Neuroprotective Effect of Curcumin in An Experimental Rat Model of Subarachnoid Hemorrhage

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CRITICAL CARE MEDICINE
Neuroprotective Effect of Curcumin in an Experimental Rat

Model of Subarachnoid Hemorrhage
Chang-Po Kuo, M.D.,* Chueng-He Lu, M.D.,† Li-Li Wen, Ph.D.,‡ Chen-Hwan Cherng, M.D., D.M.Sc.,§
Chih-Shung Wong, M.D., Ph.D.,# Cecil O. Borel, M.D., Da-Tong Ju, M.D.,** Chun-Mei Chen, M.S.,††
Ching-Tang Wu, M.D.‡‡
ABSTRACT
What We Already Know about This Topic
Background: Subarachnoid hemorrhage (SAH) causes a

• Oxidant stress may play an important role in neuronal injury after subarachnoid hemorrhage (SAH), and curcumin
may be high mortality rate and morbidity. It was suggested that oxidant stress plays an important role in neuronal
injury after
a promising therapeutic agent for reducing cerebral vasospasm and neurologic injury
SAH. Therefore, we assessed the effect of curcumin on reducing cerebral vasospasm and neurologic injury in a
SAH model in rat.
What This Article Tells Us That Is New
• In the double-hemorrhage rat SAH model, curcumin in multiple doses was effective against glutamate neurotoxicity and
oxidative stress, and improved the mortality rate in rats with SAH * Instructor, Department of Anesthesiology, National Defense
Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China, and Visiting Research Scholar, Department
of Anesthesiology, Duke University Medical Center, Durham, North
Methods: A double-hemorrhage model was used to induce
Carolina. † Assistant Professor and Attending Physician, Depart- ment of Anesthesiology, National Defense Medical Center and
Tri-Service General Hospital. ‡ Assistant Professor, Department of Clinical Laboratory, En Chu Kong Hospital, Taipei, Taiwan,
SAH in rats. Groups of animals were treated with intraperitoneal injection of 20 mg/kg curcumin (curcumin group, n 24) or
dimethyl sulfoxide (vehicle group, n 33), Republic of China. § Associate Professor and Director, Depart- ment of
Anesthesiology, National Defense Medical Center and Tri-Service General Hospital. # Professor and Chairman, Depart- ment of
Anesthesiology, Cathay General Hospital, Taipei, Tai-
normal saline (SAH group, n 34) or normal saline (sham group, n 22), 3 h after SAH induction and daily for 6 days. Glutamate
was measured before SAH induction and once wan, Republic of China. Professor, Department of Anesthesiol- ogy, Duke
University Medical Center. ** Assistant Professor and Attending Physician, Department of Neurosurgery, National Defense
daily for 7 days. Glutamate transporter-1, wall thickness and the perimeter of the basilar artery, neurologic scores, neuro- Medical
Center and Tri-Service General Hospital. †† Research Assistant, Department of Anesthesiology, National Defense Medical
Center and Tri-Service General Hospital. ‡‡ Associate Professor and Attending Physician, Department of Anesthesiology,
National Defense Medical
nal degeneration, malondialdehyde, superoxide dismutase, and catalase activities were assessed. Results: Changes of
glutamate levels were lower in the cur- Center and Tri-Service General Hosptial.
cumin group versus the SAH and vehicle groups, especially
Received from the Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, Taipei,
Taiwan, Republic of China. Submitted for publication February 24, 2011. Accepted for publication August 10, 2011. Supported
on day 1 (56 folds attenuation vs. vehicle). Correspondingly, glutamate transporter-1 was preserved after SAH in
curcumin-treated rats. In the hippocampus and the cortex, mal- by grant Nos. TSGH-C97-72, TSGH-C98-76, and
TSGH-C99-90 from Tri-Service General Hospital (Taipei, Taiwan, Republic of China).
ondialdehyde was attenuated (30% and 50%, respectively). Superoxide dismutase (35% and 64%) and catalase (34%
Address correspondence to Dr. Wu: Department of Anesthe-
and 38%) activities were increased in the curcumin rats
com- siology, National Defense Medical Center and Tri-Service General Hospital, #325, Section 2, Chenggung Road, Neihu 114,
Taipei, Taiwan, Republic of China. aneswu@gmail.com. Information on purchasing reprints may be found at
www.anesthesiology.org or
pared with the SAH rats. Mortality rate (relative risk: 0.59), wall thickness (30%) and perimeter (31%) of the basilar
artery, neuron degeneration scores (39%), and neurologic on the masthead page at the beginning of this issue. A
NESTHESIOLOGY
’s articles are made freely accessible to all readers, for personal use
only, 6 months from the cover date of the issue.
Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2011;
115:1229–38
scores (31%) were improved in curcumin-treated rats. Conclusions:Curcumin in multiple doses is effective against
glutamate neurotoxicity and oxidative stress and improves the mortality rate in rats with SAH.
Anesthesiology, V 115 • No 6 1229
December 2011

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Curcumin in Experimental Subarachnoid Hemorrhage
S
UBARACHNOID debilitating disease. hemorrhage (SAH) is a serious and
Animal Model Several putative mechanisms and
The current investigation was conducted in
accordance with possible treatments for SAH have been proposed.1 It is plau-
the Guide for the Care and Use of Laboratory Animals
pub- sible that the inflammatory response to oxidant stress repre-
lished by the National Institutes of Health (Bethesda,
Mary- sent a critical step in the pathogenesis of cerebral vasospasm
land) and was approved by the Animal Care and Use
Com- (CVS) pursuant to SAH.2– 4 In addition, glutamate plays an
mittee of the National Defense Medical Center
(Taipei, important role in the pathogenesis of neuronal injury after
Taiwan, Republic of China). ischemic injury.5
Glutamate transporter-1 (GLT-1) pre-
Animals were randomly allocated to the following
groups: dominates among the functional glutamate transporters, which are essential for maintaining a low
extracellular glutamate concentration and for preventing glutamate neurotox- city.6 In a previous study, we
observed down-regulation of GLT-1, neuronal degeneration, increased basilar artery wall thickness, and neuron
variability after SAH.7 It was suggested that an increase in GLT-1 expression or activity would attenuate
glutamate excitotoxicity.8
Oxidative stress contributes to damage and misfolding of proteins, including glutamate transporters.9 Therefore,
therapeutic strategies that confer antioxidant effects should attenuate the increase in glutamate level and increase
GLT-1 expression after SAH.
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione] (diferuloyl methane), possesses an-
tioxidant10,11 and antiinflammatory effects.12,13 Several studies have indicated a single, high dose of curcumin
has protective effects against cerebral ischemia14,15 and CVS after SAH, and that they are mediated by its
antioxidant effect.3 We hypothesized that multiple doses of curcumin may reduce CVS and neurologic injury via an
antioxidant effect and attenuate glutamate-induced neurotoxicity after SAH in rats.
sham (n 22), SAH (n 34), vehicle (n 33), or curcumin (curcumin 20 mg/kg; n 24). Dimethyl sulfoxide, 10%, was
used as a vehicle for curcumin. Ten male Wistar rats (300–380 g) in each group were implanted with a mi-
crodialysis loop (2 2 cm) after intraperitoneal injection of sodium pentobarbital anesthetic (30 mg/kg). The microdi-
alysis loop was placed into the intrathecal space through the cisternal membrane until the level of fourth cervical
vertebra, and externalized on top of head. After then, the rats were allowed to recover for 5 days. The microdialysis
probes were perfused once per day to keep the catheter patent. One end of the microdialysis probe was connected to
a microdialysis pump (CMA 102; CMA Microdialysis, Holliston, MA) (in- flow) for continuous infusion of
artificial CSF, and the other end was connected to a polyethylene-10 tube (outflow) to collect the CSF dialysate as
mentioned in our previous study.7 All rats were housed individually under a 12 h light and 12 h dark cycle at room
temperature (25°C 1°C) and humidity (60 10%) with ad libitum access to food and water. Rats were excluded if they
showed any evidence of neurologic injury after microdialysis probe inseration.
Five days after microdialysis loop implantation, rats were anesthetized by intraperitoneal injection of sodium
pentobarbital (30 mg/kg). SAH was induced using a prechiasmatic approach in which a needle with a rounded tip
and a side hole
Materials and Methods
(Withcare spinal set, 0.41 90 mm; Becton Dickinson, Madrid, Spain) was stereotactically inserted into the prechi-
Construction of the Microdialysis Probe
asmatic cistern. We tilted the needle 30° anteriorly and
put The microdialysis probe with each end of a 4 cm cuprophan
7.5 mm anterior to the bregma in the midline. With the
hollow fiber (300-μm OD, 200-μm ID, 50-kd molecular
aperture directing to right, the needle was lowered
until the weight cut-off [DM-22; Eicom Co., Kyoto, Japan]), was
tip came to the skull base 2–3 mm anterior to the
chiasma, connected via a polycarbonate tube (194-μm OD, 102-μm
about 10 mm to the brain surface. Autologous arterial
blood ID; 0.7 cm in length) to a 7-cm polyethylene 5 tube (0.008- in. ID, 0.014-in. OD). To make the probe firm
enough for
(200 μl) was injected by a pump to maintain intracranial pressure at the mean arterial blood pressure level.17 In the
implantation, a 0.0026-in. Nichrome–Formavar wire (A-M system, Everret, WA) was passed through the
polycarbonate tubes and the cuprophan hollow fiber (the active dialysis region) and fixed inside the polyethylene 5
tubes with epoxy glue. The probe was then bent in the middle part of the cuprophan hollow fiber, forming a
U-shaped loop. The two ends of the microdialysis probe, which consisted of silastic tubes, were sealed with silicon
sealant. The dead space of the
beginning, the burr hole was left open without filling the wax, which resulted in CSF leakage in some animals;
conse- quently, the intracranial pressure increased only minimally. A second blood injection was administered 48 h
after the first injection.7 The first SAH induction was defined as day 1. Sham rats received normal saline instead of
blood. Arterial blood pressure was monitored via a 4-French intra-arterial sheath placed in the right femoral artery.
dialysis probe was 8 μl. During the in vitro measurements, the recovery rate of the dialysis probe was 40% at an
infusion
CSF Sample Collection and Measurement of
Glutamate rate of 5 μl/min. Using this technique, it was possible to
Concentrations measure levels of cerebrospinal fluid
(CSF) glutamate levels
On day 6 after microdialysis loop implantation, a
mini-os- for up to 12 days after implantation.16
motic pump with a pump rate of 5 μl/h was filled with
Anesthesiology 2011; 115:1229–38 1230
Kuo et al.

artificial CSF and attached to the dialysis loop for 2 h to
Histology: Tissue Preparation achieve equilibration,
after which dialysate was collected be-
On day 7 after the first SAH induction, the rat was
decapi- fore the first SAH induction (baseline) and daily for 7 days
tated and the brain was harvested right after
anesthesia. The thereafter.7 The collected dialysate samples were frozen at
brains were postfixed in 4% paraformaldehyde for 3
days. 80°C until analysis.
The brain tissue with the basilar artery and the pons was
Analysis of extracellular concentrations of glutamate in
sectioned to a thickness of 6 μm at 200-μm intervals
using a the microdialysates was performed using high-pressure liq-
cryostat (Leica CM3050 S; Leica Microsystems,
Wetzlar, uid chromatography (Agilent 1100; Agilent Technologies,
Germany). Every eighth section of the brain was
collected on Palo Alto, CA), with fluorescence detection (Gilson model
a slide and stained with hematoxylin and eosin. Six
rats from 121, set at 428 nm; Gilson, Middleton, WI) after precolumn
each group were used for histologic analysis.
derivatization with o-phthalaldehyde. Glutamate concentrations were assayed using precolumn derivatization
Measurements of Wall Thickness and Perimeter of
with o-phthalaldehyde/t-butylthiol reagent and iodoacet-
Basilar Artery amide/methanol scavenger.
Derivatization was performed
The mean thickness and the perimeter of the basilar
artery by adding 4 ml of o-phthalaldehyde/t-butylthiol reagent to
wall were measured using Imaging-Pro-Plus software
(Media 40 ml of sample and shaking the mixture for 2 min to enable
Cybernetics, Bethesda, MD) and an Olympus
microscope it to react. Four milliliters of reagent B (185 mg of iodoacet-
(Olympus, Optical Tokyo, Japan). Light microscopic
sec- amide/ml of methanol) was then added and the mixture was
tions of basilar artery were projected as digitized
video im- again shaken for 2 min. The sample was then injected into a
ages. From each animal, three slices of the basilar
artery were C18 reverse-phase column and eluted at a flow rate of 0.45
taken from the proximal, distal, and middle portions of
the ml/min. A linear gradient from 100% eluent A [0.1 M so-
vessel, and measurements were made at four points (at
the dium acetate buffer, pH 6.8/acetonitrile (80:20)] to 100%
hours 3, 6, 9, and 12, as if on the face of a clock), from
which eluent B [acetonitrile/double-distilled water (80:20)] was
the mean wall thickness and perimeter were
calculated.20 A used to separate glutamate. All solvents were vacuum-filtered
blinded technician took the measurements. through a
0.22-μm membrane (Millipore, Billerica, MA) and degassed by sonication before use. Solutions containing 0, 10 8,
10 7, 10 6, and 10 5 M of glutamate standard were run before and after running each sample group.18 The dialysate
samples from the survival rats were analyzed. The technicians who performed the analysis were blinded to treatment
group.
Anesthesiology 2011; 115:1229–38 1231
Kuo et al. Quantitative Analysis of Neuronal Cell Bodies in the Hippocampus The tissues from the rats used for
measuring wall thickness and perimeter were studied using a bright-field microscope (Eclipse E600W microscope;
Nikon, Tokyo, Japan) and photographed by a digital camera (Nikon DP70; Nikon). Degeneration of the neuron
(shrinkage of the neuron, hyper- Drug Preparation and Treatment Schedule
chromasia, and nuclear pyknosis) was evaluated by a
light Curcumin (purity 94%) was purchased from Sigma-Aldrich
microscopy. The dentate gyrus, cornu ammonis 1 and
cornu (St. Louis, MO). Three hours after the first SAH induction and
ammonis 3 were scored semiquantitatively for the
presence daily for 6 days, 0.25– 0.3 ml curcumin/dimethyl sulfoxide so-
and extent of neuronal degeneration. The scoring was
1 lution was administered intraperitoneally to the curcumin
point for normal appearance; 2 points for a few
degenerated group. Equal volumes of 10% dimethyl sulfoxide solution
neurons among normal neurons; 3 points for a lot of
degen- were given to the vehicle group, whereas equal volumes of
erated neurons with scattered normal neurons; and 4
points normal saline were administered intraperitoneally to the
for complete degeneration with no residual normal
neurons. sham and SAH groups.
Each of the three regions of the hippocampus was scored. “Degeneration score” was designated as the sum of these
Mortality Rate and Neurologic Assessment The rats’ mortality rate was recorded during and after the
three scores, and the means were analyzed for statistical sig- nificance by a blinded observer.21 SAH procedure.
Neurologic scoring (n 6 in each group) was done in a blinded fashion at 6 h and days 1, 3, 5, and 7
Western Blotting after first SAH induction. This
assessment evaluated motor
The harvested brain tissues were subjected to Western
blots function based on spontaneous activity (0 to 3), symmetry
as described in our previous study.7 Six rats from each
group of limb movements (0 to 3), and climbing the walls of a
were sacrificed on day 7 after SAH. The hippocampus
and wire cage (1 to 3). Sensory score was examined by re-
cerebral cortex were dissected out and homogenized in
a 10 sponses to touch on vibrissae or on the sides of the trunk.
mM Tris buffer containing 0.32 M sucrose, 1 m
M Each
scored from 1 to 3. The neurologic score of each rat at the end of the evaluation was the summation of all six
individual scores. The minimum neurologic score was 3 and the maximum was 18.19
EDTA, 1 mM teinase Na
inhibitors 3
VO
4
,5m
followed M
dithiothreitol, by and a mixture of pro- centrifugation for 30 s at 11,000 g. The resulting pellets were dissolved in
gel-load- ing buffer and centrifuged for 30 min at 20,000 g. For gel

Anesthesiology 2011; 115:1229–38 1232 Kuo et al. electrophoresis, each lane was loaded with approximately 40
Statistical Analysis μg of protein from the supernatant, and the amount of pro-
The data are presented as mean and corresponding
95% CI. tein was determined using the Coomassie blue protein assay.
Mortality rate was analyzed by Fisher exact test. The
mean Each sample was denatured by heating at 90°C for 10 min in
values of glutamate concentration and neurologic
scores over an equal volume of sodium dodecyl sulfate sample buffer,
time were compared using a two-way ANOVA with
group as separated on a 10% sodium dodecyl sulfate gel, and transferred to a polyvinylidene difluoride membrane
(Millipore). After separation by electrophoresis using 10% polyacryl- amide gels, the resolved proteins were
electro-transferred onto a nitrocellulose filter (Bio-Rad Laboratories, Hercules, CA). The filters were placed in a
blocking buffer for 1 h at room temperature and were then incubated overnight (16 h) with anti-GLT-1 (1:600;
Chemicon, Temecula, CA) anti- bodies. After three 10 min washes with phosphate-buffered saline-containing 0.1%
Tween 20, the filters were then incubated for 1 h with a horseradish peroxidase-conjugated secondary antibody
(1:1,500; Amersham, Piscataway, NJ).
a between-subjects factor and time as a repeated-measures factor. If the comparison was significant, post hoc
analysis using Bonferroni correction for multiple comparisons was performed. The basilar artery wall thickness and
perimeter, neuronal degeneration scores, GLT-1, malondialdehyde, SOD, and catalase were measured with one-way
ANOVA analysis among four groups; if analysis of variance results were significant, post hoc analysis with
Bonferroni correction for multiple comparisons between groups was performed. A P value 0.05 with two-tailed
testing was considered to be significant. Analysis of variance was performed using Graph- Pad Instat (GraphPad
Software, San Diego, CA).
After two washes with phosphate-buffered saline-containing 0.1% Tween 20, the blots were incubated for 1 min
with the enhanced chemiluminescence reagent (Amersham, Arling- ton Heights, IL) and exposed immediately to
Hyperfilm- enhanced chemiluminescence (Syngene, Cambridge, United Kingdom). The densities of the gel bands
were analyzed using computer software and were normalized to the density of a reprobed ß-actin signal on the
same blot as an internal control.
Results
Changes in Glutamate Concentrations Significantly lower glutamate levels were observed between day 1 and day 7
in the curcumin group compared with the SAH and vehicle groups (both P 0.001). However, glutamate levels in the
curcumin group were higher than in the sham group on days 1, 2, and 3 after SAH (fig. 1; P 0.01). The mean
percentage changes (95% CI) in glutamate levels from baseline for the sham (n 10), SAH (n 6), vehicle (n 6), and
curcumin (n 8) groups were 14.5 Measurement of Malondialdehyde, Superoxide
( 45.2–16.2)%, 135.9 (57.3–214.5)%, 130.2 (19.0–
Dismutase, and Catalase
241.5)%, and 2.3 (22.7–27.4)% on day 1; 17.1 ( 40.8–
Malondialdehyde was assayed on brain samples using a thio-
6.7)%, 65.8 ( 17.7–149.4)%, 63.7 (10.0–117.4) %, and
barbituric assay. In brief, brain samples were homogenized in
3.6 (12.5–19.6)% on day 2; 15.5 ( 44.7–13.7)%, 43.3
ice-cold phosphate buffer. The homogenate was mixed with
(25.2–61.5) %, 47.6 (3.4–91.7)%, and 9.4 ( 36.6–
thiobarbituric acid and butylated hydroxytoluene and heated in a water bath at 90°C for 45 min. After cooling,
n-butanol was added to the mixture, which was centrifuged at 1,000 g for 5 min. The maximum absorbance was 532
n
M
. Serial dilutions of 1,1,3,3-tetraethoxypropane were used as stan-
dards.22 Malondialdehyde concentration was expressed as n
M
/g tissue. Superoxide dismutase (SOD) activity was determined using a SOD assay kit (Cayman, Ann Arbor, MI).
The assay kit involved detection of superoxide radicals generated by xan-
17.8)% on day 3; 5.7 ( 28.6–17.2)%, 27.5 (4.6– 50.4)%, 32.1 (17.2–47.0)%, and 1.5 ( 23.6–26.7)% on day 4; 1.4 (
21.3–24.1)%, 68.1 (41.1–95.1)%, 60.9 (22.6 – 99.2)% and 2.3 ( 29.2–33.8)% on day 5; 17.0 ( 25.4– 8.6)%, 13.8
(7.4–20.3)%, 12.4 (7.7–17.2)%, and 6.5 ( 31.6–18.7)% on day 6; and 10.0 ( 30.9–10.9)%, 18.0 (1.7–34.3)%, 17.7
(3.0–32.4)%, and 2.5 ( 0.1– 5.2)% on day 7, respectively. Curcumin attenuated the percent increase of glutamate
levels by 56-fold than the vehicle group on day 1.
thine oxidase and hypoxanthine using a tetrazolium salt. One unit of SOD was defined as the amount of enzyme
needed to exhibit 50% dismutation of the superoxide radicals.23 SOD concentration was expressed as U/mg protein.
Catalase activity was determined with catalase assay kit (Cayman). The method was based on the reaction of the
enzyme with methanol in the presence of an optimal concen-
Mortality Rate No animal in the sham group (n 22) died after the first SAH induction. The mortality rate was
significantly lower in the curcumin group (8.3%) than in the SAH (35.3%) and vehicle (33.3%) groups: Both P 0.03;
relative risks were 0.58 and 0.59; 95% CI: 0.405 to 0.841 and 0.406 to 0.860, respectively (table 1). tration of H
2
O
2
. The formaldehyde produced was measured colorimetrically with 4-amino-3-hydrazino-5-mercapto-
Neurologic Scores 1,2,4-triazole as the chromogen.23
Catalase activity was ex-
None of the rats showed neurologic injury after
intrathecal pressed as mg n
M
1 min 1 protein.
catheterization. The SAH and vehicle groups had the clini-

Fig. 1. Time-course analysis of extracellular glutamate concentration changes in rats. Percent change of baseline glutamate
levels was lower in the curcumin group versus the subarachnoid hemorrhage and vehicle groups and higher than in the sham
group on days 1, 2, and 3 after subarachnoid hemorrhage. Glutamate concentration in the microdialysates was measured using
high-pressure liquid chromatography and a fluorescence detector. Data are expressed as mean (95% CI) percentage changes
relative to baseline analyzed by two-way ANOVA. * P 0.001 for subarachnoid hemorrhage and vehicle groups versus the sham
and curcumin groups; # P 0.01 for the curcumin versus sham group; n 10, 6, 6, and 8 in the sham, subarachnoid hemorrhage,
vehicle, and curcumin groups, respectively. The curcumin group is subarachnoid hemorrhage rats treated with curcumin; the
vehicle group is subarachnoid hemorrhage rats treated with dimethyl sulfoxide. Cur curcumin; SAH subarachnoid hemorrhage.
cally significant lowest neurologic scores compared with the sham and curcumin rats after SAH induction on day
1[11.0 (136.0–17.4) versus 12.3 (7.5–14.5) versus 15.5 (9.2–15.4) versus 15.8 (14.0 –17.5), respectively; P 0.05],
day 3 [9.2 (14.5–17.3) versus 10.3 (6.7–11.7) versus 15.9 (7.1–13.5) versus 14.4 (12.1–16.6), respectively; P 0.05],
day 5 [9.8 (13.5–16.9) versus 9.6 (7.3–12.3) versus 15.2 (6.7–12.5) versus 15.6 (14.7–16.5), respectively; P 0.05],
and day 7 [13.6 (16.0–17.4) versus 13.4 (10.9–16.3) versus 16.7 (10.6–16.2) versus 15.8 (14.8–16.7), respectively; P
0.05]. Neurologic scores in the curcumin-treated rats increased 31% compared with the vehicle rats. However, the
curcumin group had a clinically lower neurologic score com-
Table 1. Mortality Rate of Rats during Experimental Period
Mortality Rate
Group of Rats
Less than 6 h Day 1 Day 2 Day 4 Total Sham (n 22) 0 0 0 0 0 Subarachnoid
Hemorrhage (n 34) 5 (14.7%) 4 (11.7%) 2 (5.9%) 1 (2.9%) 12 (35.3%)* Vehicle (n 33) 5 (15.2%) 3 (9.1%) 2 (6.1%) 1 (3.0%) 11
(33.3%)* Curcumin (n 24) 1 (4.2%) 1 (4.2%) 0 0 2 (8.3%)
Fisher exact test used. The curcumin group is subarachnoid hemorrhage rats treated with curcumin; the vehicle group is
subarachnoid hemorrhage rats treated with dimethyl sulfoxide. * P 0.03 versus rats in the curcumin group and P 0.002 versus rats
in the sham group.
Anesthesiology 2011; 115:1229–38 1233
Kuo et al.
pared with the sham group only on day 3, after the first SAH induction (fig. 2).
Histologic Examination Representative cross-sectional images of the basilar artery on day 7 after the first SAH
induction are shown (fig. 3A). The mean (95% CI) wall thickness of the basilar artery was thin- ner in the sham
group [27.9 (24.7–31.1) μm] than in the SAH [43.4 (39.5–47.3) μm, P 0.028] and the vehicle group [43.6
(36.1–51.2) μm, P 0.004]. Wall thickness of the basilar artery in the curcumin group [30.3 (19.7–40.9) μm] was
decreased compared with that of the SAH and vehicle groups (P 0.012 and P 0.028, respectively). However, basilar
artery wall thickness in the sham and curcumin groups was similar (fig. 3B). The mean perimeter of the basilar
artery was significantly less in the SAH group [262
Fig. 2. Effect of curcumin on neurologic score after subarachnoid hemorrhage. The curcumin rats exhibited clinically sig-
nificant higher neurologic scores compared with rats in the subarachnoid hemorrhage or vehicle groups. The curcumin rats
showed lower neurologic scores than sham rats only on day 3. * P 0.05 for the subarachnoid hemorrhage and vehicle groups
versus the sham and curcumin groups. # P 0.05 for the sham versus curcumin groups on day 3. All data points were presented as
means (95% CI) of six rats in each group using two-way ANOVA. The curcumin group is subarachnoid hemorrhage rats treated
with curcumin; the vehicle group is subarachnoid hemorrhage rats treated with dimethyl sulfoxide. Cur curcumin; SAH
subarachnoid hemorrhage.

Fig. 3. Effect of curcumin on basilar artery wall thickness after subarachnoid hemorrhage. (A) Representative images of basilar
artery cross-section on day 7. (B) Basilar artery wall was significantly thicker in rats in the subarachnoid hemorrhage and vehicle
groups than rats in the sham and curcumin groups. (C) The mean (95% CI) perimeter of the basilar artery wall was significantly
smaller in the subarachnoid hemorrhage and vehicle groups compared with the sham and curcumin groups. * P 0.01 for the
subarachnoid hemorrhage and vehicle groups compared with the sham and curcumin groups analyzed using one-way ANOVA; n
6 in each group; scale bar 50 μm. The curcumin group is subarachnoid hemorrhage rats treated with curcumin; the vehicle group
is subarachnoid hemorrhage rats treated with dimethyl sulfoxide. BA Basilar artery; Cur curcumin; SAH subarachnoid
hemorrhage.
(199.8–300.0)μm] and the vehicle group [241 (194.9 –290.6) μm] compared with the sham group [304 (270.1–
334.3) μm; P 0.001 and P 0.008, respectively] and curcumin group [292 (239.1–345.1) μm; P 0.019 and P 0.041,
respectively] (fig. 3C). The cerebral vasospasm was attenuated by 30% by wall thickening and by 31% of
perimeter narrowing of the basilar artery compared with the vehicle group.
The morphology of neurons in the dentate gyrus, cornu ammonis 1 and cornu ammonis 3 are shown in figure 4.
Histopathologic analysis revealed that the morphology of neurons in the dentate gyrus, cornu ammonis 1 and cornu
ammonis 3 was normal in the sham group (figs. 4A, E, and I, respectively). The curcumin rats exhibited mild to
moderate degenerative changes in the dentate gyrus, cornu ammonis 1 and cornu ammonis 3 (figs. 4D, H, and L,
respectively). The SAH (figs. 4B, F, and J, respectively) and vehicle (figs. 4C, G, and K, respectively) rats exhibited
moderate to severe degenerative changes in the dentate gyrus, cornu ammonis 1 and cornu ammonis 3 (shrunken
cytoplasm, extensivel dark pyknotic nuclei, dark cells, and vacuolar spaces). The mean (95% CI) degeneration
scores for the sham, SAH, vehicle, and curcumin groups were 3.3 (2.8 –3.8), 8.0 (7.3– 8.7), 7.7 (6.7–8.5), and 4.7
(4.1–5.3), respectively. There was less
Anesthesiology 2011; 115:1229–38 1234
Kuo et al.
neuronal degeneration in the sham and the curcumin groups compared with the SAH and vehicle rats (P 0.001).
There was a clinically significant difference in neuronal degeneration between the sham and curcumin groups (P
0.05). The neuronal degeneration score attenuated 39% compared with the vehicle group.
Western Blot Analysis of GLT-1 The mean (95% CI) GLT-1 expression in the hippocampus (fig. 5A) and cortex
(fig. 5B) of the SAH group [70.0 (0.53– 0.87)% and 87.0 (0.74 –1.0)%] and the vehicle group [69.0 (0.59–0.81)%
and 81.0 (0.69–0.93)%] were decreased compared with the sham (P 0.002, P 0.003, P 0.017 and P 0.012,
respectively) and curcumin (P 0.001, P 0.002, P 0.019 and P 0.036, respectively) rats. There was no clinically
significant difference between the sham and curcumin rats [99.0 (0.84 –1.14)% and 92.0 (0.72–1.12)%] in GLT-1
expression.
Malondialdehyde, SOD and Catalase The mean (95% CI) contents of malondialdehyde (n
M
/g tissue) in the hippocampus and cortex were increased in
SAH

Fig. 4. Effect of curcumin on hippocampus neuronal degeneration after subarachnoid hemorrhage. The samples were obtained
from rats on day 7. The rats in the sham group showed no neuronal degeneration in the dentate gyrus, cornu ammonis 1 or cornu
ammonis 3 (A, E, and I, respectively). In the rats in the subarachnoid hemorrhage group (B, F, and J) and vehicle group (C, G,
and K), there was moderate to severe neuronal degeneration in the dentate gyrus, cornu ammonis 1, and cornu ammonis 3. In the
curcumin group, there was normal to mild neuronal degeneration in the dentate gyrus, cornu ammonis 1, and cornu ammonis 3
(D, H, and L, respectively). Normal neuron cell bodies with distinct nuclei and nucleoli are evident. Degenerated neurons have
pyknotic nuclei, dark cells, and vacuolar spaces (indicated with arrows). Magnified at 400x; n 6 in each group; scale bar 50 μm.
The curcumin group is subarachnoid hemorrhage rats treated with curcumin; the vehicle group is subarachnoid hemorrhage rats
treated with dimethyl sulfoxide. CA1 cornu ammonis 1; CA3 cornu ammonis 3; Cur curcumin; DA dentate gyrus; SAH
subarachnoid hemorrhage.
[733.2 (509.7–956.6) and 471.4 (278.2–664.7)] and vehicle [743.2 (537.4–949.0) and 452.2 (254.2–650.1)] rats
compared with the sham rats [317.1 (290.5–343.6) and 211.7 (147.5–276.0)] on day 7 after SAH induction (P 0.001,
P 0.002, P 0.028, and P 0.025, respectively). Treatment with curcumin decreased malondialdehyde con- tent
compared with the SAH and vehicle rats in the hippocampus [496.3 (437.0 –555.5)] and cortex [259.7 (229.5–
290.0)] (P 0.01, P 0.034, P 0.048, and P 0.031, respectively). The malondialdehyde levels in the hippocampus and
the cortex were attenuated by 30% and 50% compared with the vehicle group (figs. 6A and B).
The mean (95% CI) SOD levels (U/mg protein) in the hippocampus and cortex were decreased in SAH [18.8
(17.0 –20.5) and 23.2 (20.2–26.2)] and vehicle [19.0 (15.5– 22.4) and 19.7 (13.6–25.8)] rats compared with the
sham rats [31.1 (18.3– 43.9) and 35.9 (21.4 –50.4)] on day 7 after SAH induction (P 0.006, P 0.009, P 0.004, and P
0.007, respectively). Treatment with curcumin preserved SOD levels in the hippocampus [25.7 (23.2–28.2)] and cor-
tex [32.2 (30.8 –33.5)] compared with the SAH and vehicle rats (P 0.032, P 0.023, P 0.001, and P 0.027,
respectively). The SOD activity in the hippocampus and the cortex were increased by 35% and 64% compared with
the vehicle group (figs. 6C and D).
The mean (95% CI) catalase activities (mg n
M
1 min 1 protein) in the hippocampus and cortex were decreased in
SAH [4.6 (3.5–5.7) and 6.4 (5.4–7.5)] and vehicle [4.9
Anesthesiology 2011; 115:1229–38 1235
Kuo et al.
(4.5–5.3) and 6.2 (5.3–7.1)] rats compared with the sham rats [8.4 (7.9 – 8.8) and 10.4 7.6 –13.2)] on day 7 after
SAH induction (P 0.001, P 0.001, P 0.001, and P 0.001, respectively). Treatment with curcumin significantly
preserved the decreased catalase levels in the hippocampus [6.6 (5.2–8.0)] and cortex [8.6 (7.9–9.3)] compared with
the SAH and vehicle rats (P 0.022, P 0.026, P 0.024, and P 0.042, respectively). The catalase activity in the
hippocampus and the cortex were increased by 34% and 39% compared with the vehicle group (figs. 6E and F).
Discussion We showed that postinjury intraperitoneal administration of curcumin significantly attenuated the
glutamate surge and preserved GLT-1 expression. It also attenuated the increase in malondialdehyde and preserved
SOD and catalase activities. The basilar artery wall thickening was attenuated, but the basilar artery wall perimeter
was preserved. Curcumin also reduced mortality rate and improved neurologic score after SAH induction.
The Effect of Curcumin on Glutamate Production and GLT-1 Expression Curcumin attenuated glutamate levels
from day 1 to day 7 after SAH. It is well established that a high extracellular glutamate concentration causes
neuronal damages.24 In- creased release or decreased uptake of glutamate have neuro-

Fig. 5. Western blot analysis of glutamate transporter-1 in hippocampus (A) and cortex (B). Western blot analysis showed a
decrease in glutamate transporter-1 in rats in the subarachnoid hemorrhage and vehicle groups, but not in the curcumin group. * P
0.05 for subarachnoid hemorrhage and vehicle groups versus sham group. # P 0.05 for curcumin group versus subarachnoid
hemorrhage and vehicle groups. All data were analyzed using one-way ANOVA; n 6. The curcumin group is subarachnoid
hemorrhage rats treated with curcumin; the vehicle group is subarachnoid hemorrhage rats treated with dimethyl sulfoxide. Cur
curcumin; GLT-1 glutamate transporter-1; SAH subarachnoid hemorrhage.
toxic effects.25 In this study, curcumin attenuated glutamate levels after SAH, which may explain the
neuroprotective effect.
Germano et al.26 showed that N-methyl-
D
-aspartate excitotoxicity is involved in the central dysfunction after
SAH, and a N-methyl-
D
-aspartate receptor antagonist re-
Fig. 6. Effect of curcumin on oxidative stress after
subarachnoid duced behavioral deficits. In our previous study, an increase in glutamate level, down-regulation of
GLT-1 expression, and neuronal degeneration were also observed after SAH.7 In addition, previous studies27,28
reported
hemorrhage. (A and B) The malondialdehyde levels in hippocampus and cortex were lower in rats in the curcumin group than in
rats in the subarachnoid hemorrhage and vehicle groups, but not than the rats in the sham group. (C and D) The superoxide
dismutase activities in hippocampus and cortex that curcumin has a concentration- and time-dependent
were higher in the curcumin group than in
subarachnoid hem- neuroprotective effect against glutamate toxicity in rat
orrhage and vehicle groups, but not than the sham
group. (E cerebral cortical neurons in vitro. These reports are consistent with our in vivo study, as we showed that
curcumin attenuated glutamate levels after SAH and improved survival and neurologic functions.
The preserved GLT-1 expression observed in this study
and F) The catalase activities in hippocampus and cortex were higher in the curcumin group than in subarachnoid hemorrhage
and vehicle groups, but not than the Sham group. Data were expressed as mean (95% CI) and measured on day 7 after
subarachnoid hemorrhage. * P 0.05 for subarachnoid hemorrhage and vehicle groups versus sham group. # P 0.05 for may
explain the attenuated glutamate levels after SAH. Re-
curcumin group versus subarachnoid hemorrhage and
vehicle cently, it was suggested that increased GLT-1 expression or
groups. P values were analyzed using one-way
ANOVA; n 6 activity attenuates glutamate excitotoxicity in primary human fetal astrocytes.8Reduced glutamate
uptake contributed to the elevation of extracellular glutamate because of a reduction in GLT-1 expression by
astrocytes.29,30 Ouyang et al.31
in each group. The curcumin group is subarachnoid hemorrhage rats treated with curcumin; the vehicle group is subarachnoid
hemorrhage rats treated with dimethyl sulfoxide. Cur curcumin; MDA malondialdehyde; SAH subarachnoid hemorrhage; SOD
superoxide dismutase. found that up-regulation of GLT-1 expression protected CA1 neurons from forebrain ischemia. Therefore,
we suggest that the neuroprotective effect of curcumin may be exerted via preserved GLT-1 expression and removal of excess
glutamate after SAH.
Anesthesiology 2011; 115:1229–38 1236
Kuo et al.
The Effect of Curcumin on Neurologic Outcome and CVS Recent studies on rats and gerbils have demonstrated the
neuroprotective effect of curcumin against cerebral ischemic injury. A single dose of curcumin (200 mg/kg,
intraperito-

Anesthesiology 2011; 115:1229–38 1237 Kuo et al. neally) 30 min after ischemia significantly reduced the isch-
Disruption of the blood-brain barrier after SAH has been emia/reperfusion-induced oxidative stress.14 Moreover, in
a
reported.26In this condition, the permeability of the
brain to global cerebral ischemia model induced in Mongolian gerbils
curcumin may be higher than normal. Further
investigation by transient occlusion of the common carotid arteries, a sin-
is needed to associate the duration of the
neuroprotective gle dose of curcumin (30 mg/kg, intraperitoneally) signifi-
effect of curcumin after brain injury with the dosage
admin- cantly attenuated ischemia-induced neuronal death.15 In ad-
istered. However, extrapolation of the results of
neurologic dition, single intraperitoneal injection curcumin doses (100
treatments from rats to humans is seldom successful.
or 300 mg/kg) 30 min after middle cerebral artery occlusion
This study has limitations. We did not examine
astrocyte in rats resulted in a clinically significant reduction of infarct
or measure their GLT-1 activity directly; therefore, we
can- volume and edema in a dose-dependent manner.32,33 Most
not verify the relationships between astrocytes,
extracellular of these studies explored the effect of curcumin on ischemic
glutamate levels, GLT-1 expression, and neuronal
damage stroke. Only one study, by Wakadeet al.,3demonstrated that
after SAH. Multiple varieties of GLT-1 function after
brain a single intraperitoneal injection of curcumin (150 or 300
ischemia have been reported, and changes in GLT-1
func- mg/kg) attenuated CVS after experimental SAH via an anti-
tion may influence extracellular glutamate
concentration and oxidant effect. In this study, we used multiple doses of cur-
the associated neuronal damage. The second limitation
was cumin, which resulted in significantly improved survival rate
that we did not examine the antioxidant effect of
curcumin and neurologic scores. This might be associated with atten-
on glutamate transporters, but it is known that
glutamate uation of glutamate level and increase in malondialdehyde
transporters activity is inhibited by oxidative damage
caused level, as well as preserved SOD and catalase activities after
by reactive oxygen species and lipid peroxidation
products.9 SAH. In addition, we demonstrated that the basilar artery
Therefore, neuronal injury is mostly associated with
oxida- wall thickening and the perimeter were significantly pre-
tive stress and glutamate-induced neurotoxicity, with
cross served after SAH induction in curcumin-treated rats, which
talk between the two phenomena. Further studies are
war- may also have contributed to the neurologic outcome and
ranted to explore the relationships among the variables
used survival rate. Our results are consistent with those of previous
in this study. studies showing that a pharmacological
approach involving
In conclusion, we have shown that treatment with
multi- an antioxidant effect is a potential strategy for treatment of CVS after SAH.2– 4
ple intraperitoneal doses of curcumin after SAH reduced the mortality rate, and improved functional and histologic
out- comes after SAH in rats. Possible mechanisms responsible for The Dosage of Curcumin A wide range of
curcumin doses has been used in experimental brain ischemia studies (30–300 mg/kg, intraperitone-
ally).3,14,15,32,33 Huang et al.34 reported that a single dose of curcumin (20 or 40 mg/kg, intraperitoneally) was
effective in
these effects include attenuation of glutamate level via preservation of GLT-1 protein expression, attenuation of the
increase in malondialdehyde level, and preservation of SOD and catalase activities. Curcumin could be a potential
treatment for SAH in humans. inhibiting the increase in glutamate level in the hypothalamus during
lipopolysaccharide -induced systemic inflammation in rabbits. In addition, Chen et al.35 reported that a
The authors thank Mei-Yu Chuang, M.D., Ph.D., F.A.C.C., F.S.C.A.I., F.A.S.A., Medical Director of Cardiology Department,
Bethany Med- ical Center, High Point, North Carolina, for reviewing the manu- single intraperitoneal injection of curcumin (20
mg/kg) attenuated airway hyperreactivity induced by ischemia-reperfusion of the pancreas in rats. Moreover, inflammation
may
script, and Meei-Shyuan Lee, Ph.D., Professor, School of Public Health, National Defense Medical Center, Taipei, Taiwan,
Republic of China, for statistic consultation.
be a common pathogenic pathway in CVS after SAH and may persist for days.36 Based on these studies, we
prescribe curcumin (20 mg/kg, intraperitoneally) within 3 h of SAH and then daily for 6 days thereafter.
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Neuroprotective Effect of Curcumin in an Experimental Rat

Background: Subarachnoid hemorrhage (SAH) causes a

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