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

Abstract

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.

The Novel Synthetic Triterpene Methyl 3β-<i>O</i>-[4-(2-Aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate Inhibits Breast Tumor Cell Growth <i>in</i> <i>Vitro</i> and <i>in</i> <i>Vivo</i>

“…Naturally occurring pentacyclic triterpenoids, which are widely distributed in plants, fungi, marine invertebrates, and other organisms, show a wide range of biological activities, including antiviral, 7) antitumor, 8,9) anti-inflammatory, 10,11) antiparasitic, 12) and wound healing properties. 13) OA and UA are pentacyclic triterpenoids that can inhibit tumor initiation and growth, and induce apoptosis in various cancer cells. 2,14) The low water solubility of OA and UA results in low bioavailability.…”

Anti-COVID Drugs: Repurposing Existing Drugs Or Search for New Complex entities, Strategies and Perspectives

“…It is on the basis of triterpene compounds that we have proposed the theory of ‘molecular consortia’ [ 45 ], which are combinations of various active elements designed to act jointly to achieve an effect anticipated for such a new entity either within a single cell or a cell assembly. The first compound of this type which we described was a combination of oleanolic acid and aspirin [ 46 ] displaying a far more potent anti-inflammatory effect than the individual constituents. At the same time, it was found that the newly formed compound had a completely different mechanism of anti-inflammatory action than each of its components.…”

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

“…In the test exploring the anti-inflammatory effect, carrageenan was used for inducing inflammation, and each rat received 2000 µg of carrageenan as a 0.2 mL solution at a concentration of 1%. This dose was determined based on our previous studies [14,43]. Anti-inflammatory effects were not found after administration of OXY alone or after majority of OXY's combinations with adjuvants.…”

“…Skin inflammation was induced in the right hind paws by topical application of 2 mg/paw of carrageenan dissolved in 0.2 mL of 0.9% saline solution [14]. The rear left paw acted as the control and received the same volume of 0.9% saline solution.…”