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      Strong and Long-Lasting Antinociceptive and Anti-inflammatory Conjugate of Naturally Occurring Oleanolic Acid and Aspirin


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          The conjugate 8 was obtained as a result of condensation of 3-hydroxyiminooleanolic acid morfolide (7) and aspirin in dioxane. Analgesic effect of OAO-ASA (8) for the range of doses 0.3–300.0 mg/kg ( p.o.) was performed in mice using a hot-plate test. Anti-inflammatory activity was assessed on carrageenan-induced paw edema in rats for the same range of doses. The conjugate OAO-ASA (8) did not significantly change locomotor activity of mice, therefore sedative properties of the compound should be excluded. The compound 8 proved a simple, proportional, dose-dependent analgesic action and expressed strong anti-inflammatory activity showing a reversed U-shaped, dose-dependent relation with its maximum at 30.0 mg/kg. After its combined administration with morphine (MF, 5.0 mg/kg, s.c.) the lowering of antinociceptive activity was found; however, the interaction with naloxone (NL, 3.0 mg/kg, s.c.) did not affect the antinociceptive effect of OAO-ASA (8), therefore its opioid mechanism of action should be rather excluded. After combined administration with acetylsalicylic acid (ASA, 300.0 mg/kg, p.o.) in hot-plate test, the examined compound 8 enhanced the antinociceptive activity in significant way. It also shows that rather the whole molecule is responsible for the antinociceptive and anti-inflammatory effect of the tested compound 8, however, it cannot be excluded that the summarizing effect is produced by ASA released from the compound 8 and the rest of triterpene derivative. The occurrence of tolerance for triterpenic derivative 8 was not observed, since the analgesic and anti-inflammatory effects after chronic administration of the conjugate OAO-ASA (8) was on the same level as after its single treatment. It seemed that the anti-inflammatory mechanism of action of OAO-ASA (8) is not simple, even its chronic administration lowered both blood concentration of IL-6 and mRNA IL-6 expression. However, the effects of the conjugate OAO-ASA (8) on TNF-α level and mRNA expression were opposite. Moreover, compound 8 did not change unequivocally mRNA TLR1, and TLR3 expression. Concluding, the obtained results regarding the antinociceptive and anti-inflammatory activity of new conjugate of oleanolic acid oxime and acetylsalicylic acid (OAO-ASA 8) are very interesting, but for explanation of its mechanism of action, more detailed studies are necessary.

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          Most cited references 55

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              Oleanolic acid and ursolic acid are triterpenoid compounds that exist widely in food, medicinal herbs and other plants. This review summarizes the pharmacological studies on these two triterpenoids. Both oleanolic acid and ursolic acid are effective in protecting against chemically induced liver injury in laboratory animals. Oleanolic acid has been marketed in China as an oral drug for human liver disorders. The mechanism of hepatoprotection by these two compounds may involve the inhibition of toxicant activation and the enhancement of the body defense systems. Oleanolic acid and ursolic acid have also been long-recognized to have antiinflammatory and antihyperlipidemic properties in laboratory animals, and more research is warranted to develop a therapy for patients. Recently, both compounds have been noted for their antitumor-promotion effects, which are stimulating additional research in this field. Oleanolic acid and ursolic acid are relatively non-toxic, and have been used in cosmetics and health products. The possible mechanisms for the pharmacological effects and the prospects for these two compounds are discussed.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                12 July 2016
                : 7
                1Department of Organic Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences Poznan, Poland
                2Department of Pharmacology, Poznan University of Medical Sciences Poznan, Poland
                3Laboratory of Experimental Pharmacogenetics, Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences Poznan, Poland
                4Department of Pharmacology and Phytochemistry, Institute of Natural Fibres and Medicinal Plants Plewiska, Poland
                Author notes

                Edited by: Rosario Pignatello, University of Catania, Italy

                Reviewed by: Aida Habib, American University of Beirut, Lebanon; Haroon Khan, Abdul Wali Khan University Mardan, Pakistan

                *Correspondence: Barbara Bednarczyk-Cwynar, bcwynar@ 123456ump.edu.pl

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Copyright © 2016 Bednarczyk-Cwynar, Wachowiak, Szulc, Kamińska, Bogacz, Bartkowiak-Wieczorek, Zaprutko and Mikolajczak.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 12, Tables: 1, Equations: 1, References: 62, Pages: 18, Words: 0
                Funded by: Narodowe Centrum Nauki 10.13039/501100004281
                Award ID: UMO-2013/09/B/NZ7/01279
                Original Research


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