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

Bednarczyk-Cwynar B, Wachowiak N, Szulc M, Kamińska E, Bogacz A, Bartkowiak-Wieczorek J, Zaprutko L, Mikolajczak PL - Front Pharmacol (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences Poznan, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of complimentary dose of ASA on analgesic action of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, control = mice treated with 5% Tween 80, data are mean ± SEM, ∗ = vs. proper Control, p < 0.05.
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Figure 3: Effect of complimentary dose of ASA on analgesic action of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, control = mice treated with 5% Tween 80, data are mean ± SEM, ∗ = vs. proper Control, p < 0.05.

Mentions: The study was performed using four groups of mice (n = 9–10 in each group) treated intragastrically with ASA (0.77, 7.7, and 77.0 mg/kg) in complimentary doses to OAO-ASA (8) of 3.0, 30.0, and 300.0 mg/kg (p.o.); referent dose of ASA in 300.0 mg/kg and control (5% Tween 80). Total variability in the tested doses for the analgesic effect of complimentary doses of ASA has been noted [ANOVA: F(3,35) = 9.04; p = 0.000], but has not detected a statistically significant effect of time on the antinociceptive effect in the analyzed experimental system [ANOVA: F(4,140) = 0.812; p = 0.519]. Analyzing the impact of group and time effects, the occurrence of variation between the values were obtained [ANOVA II: Interaction F(12,140) = 2.95; p = 0.001]. Further analysis of ASA complementary doses to conjugate 8 for an analgesic effect in the mice hot-plate assay has indicated that only administration of ASA at the dose of 300.0 mg/kg has shown significant analgesic activity in comparison to the control group (Figure 3). The effect of ASA at this dose was visible from 0.5 to 2 h after the application, but no analgesic effect was observed after 24 h. Also, no significant differences for the ASA stated in all complementary doses of ASA for the content of the analyzed compound 8 relative to control values were observed.


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

Bednarczyk-Cwynar B, Wachowiak N, Szulc M, Kamińska E, Bogacz A, Bartkowiak-Wieczorek J, Zaprutko L, Mikolajczak PL - Front Pharmacol (2016)

Effect of complimentary dose of ASA on analgesic action of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, control = mice treated with 5% Tween 80, data are mean ± SEM, ∗ = vs. proper Control, p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940421&req=5

Figure 3: Effect of complimentary dose of ASA on analgesic action of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, control = mice treated with 5% Tween 80, data are mean ± SEM, ∗ = vs. proper Control, p < 0.05.
Mentions: The study was performed using four groups of mice (n = 9–10 in each group) treated intragastrically with ASA (0.77, 7.7, and 77.0 mg/kg) in complimentary doses to OAO-ASA (8) of 3.0, 30.0, and 300.0 mg/kg (p.o.); referent dose of ASA in 300.0 mg/kg and control (5% Tween 80). Total variability in the tested doses for the analgesic effect of complimentary doses of ASA has been noted [ANOVA: F(3,35) = 9.04; p = 0.000], but has not detected a statistically significant effect of time on the antinociceptive effect in the analyzed experimental system [ANOVA: F(4,140) = 0.812; p = 0.519]. Analyzing the impact of group and time effects, the occurrence of variation between the values were obtained [ANOVA II: Interaction F(12,140) = 2.95; p = 0.001]. Further analysis of ASA complementary doses to conjugate 8 for an analgesic effect in the mice hot-plate assay has indicated that only administration of ASA at the dose of 300.0 mg/kg has shown significant analgesic activity in comparison to the control group (Figure 3). The effect of ASA at this dose was visible from 0.5 to 2 h after the application, but no analgesic effect was observed after 24 h. Also, no significant differences for the ASA stated in all complementary doses of ASA for the content of the analyzed compound 8 relative to control values were observed.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences Poznan, Poland.

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.

No MeSH data available.


Related in: MedlinePlus