Pain Mechanisms

Section Editor: Tony L. Yaksh/Quinn H. Hogan

Antiinflammatory and Antihyperalgesic Activity

of C-Phycocyanin
Chao-Ming Shih, MD* BACKGROUND: C-phycocyanin (C-PC), a biliprotein found in blue green algae, such
as Spirulina platensis, is often used as a dietary nutritional supplement due to its
Shin-Nan Cheng, MD, PhD† various therapeutic values. In addition, the antiinflammatory activity of C-PC
partly through inhibition of proinflammatory cytokine formation, inducible nitric
oxide synthase (iNOS) and cyclooxygeanase-2 (COX-2) expression has been
Chih-Shung Wong, MD, PhD‡ demonstrated in many in vitro and in vivo studies. However, whether C-PC also has
antihyperalgesic activity in inflammatory nociception has not been investigated.
Yu-Ling Kuo, MS§ METHODS: Using a carrageenan-induced thermal hyperalgesia model, we evaluated
the effect of C-PC on nociception by measuring paw withdrawal latency. To clarify
Tz-Chong Chou, PhD§ the mechanisms involved, the expression of iNOS and COX-2 and the formation of
nitrate and tumor necrosis factor-␣ (TNF-␣) in the rat paw were determined.
RESULTS: Pre- or posttreatment with C-PC (30 or 50 mg/kg, IP) significantly
attenuated carrageenan-induced inflammatory nociception and the induction of
iNOS and COX-2 at the late phase, (4 h) accompanied by an inhibition of the
formation of TNF-␣, prostaglandin E2, nitrate and myeloperoxidase activity.
CONCLUSIONS: Based on these results, it is suggested that the inhibition of NO and
prostaglandin E2 over-production through suppressing iNOS and COX-2 induction
and attenuation of TNF-␣ formation and neutrophil infiltration into inflammatory
sites by C-PC may contribute, at least in part, to its antihyperalgesic activity.
(Anesth Analg 2009;108:1303–10)

I t has been a well accepted concept that all pain,

whether acute or chronic, peripheral or central,
interleukin (IL)-1␤, IL-6, synthesis of prostaglandins
and sympathetic amines, suggesting that TNF-␣
originates from inflammation and the inflammatory plays an early and crucial role for the subsequent
response.1 The carrageenan-induced inflammatory inflammatory responses.4 This concept is confirmed
response in the rat hindpaw, acting as an acute by the fact that injection of antiserum neutralizing
model of inflammation, has been widely used for endogenous TNF-␣ markedly abolishes the response
screening novel antiinflammatory drugs.2 The mecha- to carrageenan.4 Furthermore, over-production of inflam-
nisms of carrageenan-induced inflammatory nociception matory prostaglandins, such as prostaglandin E2 (PGE2)
involve a complex chain of events, in which various and NO, mainly derived from COX-2 and inducible
mediators, including histamine, serotonin, proinflamma- NO synthase (iNOS) respectively, are also critical
tory cytokines, nitric oxide (NO), cyclooxygenase (COX)- mediators accounting for the pathogenesis of inflam-
derived products and sympathomimetic amines, are matory nociception.5– 8 Another pathogenic mediator,
released.3 In addition, it is proposed that carrageenan- reactive oxygen species (ROS), has been reported to
induced hyperalgesia is associated with a cascade of play an important role in the maintenance of
cytokine release. The first cytokine released is tumor carrageenan-induced paw edema.9
necrosis factor-␣ (TNF-␣), which triggers the release of C-phycocyanin (C-PC), a biliprotein found in
blue green algae, such as Spirulina platensis, is used
From the *Chia-Yi Christian Hospital; †Department of Pediat- in many countries as a dietary supplement due to its
rics, Tri-Service General Hospital, National Defense Medical Center; various beneficial activities, including hepatoprotective, an-
‡Department of Anesthesiology, Tri-Service General Hospital, Na-
tional Defense Medical Center; and §Department of Physiology,
tiaggregatory, neuroprotective, and ROS-scavenging
National Defense Medical Center, Taipei, Taiwan, Republic of actions observed in various experimental models.10 –12
China. In addition, the antiinflammatory activity of C-PC,
Accepted for publication August 31, 2008. including attenuation of lipopolysaccharide-induced
Supported, in part, by a research grant from the National Science iNOS expression and TNF-␣ formation through
Council of Taiwan (NSC 92-2320-B016-023), Republic of China.
suppressing nuclear factor-␬B activation in RAW
Address correspondence and reprint requests to Tz-Chong
Chou, PhD, Department of Physiology, National Defense Medical 264.7 macrophages, and inhibition of COX-2 activity
Center, No. 161, Min-Chuan E. Rd., Sec. 6, Taipei, Taiwan, Republic and leukotriene B4 formation, has been demon-
of China. Address e-mail to [email protected]. strated in vitro.13–15 Based on the importance of
Copyright © 2009 International Anesthesia Research Society inflammation in nociception and its antiinflamma-
DOI: 10.1213/ane.0b013e318193e919
tory characteristics, we propose that C-PC may also
Vol. 108, No. 4, April 2009 1303
exert antihyperalgesic activity against inflammatory
nociception through inhibition of these proinflam-
matory mediators. Although several protective ef-
fects of C-PC have been reported, there is no
information on carrageenan-evoked inflammatory
nociception. In the present study, we first demon-
strated that C-PC exhibits antihyperalgesic activity
in carrageenan-evoked thermal hyperalgesia and
that the inhibition of TNF-␣, NO, and PGE2 forma-
tion may be involved.

METHODS
Animals
Male Sprague-Dawley rats (200 –250 g) purchased
from the National Animal Center (Taipei, Taiwan)
were used in this study, which was approved by the
local institutional animal care and use committee. Measurement of Cytokines, Nitrate, and PGE2 Production
Animals were housed in standard environment and in Paw Exudates
maintained on tap water and rat chow (Rodent Diet To obtain paw exudates, the hindpaws of rats were
5010, LabDiet) ad libitum throughout the investigation. cut at the level of the calcaneus bone and centrifuged
at 400g for 15 min at 4°C to collect the edematous
fluid.16 The levels of cytokines and PGE2 in paw
Carrageenan-Evoked Thermal Hyperalgesia exudates were then measured by enzyme immunoas-
This test was performed as described in our previous say kits, respectively (Genzyme Corporation, Cam-
study.16 First, rats were allowed 30 min to acclimatize to bridge). The concentrations of nitrate in paw exudates
the device before testing. Acute inflammation was then were measured by a Sievers Nitrite Oxide Analyzer
produced by the subplantar (i.pl.) administration of 100 (Sievers 280 NOA, Sievers, Boulder, CO).
␮L of 2% (w/v) ␭-carrageenan (Sigma, St. Louis, MO)
dissolved in normal saline into the right hindpaw of each Western Blot Analysis
rat. The hyperalgesia was assessed by placing the hind- Soft tissues were removed from rat paws and homog-
paw above a radiant heat source and measuring paw enized in a lysis solution containing 10 mM 3-[(3-
withdrawal latency to evaluate thermal hyperalgesia cholamidopropyl)dimethylammonio]-propanesulfonate
every 60 min for 240 min after injection of carrageenan (CHAPS), 1 mM phenylmethylsulfonyl fluoride, 5
with a commercially available device (7370 Plantar Test, ␮g/mL aprotinin, 1 ␮M pepstatin, and 10 ␮M leupeptin
UGO Basile, Comerio, Italy). Data were calculated as a to obtain supernatant by centrifugation at 12,000g for 20
mean of three repeated measurements. min. Proteins (50 ␮g) were then applied on 10% sodium
dodecylsulphate-polyacrylamide minigel using a stan-
dard method. The proteins were transferred to polyvi-
Experimental Design nylidene difluoride membranes and Western blotting
In additional groups, rats were treated with either was performed by adding an anti-COX-2, anti-iNOS
normal saline (0.2 mL, IP), C-PC (30 or 50 mg/kg, IP, (Transduction Lab, Lexington, KY) or anti-␤-actin (Santa
C-PC with a purity of A620/A280 ⬎3.5, Sigma, St. Cruz, San Francisco, CA) antibodies overnight at 4°C
Louis, MO) or ibuprofen (50 mg/kg, IP, Sigma, St. followed by incubation with horseradish peroxidase-
Louis, MO) at 30 min before or 75 min after the conjugated secondary antibody. The ECL reagent (Am-
injection of carrageenan. The experimental design ersham International Plc., Buckinghamshire, UK) was
scheme is shown below. After injection of carrageenan used to detect the protein bands and the relative density
for 4 h, the paw exudates and paw tissues were of iNOS and COX-2 was quantified by densitometry.
collected to measure the levels of PGE2, nitrate, and
TNF-␣, COX-2 and iNOS expression and myeloperox- MPO Activity Assay
idase (MPO) activity. Rats receiving saline (IP) at 30 Soft tissues from paws were removed and washed
min before injection of saline (i.pl.) acted as the control with sterile normal saline and homogenized in ice-cold
group and the saline (IP) and carrageenan (i.pl.) 0.5% hexadecyltrimethylammonium bromide in 50 mM
injected rats acted as the carrageenan group. At 4 h phosphate buffer (pH ⫽ 6.0, 5 mL hexadecyltrimethyl-
after injection of carrageenan, the levels of TNF-␣, ammonium bromide/g tissue) by using a homogenizer
PGE2 and nitrate in paw exudates and the expression (Pro model 200, Monroe, CT), and then sonicated and
of COX-2 and iNOS in paw tissues were measured. centrifuged at 15,000g for 15 min at 4°C. The supernatant
Each group contained 5– 6 rats. was mixed 1:30 (supernatant: assay buffer) and read at

1304 C-PC Inhibits Inflammatory Nociception ANESTHESIA & ANALGESIA

Figure 1. Effect of C-phycocyanin (C-
PC) on carrageenan-evoked paw ther-
mal hyperalgesia. Saline (0.2 mL, IP),
C-PC (30 or 50 mg/kg, IP) or ibuprofen
(50 mg/kg, IP) was administered 30
min before or 75 min after injection of
carrageenan (1 mg/paw, i.pl.). Paw
withdrawal latencies of rat hindpaws
were assessed at specific times. Rats
receiving saline (IP) at 30 min before
injection of saline (i.pl.) acted as the
control group and the saline (IP) and
carrageenan (i.pl.)-injected rats acted as
the carrageenan groups (n ⫽ 6 in each
group). *P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍
0.001 vs carrageenan group.

460 nm. The assay buffer consisted of 100 mM potassium RESULTS

phosphate, pH 6.0, 0.083 mL H2O2 (Sigma; 30% stock
diluted 1:1000) and 0.834 mL o-dianisidine hydrochlo- Effect of C-PC on Carrageenan-Evoked Thermal Hyperalgesia
ride (Sigma; 10 mg/mL). MPO activity was calculated
Injection of carrageenan into the rats’ right hind-
and expressed as ⌬A460/min/mg protein.
paws evoked thermal hyperalgesia with a signifi-
Statistical Analysis cant decrease of withdrawal latency compared with
Data are expressed as mean ⫾ sem. The difference that of the control group. Pretreatment with C-PC
among groups was assessed using a one-way anal- (30 or 50 mg/kg, IP) at 30 min before injection of
ysis of variance with post hoc analysis via Scheffe carrageenan inhibited hyperalgesia from 1 h to 4 h
test. P values ⬍0.05 were considered statistically compared with results in the carrageenan group
significant. (Fig. 1). Potent antihyperalgesic activity from ibu-

Vol. 108, No. 4, April 2009 © 2009 International Anesthesia Research Society 1305
 Figure 2. Effect of C-phycocyanin (C-
PC) on prostaglandin E2 (PGE2)
formation and cyclooxygeanase-2
(COX-2) expression in carrageenan-
injected paws. C-PC (30 or 50 mg/kg,
IP) was administered 30 min before
injection of carrageenan and the lev-
els of PGE2 in the paw exudates
(upper) and the COX-2 protein ex-
pression of the tissue of paws (bot-
tom) were measured at 4 h after
injection of carrageenan. The relative
density of COX-2 was quantified by
densitometry and the density of con-
trol group was set as 1. *P ⬍ 0.05,
**P ⬍ 0.01 vs carrageenan group (n ⫽
5 in each group).

profen (50 mg/kg, IP), a nonsteroidal antiinflamma- carrageenan-injected paws at 4 h compared with re-
tory drug (NSAID), was also observed. Similarly, sults in the carrageenan group (Fig. 3).
posttreatment with C-PC at 75 min after injection of
carrageenan also significantly reduced hyperalgesia Effect of C-PC on TNF-␣ and IL-10 Formation
(Fig. 1). The withdrawal latencies of the contralat- Pretreatment with C-PC (30 or 50 mg/kg, IP) sig-
eral left hindpaw (no injection in this paw) re- nificantly inhibited the carrageenan-induced rise of
mained constant at basal levels (18.5 ⫾ 1.5 s) TNF-␣ formation in paw exudates at 4 h compared
through the entire experiment (data not shown). with results of the carrageenan group (Fig. 4). How-
ever, C-PC had no significant effect on IL-10 formation
Effect of C-PC on PGE2 Formation and COX-2 Expression (data not shown).
Treatment with a higher dose of C-PC (50 mg/kg,
IP) at 30 min before injection of carrageenan caused an Effect of C-PC on MPO Activity
inhibition of PGE2 formation and COX-2 protein ex- The carrageenan-induced increase of MPO activity
pression in carrageenan-injected paws at 4 h com- in paws was also significantly suppressed by treat-
pared with results in the carrageenan group (Fig. 2). ment with C-PC (30 or 50 mg/kg, IP) (Fig. 5).
Effect of C-PC on Nitrate Formation and iNOS Expression
Treatment with C-PC (30 or 50 mg/kg, IP) at 30 min DISCUSSION
before injection of carrageenan resulted in a reduction Although a previous study has shown that C-PC re-
of nitrate formation and iNOS protein expression in duces carrageenan–induced paw edema,17 the effect of

1306 C-PC Inhibits Inflammatory Nociception ANESTHESIA & ANALGESIA

Figure 3. Effect of C-phycocyanin (C-
PC) on nitrate formation and induc-
ible nitric oxide synthase (iNOS)
expression in carrageenan-injected
paws. C-PC (30 or 50 mg/kg, IP) was
administered 30 min before injection
of carrageenan and the levels of ni-
trateinthe paw exudates (upper) and
iNOS protein expression of the tissue
of paws (bottom) were measured at
4 h after injection of carrageenan. The
relative density of iNOS was quanti-
fied by densitometry and the density
of control group was set as 1. *P ⬍
0.05, **P ⬍ 0.01 vs carrageenan group
(n ⫽ 5 in each group).

C-PC on inflammatory nociception has not been reported. attenuates carrageenan-evoked thermal hyperalgesia, sug-
Thus, the present study is the first to evaluate whether gesting that C-PC may have preventive and therapeutic
C-PC may also exert antihyperalgesic activity and further activity on inflammatory nociception. In addition, we also
investigate the possible antiinflammatory mechanisms in- found that C-PC exhibited significantly antihyperalgesic
volved in a rat model of carrageenan-evoked thermal activity both in early and late phases. Since histamine plays
hyperalgesia. In this model, the development of edema and an important role in the development of carrageenan-
nociception in the rat hindpaw was described as a biphasic induced vascular permeability and edema in the early
event.18 The initial phase observed during the first hour phase, the result suggests that C-PC may have an immedi-
was attributed to a release of histamine and serotonin; the ate inhibitory effect on histamine release. This hypothesis
second phase (4 h after carrageenan injection) was due was supported by C-PC suppression of compound 48/80
to a release of proinflammatory mediators, including (a histamine releaser)-induced histamine release from rat
prostaglandin-like substances.3 In this study, we first dem- peritoneal mast cells.19 Accordingly, C-PC may also affect
onstrated that pre- or posttreatment with C-PC significantly the function of mast cells that are an important resource for
Vol. 108, No. 4, April 2009 © 2009 International Anesthesia Research Society 1307
 Figure 4. Effect of C-phycocyanin (C-PC)
on tumor necrosis factor-␣ (TNF-␣) for-
mation in carrageenan-injected paws.
C-PC (30 or 50 mg/kg, IP) was adminis-
tered 30 min before injection of carra-
geenan and the levels of TNF-␣ in paw
exudates were measured at 4 h after
injection of carrageenan. ***P ⬍ 0.001 vs
carrageenan group (n ⫽ 6 in. each
group).

Figure 5. Effect of C-phycocyanin (C-

PC) on myeloperoxidase (MPO) ac-
tivity in carrageenan-injected paws.
The C-PC (30 or 50 mg/kg, IP) was
administered 30 min before injection
of carrageenan. Paw tissue was then
removed for MPO activity determi-
nation at 4 h after injection of carra-
geenan. **P ⬍ 0.01 vs carrageenan
group (n ⫽ 6 in each group).

synthesis and release of prostaglandin D2, leukotrienes, over production of prostaglandins and NO mainly syn-
ROS and cytokines, such as TNF-␣.20 In this model, TNF-␣ thesized by COX-2 and iNOS is a key mediator for the
plays an early and crucial role for the subsequent inflam- maintenance of inflammation.8,22,23 Furthermore, over-
matory response through stimulating the production of production of NO may react with superoxide anion to
COX products and IL-8 that induce local production of form more cytotoxic peroxynitrite, which is often seen in
sympathetic amines.2,21 Thus, inhibition of TNF-␣ forma- carrageenan-injected paws.24 Blocking COX-2 induction
tion by C-PC in carrageenan-injected paws may contribute and PGE2 formation or iNOS-derived NO formation has
to its antihyperalgesic activity. However, C-PC had no been demonstrated to exert a protective effect against
effect on IL-10 (an antagonist cytokine) formation, suggest- inflammatory nociception and sepsis.6,16,25 In this study,
ing that its antiinflammatory activity may be not mediated C-PC significantly inhibited the carrageenan-induced
by IL-10 production. increase of PGE2 and nitrate production accompanied by
It has been reported that, during the development of a suppression of COX-2 and iNOS expression in rat
carrageenan-evoked inflammatory nociception, periph- paws at the late phase, suggesting that C-PC may be a
eral constitutive COX-1 and constitutive NOS play a selective inhibitor for COX-2 and iNOS. Thus, it was
primary role in the early phase (1 h); in the late phase (4 possible that attenuation of over-production of NO and
h), in which COX-2 and iNOS are fully activated. The PGE2 by C-PC, through suppressing iNOS and COX-2

1308 C-PC Inhibits Inflammatory Nociception ANESTHESIA & ANALGESIA

induction, may be associated with its beneficial effect prevent or reduce the adverse effects of NSAIDs. It has
against inflammatory nociception. been reported that the LD50 of indomethacin is 12
Inflammation often causes neutrophil activation mg/kg PO in rats.36 However, there is no enhanced
and infiltration into the damaged tissues. The infil- mortality in rats, and alterations in behavior or in
trated neutrophils may also be an important source organs, even at the high dose of C-PC (3 g/kg, PO),17
of various proinflammatory mediators, including suggesting that C-PC is much safer than traditional
cytokines and oxygen-derived free radicals.26 The NSAIDs. Based on these characteristics, C-PC may be
increased MPO activity, an indicator of neutrophil a better choice than NSAIDs for treating inflammatory
infiltration observed in carrageenan-injected paws nociception.
was significantly reduced by C-PC, suggesting that In this study, we first demonstrate that C-PC at-
suppression of neutrophil infiltration may be an- tenuates carrageenan-evoked thermal hyperalgesia.
other possible mechanism accounting for its antiin- Furthermore, we propose that the antihyperalgesic
flammatory activity. In addition, research done in mechanisms of C-PC may be associated with the
different models of inflammation has indicated that inhibition of NO and PGE2 over-production through
C-PC exerted antiinflammatory activity, not only in suppressing iNOS and COX-2 induction. In addition,
the acute models of inflammation, but also in a the inhibition of TNF-␣ formation and neutrophils
subchronic model, such as the cotton pellet granu- infiltration in inflammatory sites may be also in-
loma in rats.17 volved. These findings suggest that C-PC may be a
The mitogen-actived protein kinases (MAPKs) fam- potential therapeutic drug for reducing inflammatory
ily includes extracellular signal-regulated kinases nociception.
(ERK), p38, and c-Jun N-terminal kinases. The p38
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1310 C-PC Inhibits Inflammatory Nociception ANESTHESIA & ANALGESIA