced reduction in ADP induced platelet aggregation. The compounds showed weaker antipyretic activity than acetylsalicylic acid in pyretic animals. MHSK showed analgesic activity using the tail clip method and antagonised acetic acid induced writhing syndrome. The compounds lacked any local anaesthetic activity. The low ulcerogenic potential of these compounds in animal models may be related to their relative inability to inhibit PG synthetase.

Topics: Adrenal Glands; Alanine Transaminase; Analgesics; Anesthetics, Local; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Aspartate Aminotransferases; Cell Movement; Edema; Leukocyte Count; Male; Rats; Stomach Ulcer; Styrenes