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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 OAO-ASA (8) on antinociceptive activity of ASA (300.0 mg/kg p.o.) 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, + = vs. ASA 300 mg/kg, p.o., p < 0.05.
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Figure 4: Effect of OAO-ASA (8) on antinociceptive activity of ASA (300.0 mg/kg p.o.) 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, + = vs. ASA 300 mg/kg, p.o., p < 0.05.

Mentions: The study was performed using 6 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 (p.o.) and ASA in the dose of 300.0 mg/kg, p.o.; for control purposes the effect of ASA only in the dose of 300.0 mg/kg was also measured in comparison to control rats (5% Tween 80). When analyzing the effect of the co-administration of OAO-ASA (8) and ASA for antinociceptive activity in the hot-plate assay, the existence of a general statistical variation in experimental system has been confirmed [ANOVA, effect of group, F(5,53) = 35.7; p = 0.000], as well as the significant effect of time on the antinociceptive activity [ANOVA: F(4,212) = 51.5; p = 0.000]. The interaction of these two effects (i.e., the effect of group and time) showed the existence of significant differences between these two parameters [ANOVA: interaction F(20,212) = 3.827; p = 0.000]. Post hoc analysis has shown the presence of the antinociceptive effect of ASA given at a dose of 300.0 mg/kg in the range of 0.5–2 h from the start of the study (p < 0.05), but after 24 h, there was no significant difference in comparison to the control value (Figure 4). For the combined administration of the examined substance OAO-ASA (8) and ASA over the range of doses used, the significant differences between obtained values and control at the time 0.5, 1, 1.5, and 2 h were noted. After 24 h, the effect after co-administration of ASA and the compound 8 at doses of 0.3–30.0 mg/kg was not significantly different from that of the control group administered with vehicle alone, only in the highest dose of the OAO-ASA (8) co-administered with ASA has differed significantly from control values (p < 0.05). It has been noted that conjugate 8 in a dose of 300.0 mg/kg significantly increased the strength and prolonged the duration of antinociceptive action of ASA in each of the time points tested; while at a dose of 3.0 mg/kg the increased potency of ASA after combined administration was seen only in 0.5, 1, and 1.5 h of the experiment.


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 antinociceptive activity of ASA (300.0 mg/kg p.o.) 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, + = vs. ASA 300 mg/kg, p.o., p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Effect of OAO-ASA (8) on antinociceptive activity of ASA (300.0 mg/kg p.o.) 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, + = vs. ASA 300 mg/kg, p.o., p < 0.05.
Mentions: The study was performed using 6 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 (p.o.) and ASA in the dose of 300.0 mg/kg, p.o.; for control purposes the effect of ASA only in the dose of 300.0 mg/kg was also measured in comparison to control rats (5% Tween 80). When analyzing the effect of the co-administration of OAO-ASA (8) and ASA for antinociceptive activity in the hot-plate assay, the existence of a general statistical variation in experimental system has been confirmed [ANOVA, effect of group, F(5,53) = 35.7; p = 0.000], as well as the significant effect of time on the antinociceptive activity [ANOVA: F(4,212) = 51.5; p = 0.000]. The interaction of these two effects (i.e., the effect of group and time) showed the existence of significant differences between these two parameters [ANOVA: interaction F(20,212) = 3.827; p = 0.000]. Post hoc analysis has shown the presence of the antinociceptive effect of ASA given at a dose of 300.0 mg/kg in the range of 0.5–2 h from the start of the study (p < 0.05), but after 24 h, there was no significant difference in comparison to the control value (Figure 4). For the combined administration of the examined substance OAO-ASA (8) and ASA over the range of doses used, the significant differences between obtained values and control at the time 0.5, 1, 1.5, and 2 h were noted. After 24 h, the effect after co-administration of ASA and the compound 8 at doses of 0.3–30.0 mg/kg was not significantly different from that of the control group administered with vehicle alone, only in the highest dose of the OAO-ASA (8) co-administered with ASA has differed significantly from control values (p < 0.05). It has been noted that conjugate 8 in a dose of 300.0 mg/kg significantly increased the strength and prolonged the duration of antinociceptive action of ASA in each of the time points tested; while at a dose of 3.0 mg/kg the increased potency of ASA after combined administration was seen only in 0.5, 1, and 1.5 h of the experiment.

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