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

Mentions: The study was performed using two groups of mice (n = 10 in each group) treated with OAO-ASA (8) in a dose of 30.0 mg/kg and analgesic activity was assessed after first and after 28 applications of triterpene 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) = 76.2; p = 0.000] and for time as a factor associated with this activity in the experimental model [ANOVA, effect of time, F(4,144) = 25.0; p = 0.000]. Post hoc analysis showed that both, after single and subchronic administration OAO-ASA (8) produced significant analgesic activity (p < 0.05) in time range of 0.5–2 h when compared with proper control values (Figure 10). However, due to the fact that obtained values did not differ between each other for the time, therefore an occurrence of tolerance for analgesic activity might 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 analgesic activity of OAO-ASA (8) after single and subchronic administration in mice. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of mice = 10 in each group, data are mean ± SEM, control – mice treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05, + = vs. proper OAO-ASA (8) single, p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 10: Comparison of analgesic activity of OAO-ASA (8) after single and subchronic administration in mice. OAO-ASA (8) treatment with a dose of 30 mg/kg, p.o. Number of mice = 10 in each group, data are mean ± SEM, control – mice treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05, + = vs. proper OAO-ASA (8) single, p < 0.05.
Mentions: The study was performed using two groups of mice (n = 10 in each group) treated with OAO-ASA (8) in a dose of 30.0 mg/kg and analgesic activity was assessed after first and after 28 applications of triterpene 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) = 76.2; p = 0.000] and for time as a factor associated with this activity in the experimental model [ANOVA, effect of time, F(4,144) = 25.0; p = 0.000]. Post hoc analysis showed that both, after single and subchronic administration OAO-ASA (8) produced significant analgesic activity (p < 0.05) in time range of 0.5–2 h when compared with proper control values (Figure 10). However, due to the fact that obtained values did not differ between each other for the time, therefore an occurrence of tolerance for analgesic activity might 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