Limits...
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 OAO-ASA (8) on anti-inflammatory activity of ASA (200.0 mg/kg, p.o.) in rats. Number of rats = 8 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

License
getmorefigures.php?uid=PMC4940421&req=5

Figure 9: Effect of OAO-ASA (8) on anti-inflammatory activity of ASA (200.0 mg/kg, p.o.) in rats. Number of rats = 8 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.

Mentions: The study was performed using five groups of rats (n = 8 in each group) treated with OAO-ASA (8) in doses of 0.3, 3.0, and 30.0 mg/kg and ASA in a dose of 200.0 mg/kg; referent single dose of ASA in 200.0 mg/kg and control (5% Tween 80). The following experimental system was found to have significant variability in the results of the performance of the combined administration of ASA and OAO-ASA (8) in rats [ANOVA, main effect, F(4,35) = 34.2; p = 0.000]. It also indicated the importance of activity of time after the administration of carrageenan and the compounds [ANOVA, effect of time F(4,140) = 284.3; p = 0.000]. Analysis of the interaction of both factors pointed at the significance of the action of both [ANOVA II interaction F(16,140) = 20.8; p = 0.000]. Post hoc analysis showed that both, the single ASA administration and conjugate 8 with ASA demonstrated the anti-inflammatory effect in a range 1–10 h when compared with the proper control values (p < 0.01; Figure 9). It was also shown that the effects did not differ between the values for combined administration of OAO-ASA (8) in all doses with ASA and the single ASA administration (p > 0.05).


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 OAO-ASA (8) on anti-inflammatory activity of ASA (200.0 mg/kg, p.o.) in rats. Number of rats = 8 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

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

Figure 9: Effect of OAO-ASA (8) on anti-inflammatory activity of ASA (200.0 mg/kg, p.o.) in rats. Number of rats = 8 in each group, data are mean ± SEM, control = rats treated with 5% Tween 80, ∗ = vs. proper Control, p < 0.05.
Mentions: The study was performed using five groups of rats (n = 8 in each group) treated with OAO-ASA (8) in doses of 0.3, 3.0, and 30.0 mg/kg and ASA in a dose of 200.0 mg/kg; referent single dose of ASA in 200.0 mg/kg and control (5% Tween 80). The following experimental system was found to have significant variability in the results of the performance of the combined administration of ASA and OAO-ASA (8) in rats [ANOVA, main effect, F(4,35) = 34.2; p = 0.000]. It also indicated the importance of activity of time after the administration of carrageenan and the compounds [ANOVA, effect of time F(4,140) = 284.3; p = 0.000]. Analysis of the interaction of both factors pointed at the significance of the action of both [ANOVA II interaction F(16,140) = 20.8; p = 0.000]. Post hoc analysis showed that both, the single ASA administration and conjugate 8 with ASA demonstrated the anti-inflammatory effect in a range 1–10 h when compared with the proper control values (p < 0.01; Figure 9). It was also shown that the effects did not differ between the values for combined administration of OAO-ASA (8) in all doses with ASA and the single ASA administration (p > 0.05).

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