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Phytomedicine 11: 315322, 2004


Analgesic and anti-inflammatory activities

of a fraction rich in oncocalyxone A isolated
from Auxemma oncocalyx
M. A. D. Ferreira1, Osmar D. R. H. Nunes1, Juvenia B. Fontenele3, Otlia D. L. Pessoa2,
Telma L. G. Lemos2 and Glauce S. B. Viana3
Departamento de Farmcia
Departamento de Qumica Orgnica e Inorgnica
Departamento de Fisiologia e Farmacologia Universidade Federal do Cear, Fortaleza Ce Brasil

In the present work we studied the antinociceptive and antiedematogenic effects of a quinone frac-
tion (QF) isolated from the heartwood of Auxemma oncocalyx Taub. The major constituent of QF,
which represented around 80% of this fraction, was a terpenoid quinone named oncocalyxone A
(1). Results show that QF (10 and 30 mg/kg body wt., i.p.) significantly inhibited paw edema in-
duced by carrageenan at the second, third, and fourth hours. The effect was dose-dependent and
long lasting, and QF was less effective orally. An antiedematogenic effect was also demonstrated in
the dextran-induced paw edema. In this model, however, QF was somewhat less potent. QF (1 and
5 mg/kg body wt., i.p.) inhibited acetic acid-induced abdominal contractions in mice in a dose-de-
pendent manner. In addition, QF (5 and 10 mg/kg body wt., i.p.) inhibited only the second phase
(inflammatory) in the formalin test, and showed no effect in the hot-plate test in mice. The
antinociceptive activity of QF was predominantly peripheral and independent of the opioid sys-
tem. The observed effects of QF are, at least in part, probably due to the presence of oncocalyxone
A (1).

Key words: Analgesic and antiinflammatory activities, oncocalyxone A, Auxemma oncocalyx, quinones

Auxemma oncocalyx Taub. belongs to the Boragi- quinones, among them oncocalyxone A, 1 (Pessoa
naceae family and is native to the northeastern Brazil- et al. 1993; Pessoa et al. 1995).
ian caatinga, where it is known as pau branco. The Previous pharmacological studies showed that the
stem bark of the tree is astringent and used popularly in stem hydroalcoholic extract possesses anti-platelet ac-
the treatment of wounds (Braga, 1976; Pessoa, 1994). tivity (Fontenele and Sousa, 1992) and this effect was
Alantoin isolated from the stem hydroalcoholic extract confirmed recently in a hydrosoluble fraction, obtained
(Pessoa and Lemos, 1997) explains partially the bene- from the heartwood methanolic extract, which also pre-
ficial use of the plant in wound healing. Several other sented antioxidant activity (Ferreira et al. 1999; Fer-
compounds were also isolated from the hydroalcoholic reira et al. 2001). Other effects were also attributed to
extract, including -sitosterol, its glycoside (3-O-D- the hydroalcoholic extract, such as antitumoral (Pessoa
glucopyranosylsitosterol) and seven terpenoidic et al. 1992), analgesic and anti-inflammatory (Lino

0944-7113/04/11/04-315 $ 30.00/0
316 M. A. D. Ferreira et al.
et al. 1996) activities. Recently, in vitro studies demon- Test animals
strated the antitumoral activity not only of oncocalyx- Male Wistar rats (150200 g each) and male Swiss mice
one A (1), but also of oncocalyxone C, isolated from A. (2530 g each) were obtained from the Animal House
oncocalyx (Pessoa et al. 2000; Leyva et al. 2000). of the Federal University of Cear. Animals were main-
Quinones show several types of biological activity, tained in an air-conditioned room at 2325 C, 12 h
including, platelet antiaggregant (Teng et al. 1993; light-12 h dark cycle, and fed with a standard laboratory
Chung et al. 1994), antioxidant (Belisario et al. 1992; diet and tap water ad libitum. Experiments were per-
Houghton et al. 1995; Tripathi et al. 1995; Mori et al. formed according to the Guide for use and care of labo-
1998), anti-inflammatory (Kuo et al. 1995; Vazquez et ratory animals of the Department of Health and Human
al. 1996; Odukoya et al. 1999), analgesic (Hernndez- Services of the United States of America.
Perez et al. 1995; Abdel-Fattah et al. 2000), antitumoral
(Morello et al. 1995; Itoigawa et al. 2000), antifungal Drugs
(Perry et al. 1991; Gafner et al. 1996), antimalarial Carrageenan, dextran and naloxone were purchased
(Figueiredo et al. 1998), and leishmanicidal (Sauvain et from Sigma, U.S.A. Morphine sulfate was obtained
al. 1993; Sittie et al. 1999). The objectives of the present from Cristlia, Brazil. All other drugs were of analyti-
work were to study the analgesic and anti-inflammatory cal grade.
effects of the quinone-enriched fraction from A. oncoca-
lyx and to elucidate its possible mechanism of action. Pharmacological tests
Carrageenan-induced paw edema (Winter et al. 1962):
Male Wistar rats (150200 g each) divided into groups
 Materials and Methods of 6 animals each were used. QF was administered at
doses of 1, 10 and 30 mg/kg body wt., i.p., 30 min be-
Plant material and fractionation fore the intraplantar injection of a 1% carrageenan so-
The plant was collected at the city of Pentecoste, state lution (0.1 ml in the right hind paw). Paw volume was
of Cear, in northeastern Brazil, and identified by Prof. measured using a plethysmometer (Ugo Basile, Italy),
A. G. Fernandes of the Biology Department of the Fed- before and at 1; 2; 3; 4 and 24 h after carrageenan ad-
eral University of Cear. A voucher specimen (No. ministration. The difference between the paw volume
18459) has been deposited at the Prisco Bezerra before and after carrageenan administration was con-
Herbarium. The quinone fraction (QF) was prepared sidered as an index of edema formation at each obser-
from the ground heartwood methanolic extract through vation time. Controls received saline (10 ml/kg body
exhaustive aqueous extraction followed by lyophiliza- wt., i.p.). QF (100 and 200 mg/kg body wt.) was also
tion. The hydrosoluble fraction contained around 80% administered orally, 60 min before injection of car-
of oncocalyxone A (1) (Fig. 1), which was previously rageenan, and in this case controls received a 2%
characterized by spectroscopy analysis as MS, IR and DMSO solution in saline (used as vehicle for QF) and
NMR including 2D sequences such as COSY, HET- animals were fasted for approximately 12 h.
COR and COLOC (Pessoa et al. 1993). The concentra- Dextran-induced paw edema (Parrat and West,
tion of (1) in the hydrosoluble fraction was calculated 1958): Male Wistar rats (150200 g each) divided into
on the basis of the HPLC-fingerprint analysis using 6 animals per group were used. QF was administered at
YMC-Pack C-18 column, acetonitrile :H2O (1:1, v/v) doses of 1, 10 and 30 mg/kg body wt., i.p., 30 min be-
as mobile phase with an isocratic elution program at fore the intraplantar injection of 0.1 ml of 1.5% dextran
room temperature and detection at 280 nm. solution in the right hind paw. The paw volume was
measured using a plethysmometer before and 1/2; 1; 2; 3
and 4 h after dextran injection. The difference between
the paw volume before and after dextran injection is
considered as an index of edema at each observation
time. Controls received saline (10 ml/kg body wt., i.p.).
Acetic acid-induced abdominal contractions (Koster
et al. 1959): Male Swiss mice (2030 g each), divided
into groups of 10 animals each were used. The quinone
fraction (QF) was administered once at doses of 0.1,
1 and 5 mg/kg body wt., i.p., 30 min before the 0.6%
acetic acid injection (10 ml/kg body wt., i.p.). Ten min-
utes later, the number of abdominal contractions was
Fig. 1. Chemical structure of Oncocalyxone A (Pessoa et al, registered for 20 min. The control group received
1993). saline, used as vehicle for QF.
Analgesic and anti-inflammatory activities 317
Formalin test (Hunskaar et al. 1985; Tjolsen et al. group received saline (10 ml/kg body wt., i.p.). Mor-
1992): Male Swiss mice (2030 g each) divided into phine (5 mg/kg body wt., i.p.) was used as a standard.
groups of 6 animals each were used. QF was adminis-
tered once at doses of 1, 5, 10 and 30 mg/kg body wt., Statistical analysis
i.p., 30 min before the intraplantar injection of 20 l of Data were analyzed by one-way Analysis of Variance
1% formalin in the right hind paw. The licking time (in (ANOVA) followed by the Tukey-Kramer test for mul-
seconds) was registered at 5 min (first phase, neuro- tiple comparisons.
genic), and after 20 min for 5 min (second phase, in-
flammatory), after formalin injection. The control
group received saline, 10 ml/kg body wt., i.p. Mor-
phine was used as a standard (5 mg/kg body wt., i.p.).
In order to verify the possible involvement of the opi-
oid system in the analgesic effect of QF, the formalin The quinone fraction was very active in reducing the rat
test was performed also in the presence of the opioid paw edema after carrageenan administration (Table 1).
antagonist, naloxone (2 mg/kg body wt., subcutaneous- The results show inhibitions of approximately 46, 57
ly). QF (30 mg/kg body wt., i.p.) and morphine were and 48%, at the second, third and fourth hours, respec-
administered 15 min after and 30 min before naloxone tively, after the dose of 10 mg/kg body wt., i.p. and of
and formalin injections, respectively. 50, 60 and 51% at the same intervals following the
Hot-plate test (Eddy and Leimback, 1953): Male dose of 30 mg/kg body wt., i.p. The effect was long-
Swiss mice (2030 g each) divided into groups of 10 lasting and reductions of 38% in the edema could still
animals each were used. Animals were selected previ- be seen after a 24-h period (with the highest dose).
ously from those presenting a latency to the thermal Although less potent, QF was also effective after oral
stimulus equal to or less than 20 sec; and the cut off administration (100 and 200 mg/kg body wt.); howev-
point was set at 40 sec. QF was administered once at er, under these conditions, decreases of edema ranging
doses of 5, 10 and 30 mg/kg body wt., i.p. Latency to from 25 to 29% were observed at the third, fourth and
the thermal stimulus was registered before and at 30, twenty-fourth hours after carrageenan administration,
60 and 90 min after QF administration. The control as compared to controls.

Table 1. Effect of the quinone fraction (QF) of Auxemma oncocalyx Taub. on carrageenan-induced paw edema in rats.

Group (n) Edema volume in ml (% Inhibition)

1h 2h 3h 4h 24 h

Control, i.p. (6) 0.61 0.03 1.03 0.10 1.62 0.10 1.41 0.13 0.29 0.04
1 mg/kg body wt., i.p. (6) 0.59 0.06 0.98 0.09 1.35 0.17 1.28 0.11 0.27 0.03
(3.3) (4.9) (16.7) (9.2) (6.9)
10 mg/kg body wt., i.p. (6) 0.45 0.05 0.56 0.05* 0.69 0.06* 0.74 0.06* 0.20 0.02
(26.2) (45.6) (57.4) (47.5) (31.0)
30 mg/kg body wt., i.p. (6) 0.44 0.04 0.52 0.05* 0.65 0.05* 0.69 0.05* 0.18 0.02
(27.9) (49.5) (59.9) (51.0) (37.9)

Control, p.o. (6) 0.94 0.06 1.54 0.13 2.06 0.10 2.09 0.11 0.24 0.04
100 mg/kg body wt., p.o. (6) 0.79 0.14 1.57 0.08 1.70 0.13 1.93 0.09 0.19 0.02
(15.9) () (17.5) (7.7) (20.8)
200 mg/kg body wt., p.o. (6) 0.73 0.06 1.47 0.18 1.54 0.16* 1.58 0.12* 0.17 0.02
(22.3) (4.6) (25.2) (24.4) (29.2)

Male Wistar rats (150200 g each) were used. Control animals received saline (10 ml/kg body wt.) and treated groups received
QF intraperitoneally or orally, 30 or 60 min, respectively, before the intraplantar administration of 1% carrageenan solution
(0.1 ml, right hind paw). Edema volume (expressed in ml) was estimated at 1, 2, 3, 4 and 24 h after carrageenan administration.
Values are expressed as means S.E.M. of the number of animals. *p < 0.05 vs. control (One-way ANOVA and Tukey-Kramer
as post-hoc test).
318 M. A. D. Ferreira et al.
Table 2. Effect of the quinone fraction (QF) of Auxemma oncocalyx Taub. on dextran-induced paw edema in rats.

Group (n) Edema volume in ml (% Inhibition)

/2 h 1h 2h 3h 4h

Control, i.p. (6) 2.4 0.13 3.0 0.13 3.1 0.11 3.1 0.08 2.4 0.15
QF 1 mg/kg body wt., i.p. (6) 2.8 0.21 3.1 0.18 3.0 0.12 2.7 0.14 2.7 0.12
QF 10 mg/kg body wt., i.p. 2.2 0.11 2.4 0.08 2.0 0.24* 1.8 0.24* 1.6 0.25
(8.3) (20.0) (35.5) (41.9) (33.3)
QF 30 mg/kg body wt., i.p. (6) 2.0 0.30 2.2 0.27* 1.7 0.23* 1.6 0.28* 1.4 0.24*
(16.7) (26.7) (45.2) (48.4) (41.7)

Male Wistar rats (150200 g each) were used. Control animals received saline (10 ml/kg body wt.) and treated groups received
QF 30 min before the intraplantar injection of 0.1 ml, 1.5% dextran solution in the right hind paw. Edema volume (in ml) was
estimated at 1/2, 1, 2, 3 and 4 h after dextran administration. Values are expressed as means S.E.M. of the number of animals.
*p < 0.05 vs. control (One-way ANOVA and Tukey-Kramer as post-hoc test).

Table 3. Antinociceptive effect of the quinone fraction (QF) Table 4 shows the effects of QF on formalin-induced
of Auxemma oncocalyx Taub. on acetic acid-induced abdomi- nociception in mice. QF at doses of 5, 10 and 30 mg/kg
nal contractions in mice. body wt., i.p., significantly inhibited licking time in the
second phase of the response by 27, 52 and 62%, re-
Group (n) Number of % Inhi- spectively, as compared to controls. No effect was ob-
contractions bition
served in the first phase of the response. On the other
Control, i.p. (16) 24.5 1.80 hand, morphine inhibited licking time in the first and
QF 0.1 mg/kg body wt., i.p. (10) 23.6 1.09 second phases of the response by 55 and 85%, respec-
QF 1 mg/kg body wt., i.p. (10) 18.2 1.42* 26 tively. Although the effects of morphine were totally
QF 5 mg/kg body wt., i.p. (10) 9.7 0.92* 60 reversed, no change was seen in the effect of QF in the
presence of naloxone, as compared to the effect of QF
Male Swiss mice (2030 g each) were used. Control animals alone.
received saline (10 ml/kg body wt.) and treated groups re- QF at doses of 5, 10 and 30 mg/kg body wt., i.p. did
ceived QF 30 min before an 0.6% acetic acid injection not, however, alter latency of reaction to the thermal
(10 ml/kg body wt., i.p.). Ten minutes later, the number of ab- stimulus, as demonstrated by the hot-plate test. Mor-
dominal contractions was registered over 20 min. Values are phine, used as positive control, produced increases on
expressed as means S.E.M. of the number of animals used
in the test (in parentheses). *p < 0.05 vs. control (One-way
the order of 84, 57 and 65% after 30, 60 and 90 min, re-
ANOVA and Tukey-Kramer as post-hoc test). Percentages of spectively, as compared to control (Table 5).
inhibition of contraction number relative to control are also
Data in Table 2 show the effect of QF (1, 10 and The present work showed that QF, administered in-
30 mg/kg body wt., i.p.) on dextran-induced paw traperitoneally or orally, inhibited carrageenan-induced
edema in rats. Significant reductions of paw edema rat paw edema in a dose-dependent manner. The maxi-
were observed at the dose of 30 mg/kg body wt., i.p., at mum effect was observed even at the dose of 10 mg/kg
the first (27%), second (45%), third (48%) and fourth body wt., i.p. The inhibition was long-lasting, still ob-
(42%) hours. QF was active at the dose of 10 mg/kg servable 24 h after carrageenan administration. The in-
body wt., i.p., only at the second (36%), third (42%) hibition was significant at the second, third and fourth
and fourth (33%) hours. hours, when bradykinin is being released and there oc-
Table 3 shows the effects of QF on acetic acid-induced curs an accumulation of prostaglandins and infiltration
abdominal contractions in mice. QF (1 and 5 mg/kg body of polymorphonuclear cells. At this stage, there is also
wt., i.p.) inhibited abdominal contractions by 26 and production of free radicals, among other mediators.
60%, respectively, as compared to controls (24.5 1.8 The antiedematogenic effect of QF was greater after in-
contractions/20 min). No effect was observed, however, traperitoneal administration, indicating that oral ab-
at the lower dose of QF (0.1 mg/kg body wt., i.p.). sorption is less efficient. This effect was also seen in
Analgesic and anti-inflammatory activities 319
Table 4. Evaluation of the opioid systems involvement in the effect of the quinone fraction (QF) of Auxemma oncocalyx
Taub. on formalin-induced nociception in mice.

Group Licking time (sec) % Inhibition

first phase second phase first phase second phase

Control, i.p. (21) 56.6 2.57 26.4 1.86

QF 1 mg/kg body wt. (11) 55.1 3.06 25.3 1.26
QF 5 mg/kg body wt. (12) 53.5 3.14 19.3 1.68* 27
QF 10 mg/kg body wt. (10) 58.5 2.73 12.8 1.22* 52
Control, i.p. (12) 50.9 2.63 28.2 2.77
QF 30 mg/kg body wt. (11) 48.4 3.24 10.7 1.35* 62
Mor (12) 22.9 1.75* 4.2 0.89* 55 85
Nal + QF (10) 47.4 3.34 9.1 1.57* 68
Nal + Mor (12) 50.6 4.41 25.6 2.69

Male Swiss mice (2030 g each) were used. Control group received saline (10 ml/kg body wt.) and treated groups received QF
or morphine (5 mg/kg body wt.) intraperitoneally, 30 min before the intraplantar injection of 20 l of 1% formalin in the right
hind paw. The licking time (in seconds) was registered at the first 5 min (first phase) and after 20 min over 5 min (second
phase) after the formalin injection. In the test using Naloxone (Nal) and the quinone fraction, QF was administered 15 min
after naloxone (2 mg/kg body wt., subcutaneously) and 30 min before formalin injection. Morphine was also administered 15
min after Naloxone (Nal) and 30 min before formalin injection. Values are expressed as means S.E.M. of the number of ani-
mals in parentheses. *p < 0.05 vs. control (One-way ANOVA and Tukey-Kramer as post-hoc test). Percentages of inhibition of
licking time relative to control are also presented.

Table 5. Effect of the quinone fraction (QF) of Auxemma oncocalyx Taub. on the hot-plate test in mice.

Group Latency time (sec)

0 min 30 min 60 min 90 min

Control, i.p. (16) 15.8 1.13 15.2 0.96 13.5 0.87 12.6 1.10
QF 5 mg/kg body wt., i.p. (10) 13.6 1.38 14.2 1.06 10.9 0.57 13.3 1.28
QF 10 mg/kg body wt., i.p.(10) 12.5 1.34 13.7 1.74 11.2 1.37 11.8 1.16
QF 30 mg/kg body wt., i.p. (10) 16.0 1.51 16.2 1.04 15.8 0.87 12.6 1.29
Morphine 5 mg/kg body wt., i.p. (10) 15.3 1.54 28.0 3.04* 23.7 2.09* 19.3 1.68*

Male Swiss mice (2030 g each) were used. Control animals received saline (10 ml/kg body wt.) and treated groups received
QF or morphine. The latency to the thermal stimulus was registered (in seconds) before (0 min) and at 30, 60 and 90 min after
QF administration. Values are expressed as means S.E.M. of the number of animals in parentheses. *p < 0.01 vs. control
(One-way ANOVA and Tukey-Kramer as post-hoc test).

the dextran-induced paw edema test, where QF inhibit- tryptamine (5-HT) occurs; and the second step (from
ed the edema dose-dependently after intraperitoneal 90 to 150 min) is mediated by kinins, while in the third
administrations of 10 and 30 mg/kg body wt. step (from 150 min on), prostaglandin release takes
Earlier research showed that in carrageenan-induced place. All these mediators are dependent upon the com-
edema, several mediators (histamine, 5-hydroxytrypt- plement system. Histamine and 5-HT are responsible
amine, kinins, prostaglandins) of the inflammatory for vasodilation and increase in vascular permeability
process are involved, including the complement sys- in the initial phase of the inflammatory process.
tem (Willis, 1969; Willoughby et al. 1969). Di Rosa Bradykinin has been implicated in acute inflammatory
et al. (1971) showed that this system participates in the processes due to its ability to induce an increase in
process from the very beginning, and that carrageenan- blood vessel permeability. Its involvement in car-
induced inflammation is divided into 3 steps according rageenan-induced edema was demonstrated by Ronald
to the mediators released. In the initial step (first and Christopher (1990) and by Damas and Remacle-
90 min), the release of both histamine and 5-hydroxy- Volon (1992). Another characteristic of carrageenan-
320 M. A. D. Ferreira et al.
induced edema is the massive infiltration of polymor- tion and lasts 3 to 5 min, resulting from chemical stim-
phonuclear leucocytes observed in the third step (Di ulation of nociceptors. The second phase initiates 15 to
Rosa and Willoughby, 1971; Ialenti et al. 1992; Masso 20 min after formalin injection, lasts 20 to 40 min and
et al. 1993). By contrast, dextran-induced edema in- seems to depend on a peripheral mechanism as well as
volves mast cell degranulation, resulting in histamine a central one. While substance P and bradykinin are in-
as well as 5-HT release. volved in the first phase, histamine, 5-HT,
Histamine, 5-HT and bradykinin are able to induce prostaglandins and bradykinin are involved in the sec-
nitric oxide (NO) release from vascular endothelial ond phase. The effect of QF was significant only in the
cells in vitro via a mechanism involving receptor occu- second phase, indicating an action related to the in-
pation and stimulation of NO synthase. In addition, flammatory process. This QF effect was not reversed
macrophages produce NO when activated by by naloxone, pointing to the non-involvement of the
lipopolysaccharide or cytokines. Thus Salvemini et al. opioid system. Finally, QF showed no effect in the hot-
(1996) pointed to NO as an important mediator of car- plate test, which involves higher brain functions and
rageenan-induced edema and suggested that constitu- consists of responses to nociceptive stimuli organized
tive NO synthase (cNOS) acts at the initial steps, while at a supraspinal level (Gardmark et al. 1998). Analgesic
inducible NO synthase (iNOS) is involved in the last drugs such as aspirin and paracetamol do not have any
step of the inflammatory reaction. effect in this test (Tjolsen et al. 1992), while it is large-
The acute or chronic inflammatory process is a ly used to measure opioid effects (Gong et al. 1991;
model of nociception (Besson, 1997) and several Plone et al. 1996).
works have shown that inflammatory mediators can
generate nociceptive impulses (Steen et al. 1996; Acknowledgements
Besson, 1997). Thus, bradykinin and 5-HT are able to The authors wish to thank the Brazilian National Research
stimulate cutaneous nociceptors and 5-HT can also in- Council (CNPq) for supporting this work and Maria V. R.
crease nociceptive response to bradykinin (Lang et al. Bastos for technical assistance.
1990; Rueff and Dray, 1993). Although prostaglandins
are not able to activate these nociceptors, they promote
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