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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

Dose-dependent analgesic effect of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
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Figure 2: Dose-dependent analgesic effect of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.

Mentions: The study was performed using five groups of mice (n = 9–10 in each group) treated with OAO-ASA (8) in doses of 0.3, 3.0, 30.0, and 300.0 mg/kg and control (5% Tween 80). Administration of conjugate 8 has shown a statistically significant analgesic activity in the hot-plate test performed on mice [ANOVA main effect F(4,56) = 53.3, p = 0.000] and has indicated a significant effect of time on this type of activity [ANOVA, F(4,224) = 4.46; p = 0.002]. The interaction between group and time effect also has shown high significance [ANOVA II: F(16,224) = 4.96; p = 0.000]. Based on further analysis performed by a post hoc test, it was found that there are significant differences in inhibition of the pain response by OAO-ASA (8) after thermal stimuli (Figure 2). The peak of analgesic effect of compound 8 was observed after administration of the compound at a dose of 300.0 mg/kg after 30 min. It was also found that the analgesic action of conjugate 8 appeared after using the lowest tested dose (0.3 mg/kg) after 2 h (p < 0.05) and this particular effect was maintained up to 24 h. However, OAO-ASA (8) given at a dose of 3.0 mg/kg was active at 0.5 h after starting the test, and the strongest activity was observed after 2 h, but the effect was not statistically significant at 24th hour of the experiment. For the analyzed compound 8 in doses of 30.0 and 300.0 mg/kg, the analgesic effect was visible throughout the course of the study and continued up to 24 h of the experiment compared to the control values (p < 0.01).


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)

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

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

Figure 2: Dose-dependent analgesic effect of OAO-ASA (8) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
Mentions: The study was performed using five groups of mice (n = 9–10 in each group) treated with OAO-ASA (8) in doses of 0.3, 3.0, 30.0, and 300.0 mg/kg and control (5% Tween 80). Administration of conjugate 8 has shown a statistically significant analgesic activity in the hot-plate test performed on mice [ANOVA main effect F(4,56) = 53.3, p = 0.000] and has indicated a significant effect of time on this type of activity [ANOVA, F(4,224) = 4.46; p = 0.002]. The interaction between group and time effect also has shown high significance [ANOVA II: F(16,224) = 4.96; p = 0.000]. Based on further analysis performed by a post hoc test, it was found that there are significant differences in inhibition of the pain response by OAO-ASA (8) after thermal stimuli (Figure 2). The peak of analgesic effect of compound 8 was observed after administration of the compound at a dose of 300.0 mg/kg after 30 min. It was also found that the analgesic action of conjugate 8 appeared after using the lowest tested dose (0.3 mg/kg) after 2 h (p < 0.05) and this particular effect was maintained up to 24 h. However, OAO-ASA (8) given at a dose of 3.0 mg/kg was active at 0.5 h after starting the test, and the strongest activity was observed after 2 h, but the effect was not statistically significant at 24th hour of the experiment. For the analyzed compound 8 in doses of 30.0 and 300.0 mg/kg, the analgesic effect was visible throughout the course of the study and continued up to 24 h of the experiment compared to the control values (p < 0.01).

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