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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

Comparison of anti-inflammatory activity of OAO-ASA (8) after single and subchronic administration in rats. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of rats = 10 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
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Figure 11: Comparison of anti-inflammatory activity of OAO-ASA (8) after single and subchronic administration in rats. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of rats = 10 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.

Mentions: The study for the assessment of the effect of subchronic treatment on anti-inflammatory activity of OAO-ASA (8) was performed using two groups of rats (n = 10 in each group) treated with the triterpenic conjugate 8 in a dose of 30.0 mg/kg and the activity was measured after first and after 28 applications of OAO-ASA (8). Analysis of variance used during the experiment has indicated a statistically significant analgesic effect either for a group [ANOVA, main effect, F(3,36) = 23.3; p = 0.000] and for time as a factor associated with this activity in the experimental model [ANOVA, effect of time, F(4,144) = 168.1; p = 0.000]. Post hoc analysis showed that both the single and subchronic conjugate 8 administration significantly reduced the carrageenan-induced edema in the range of 1–10 h of observation (p < 0.05) when compared with the proper control values (Figure 11). Similarly, as for the analgesic activity of OAO-ASA (8) there were no differences between the values for single and subchronic treatments in the time points (1–10 h), therefore effect of tolerance for the anti-inflammatory activity should be excluded.


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)

Comparison of anti-inflammatory activity of OAO-ASA (8) after single and subchronic administration in rats. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of rats = 10 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 11: Comparison of anti-inflammatory activity of OAO-ASA (8) after single and subchronic administration in rats. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of rats = 10 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
Mentions: The study for the assessment of the effect of subchronic treatment on anti-inflammatory activity of OAO-ASA (8) was performed using two groups of rats (n = 10 in each group) treated with the triterpenic conjugate 8 in a dose of 30.0 mg/kg and the activity was measured after first and after 28 applications of OAO-ASA (8). Analysis of variance used during the experiment has indicated a statistically significant analgesic effect either for a group [ANOVA, main effect, F(3,36) = 23.3; p = 0.000] and for time as a factor associated with this activity in the experimental model [ANOVA, effect of time, F(4,144) = 168.1; p = 0.000]. Post hoc analysis showed that both the single and subchronic conjugate 8 administration significantly reduced the carrageenan-induced edema in the range of 1–10 h of observation (p < 0.05) when compared with the proper control values (Figure 11). Similarly, as for the analgesic activity of OAO-ASA (8) there were no differences between the values for single and subchronic treatments in the time points (1–10 h), therefore effect of tolerance for the anti-inflammatory activity should be excluded.

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