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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 analgesic activity of MF (5.0 mg/kg, s.c.) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, 0.9% NaCl, ∗ = vs. proper Control, p < 0.05, + = vs. MF 5.0 mg/kg, s.c., p < 0.05.
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Figure 5: Effect of OAO-ASA (8) on analgesic activity of MF (5.0 mg/kg, s.c.) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, 0.9% NaCl, ∗ = vs. proper Control, p < 0.05, + = vs. MF 5.0 mg/kg, s.c., p < 0.05.

Mentions: The study was performed using six 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 MF in a dose of 5.0 mg/kg (s.c.); for comparative purposes MF in a dose of 5.0 mg/kg and proper control group were used (5% Tween 80; 0.9% NaCl). Study on the combined administration of the examined compound 8 and MF was able to show the overall variability between means [ANOVA, main effect, F(5,54) = 10.2; p = 0.000], and highlighted the importance of the effect of time on the course of the analgesic effect [ANOVA, effect of time, F(4,216) = 64.6; 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(20,216) = 6.02; p = 0.000]. Post hoc analysis revealed the analgesic effect of MF after 0.5, 1, and 1.5 h of the test when compared with the control group (p < 0.05); whereas after 2 and 24 h showed no significant effects (Figure 5). Co-administration of MF and OAO-ASA (8) in a dose of 0.3 mg/kg has shown a significant analgesic effect that lasted for 2 h from the start of the test, and in 0.5 h of the test significantly increased the analgesic activity of MF. For the compound 8 in the doses of 3.0 and 300.0 mg/kg combined with MF, the analgesic effect was shown in all tested intervals except for 24 h. The least effective was administration of MF with conjugate 8 at a dose of 30.0 mg/kg, where no significant antinociceptive activity was shown in any of the time points tested. Moreover, it has been found that the combination of the OAO-ASA (8) in a dose of 3.0 mg/kg with MF significantly lowered pain response at 0.5 and 1 h when compared with MF. There were no significant differences as compared to combined administration to the mean values of MF at other points of time.


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 analgesic activity of MF (5.0 mg/kg, s.c.) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, 0.9% NaCl, ∗ = vs. proper Control, p < 0.05, + = vs. MF 5.0 mg/kg, s.c., p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Effect of OAO-ASA (8) on analgesic activity of MF (5.0 mg/kg, s.c.) in mice. Number of mice = 9–10 in each group, data are mean ± SEM, control = mice treated with 5% Tween 80, 0.9% NaCl, ∗ = vs. proper Control, p < 0.05, + = vs. MF 5.0 mg/kg, s.c., p < 0.05.
Mentions: The study was performed using six 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 MF in a dose of 5.0 mg/kg (s.c.); for comparative purposes MF in a dose of 5.0 mg/kg and proper control group were used (5% Tween 80; 0.9% NaCl). Study on the combined administration of the examined compound 8 and MF was able to show the overall variability between means [ANOVA, main effect, F(5,54) = 10.2; p = 0.000], and highlighted the importance of the effect of time on the course of the analgesic effect [ANOVA, effect of time, F(4,216) = 64.6; 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(20,216) = 6.02; p = 0.000]. Post hoc analysis revealed the analgesic effect of MF after 0.5, 1, and 1.5 h of the test when compared with the control group (p < 0.05); whereas after 2 and 24 h showed no significant effects (Figure 5). Co-administration of MF and OAO-ASA (8) in a dose of 0.3 mg/kg has shown a significant analgesic effect that lasted for 2 h from the start of the test, and in 0.5 h of the test significantly increased the analgesic activity of MF. For the compound 8 in the doses of 3.0 and 300.0 mg/kg combined with MF, the analgesic effect was shown in all tested intervals except for 24 h. The least effective was administration of MF with conjugate 8 at a dose of 30.0 mg/kg, where no significant antinociceptive activity was shown in any of the time points tested. Moreover, it has been found that the combination of the OAO-ASA (8) in a dose of 3.0 mg/kg with MF significantly lowered pain response at 0.5 and 1 h when compared with MF. There were no significant differences as compared to combined administration to the mean values of MF at other points of time.

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