Journal of Behavioral and Brain Science, 2013, 3, 100-106 Published Online February 2013 (
Statins Protect the Blood Brain Barrier Acutely after
Experimental Intracerebral Hemorrhage*
Dongmei Yang1#, Robert A. Knight2,3#, Yuxia Han1, Kishor Karki2,3, Jianfeng Zhang1,
Michael Chopp2,3, Donald M. Seyfried1
1Departments of Neurosurgery, Henry Ford Health System, Detroit, USA
2Departments of Neurology, Henry Ford Health System, Detroit, USA
3Departments of Physics, Oakland University, Rochester, USA
Received November 2, 2012; revised December 3, 2012; accepted December 10, 2012
Objectives: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain
barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was induced in 27
male Wistar rats by stereotactic injection of 100 μL of autologous blood into the striatum. Rats were divided into three
groups (n = 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phos-
phate buffered saline daily starting 24-hour post-ICH and continuing daily for the next 3 days. On the fourth day, the
animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2
(edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blot-
ting was performed. Results: MRI data for animals receiving simvastatin treatment showed significantly reduced BBB
dysfunction and improved CBF in the ICH rim compared to controls (P < 0.05) 4 days after ICH. Simvastatin also sig-
nificantly reduced edema (T2) in the rim at 4 days after ICH (P < 0.05). Both statin-treated groups demonstrated in-
creased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB
function (P < 0.05) and increased number of blood vessels (P < 0.05). Conclusions: Simvastatin treatment administered
acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also
evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by
MRI measurement.
Keywords: Intracerebral Hemorrhage; Atorvastatin; Occludin; Simvastatin; Blood Brain Barrier
1. Introduction
Blood-brain barrier (BBB) dysfunction following intra-
cerebral hemorrhage (ICH) is assumed to contribute to
brain injury [1]. Both animal models and human studies
show that BBB disruption occurs acutely after ICH [2-5].
The mechanisms of BBB breakdown that underlie the
progression of ICH are only partially known [5], but re-
searchers have shown that BBB disruption increases ce-
rebrovascular permeability, thereby allowing the entrance
of potentially neurotoxic compounds and leukocytes into
the brain parenchyma which can in turn cause edema
formation [1,4]. The extent of edema along with the lar-
ger hematoma volume correlates with high mortality and
poor prognosis after ICH [6]. Current surgical and medi-
cal approaches for ICH treatment have been ineffective
[7], therefore, a strategy aimed at early BBB protection
after ICH would be a useful therapeutic advance.
Statins or 3-hydroxy-3-methyl-glutaryl-coenzyme A
(HMG-CoA) reductase inhibitors are widely employed as
potent inhibitors of cholesterol biosynthesis [8]. When
administered after ischemic stroke or traumatic brain in-
jury (TBI), these agents have been shown to provide neu-
roprotection with beneficial effects on the neuronal and
neurovascular systems [9-11]. This has been presumed to
be due to the capacity of statins to improve or restore en-
dothelial function, enhance angiogenesis and neurogene-
sis, increase the stability of atherosclerotic plaques, and
decrease oxidative stress and vascular inflammation [8,9].
In previous laboratory studies, we found that both atorva-
statin and simvastatin enhanced functional outcome and
promoted vascular recovery 4 weeks after ICH [12,13];
however, it is not known if statins can protect the BBB
from injury during the early stages of ICH. To test the
hypothesis that statins significantly protect BBB integrity
acutely and/or ameliorate the increases in BBB perme-
*Supported by: National Institute of Health grant RO1 NS05858101
#Both authors contributed equally to this work.
opyright © 2013 SciRes. JBBS
D. M. YANG ET AL. 101
ability often noted after ICH, we investigated the early
effects of atorvastatin and simvastatin in an experimental
ICH model. We also measured other mechanisms that
might be responsible for such an effect.
2. Materials and Methods
2.1. Experimental Model
All experimental procedures were approved by Henry
Ford Hospital’s Institutional Animal Care and Use Com-
mittee (IACUC No. 1061). Twenty-seven adult male
Wistar rats (270 - 330 g) were anesthetized intraperito-
neally with ketamine (90 mg/kg) and xylazine (5 mg/kg).
They were then subjected to ICH by direct infusion of
100 µl autologous whole blood into the striatal region ad-
jacent to the subventricular zone (SVZ) [14-16]. After
ICH, the animals were randomly assigned to atorvastatin
(2 mg/kg), simvastatin (2 mg/kg) or phosphate-buffered
saline (PBS; control) treatment groups (n = 9/group).
Treatment was given by oral gavage starting 24-h post-
ICH and continued daily for 3 days. Three rats from each
group were selected and sacrificed at 4 days after ICH
for Western blot. The remaining 6 rats in each group re-
ceived daily injections of bromodeoxyuridine (BrdU)
100 mg/kg (Sigma) from 1 to 4 days post-ICH, intraperi-
2.2. MR Imaging and Analysis
MRI measurements were performed 4 days after ICH, us-
ing a 7 Tesla, 20-cm bore superconducting magnet (Mag-
nex Scientific, Inc. Palo Alto, CA) interfaced to a Bruker
Avance console running Paravision 3.0.2 (Bruker Bio-
spin MRI, Billerica, CA) [13,14]. The imaging protocol
employed used a 32-mm field of view (FOV). Briefly,
the protocol included estimates of the following: 1) cere-
bral blood flow (CBF); 2) spin-spin relaxation times (T2);
3) spin-lattice relaxation times measured in the presence
of off-resonance saturation of the bound proton signal
(T1sat); and 4) estimates of post-ICH induced changes in
the blood-to-brain transfer constant (Ki). The Ki estimates
were obtained using an MR contrast agent (Gd-DTPA:
0.2 mmol/kg body wt) that was administered by bolus
injection via a tail vein during sequential MRI measure-
The CBF estimates were acquired using an arterial
spin labeling technique [17]. This technique is based on
the selective inversion of inflowing blood water protons
at the level of the carotid arteries prior to MRI measure-
ment in the brain. The inversion pulse was applied for 1 s
at a B1 amplitude of 0.3 kHz, and had a frequency offset
of ± 6 kHz. It was followed by an SE sequence with TR/
TE = 1060 ms/40 ms. Four averages of the image were
acquired with the gradient polarities and the RF pulse
frequency offsets reversed to remove any gradient asym-
metries in the axial direction. The labeled slice was lo-
cated approximately 2 cm distal to the imaging slice. The
imaging slice was 2-mm thick and was acquired using 64
× 64 matrix. Total time for the entire series was 17 min
55 s.
The T2 estimates were measured using a standard Carr-
Purcell-Meiboom-Gill (CPMG) multi-slice (13 slices each
of 1-mm thickness) multi-echo (6 echoes) MRI sequence.
Echo times (TEs) were 15, 30, 45, 60, 75 and 90 ms, and
repetition time (TR) was 5.0 s. Images were produced
using a 128 × 64 matrix.
The T1sat estimates were acquired using an imaging
variant of the T-one by multiple readout pulses (TOM-
ROP) sequence [18,19]. This was done by inserting two
continuous wave (CW) RF saturation pulses into the
Look-Locker sequence: the first (4.5 s long) immediately
before the inversion pulse and the second (40 ms long)
after the signal acquisition. The offset frequency of the
saturation pulses was 8 kHz, and the rotational frequency
of the B1 field was 0.5 kHz. Initially, the longitudinal
magnetization was inverted using an 8 ms non-selective
adiabatic hyperbolic secant pulse. One phase encode line
of 32 small-tip angle gradient echo images (TE = 7.0 ms)
was acquired at 80-ms intervals after each inversion.
With this sequence, a single 2-mm thick slice T1sat map
was obtained in ~9 min (TR = 8 s, 128 × 64 matrix).
The MR data were transferred to a Unix-based system
for image processing and analysis. All MR images were
reconstructed using a 128 × 128 matrix. Regions of in-
terest (ROIs) representing hematoma core and adjacent
rim were identified by windowing T2 values. All other
MRI parameter maps were coregistered to the T2 maps.
The MRI parameters were measured in these selected
ROIs and the corresponding contralateral regions, and
are reported as ipsilateral/contralateral ratios.
2.3. Immunohistochemistry
All animals were sacrificed 4 days post-ICH following
MRI for either Western blot or immunohistochemical
analysis. Endothelial barrier antigen (EBA) (1:1000 dilu-
tion; Sternberger Monoclonals, Baltimore, MD), and oc-
cludin (1:200 dilution; Invitrogen, Carlsbad, CA) immu-
nostaining were performed as described previously [16].
All immunostainings were performed at the same time
with two negative controls (i.e., the omission of primary
antibody and the use of pre-immune serum) for quality
control of the immunoassaying procedure. To determine
whether BrdU-immunoreactive endothelial cells express
EBA, double immunohistochemical staining was used to
identify BrdU (1:100 dilution; Boehringer, Indianapolis,
IN) with the endothelial marker. The tissues were coun-
terstained with 0.1 mg/ml DAPI (Sigma, St. Louis, MO)
Copyright © 2013 SciRes. JBBS
in PBS for 5 min at room temperature.
For quantitative measurements of occludin and EBA, 6
immunostained coronal sections and 8 fields of view
from the striatum in each section were digitized under a
20× objective (Olympus BX40) using a 3-color CCD
video camera (Sony DXC-970MD) interfaced with an
MCID image analysis system (Imaging Research). The
data are presented as a percentage of positive occludin
immunoreactivity area in the border and the average ves-
sel number per square mm. The proportions of BrdU+
endothelial cells were calculated based on the total num-
ber of BrdU+ endothelial cells (EBA+/BrdU+/DAPI+)
and the total number of endothelial cells (EBA+/DAPI+)
in 20 vessels adjacent to the hematoma from each rat.
2.4. Western Blots
To confirm the immunostaining data and to measure oc-
cludin expression, Western blot assays were performed.
Homogenates of tissue samples taken from the border
zone around the hematoma were obtained at 4 days after
ICH. The protein concentrations of extracts were tested
using a BCA protein assay reagent kit (Pierce, Rockford,
IL). Equal amounts of protein for each group were as-
sayed by SDS/PAGE and transferred to PVDF mem-
branes. The blots were developed with enhanced chemi-
luminescence (Pierce), digitally scanned (GS-700, Bio-
Rad), and analyzed (Molecular analystR, Bio-Rad). Anti-
β-actin antibody (Santa Cruz, Santa Cruz, CA) was used
as a control.
2.5. Statistical Analysis
An analysis of variance (ANOVA) procedure was used
to evaluate the ipsilateral/contralateral values of MR pa-
rameters at 4 days post-ICH and the results of the im-
munohistological measures of EBA and occludin expres-
sions between statin-treated and control groups. Data are
reported as mean ± standard error of the mean (SEM).
Statistical significance was inferred at P 0.05. All mea-
surements were performed by observers blinded to indi-
vidual treatments.
3. Results
3.1. MR Imaging
Representative CBF, T2, T1sat maps from control, ator-
vastatin- and simvastatin-treated animals at 4 days post-
ICH are shown in Figure 1. The CBF maps indicate that
treatment with statins increased blood flow particularly
along the periphery or outer boundary of the central core
region when compared to controls. Quantitative analysis
showed that the ipsilateral/contralateral CBF ratios in the
rim significantly increased after simvastatin treatment
(Figure 2). The control group T2 maps showed a bright
Figure 1. Representative cerebral blood flow (CBF), T2,
T1sat maps obtained from control (left panel), atorvastatin-
treated (middle panel), and simvastatin-treated animals
(right panel) at 4 days post-ICH. The CBF maps (upper
panel) indicate treatment with statins increases blood flow
particularly in the central core region when compared with
control. The T2 maps (center panels) in control group show
a bright central core region (high T2) and adjacent sur-
rounding dark rim (low T2). Conversely, T2 results for the
statin-treated animals showed a less intense response in the
core region (i.e. lower T2 values) relative to the rim area
than seen in control animals. The T1sat maps (lower panels)
show the decreased BBB permeability in the core region of
the statin-treated animals.
central core region (high T2) and an adjacent surrounding
dark rim (low T2). In comparison, the T2 results for the
statin-treated animals showed a less intense response in
the core region (i.e. lower T2 values) relative to the rim
area than in control animals. Finally, the T1sat maps
showed decreased T1sat values in the ICH border region
of the statin-treated animals indicative of lower BBB per-
meability relative to control rats. Additionally, statistical
analysis demonstrated that the ipsilateral/contralateral T2
and T1sat ratios significantly decreased in the rim after
simvastatin treatment relative to controls (Figure 2).
These findings suggest that simvastatin increases CBF,
decreases edema and modulates BBB permeability dur-
ing the acute phase of ICH. Although atorvastatin treat-
ment showed trends dissimilar to simvastatin treatment in
its effects, the differences were not significant.
3.2. Occludin Expression
To clarify how statins may protect the BBB after ICH,
the tight junction protein occludin was studied by immu-
nofluorescent staining and immunoblotting 4 days after
ICH. Occludin was expressed in the intima of cerebral
capillaries and was dramatically increased in the boun-
dary area around the hematoma after both statin treat-
ments (Figure 3). In agreement with immunohistoche-
mistry results, Western blotting showed that the expres-
sion level of occludin in the border zone of animals in
both statin-treated groups increased at the designated time
Copyright © 2013 SciRes. JBBS
Copyright © 2013 SciRes. JBBS
point, when compared to controls (Figure 4). study also revealed that both statins can promote angio-
genesis as early as 4 days after ICH.
3.3. Angiogenesis More detailed experimental and clinical evidence con-
tinues to accumulate regarding the efficacy of statins for
treatment of ICH. An earlier study indicated that 2 mg/kg
atorvastatin significantly reduced neurological deficits at
2 weeks to 4 weeks after experimental ICH, while higher
doses of 8 mg/kg did not improve functional outcome or
lessen brain damage [15]. In a collagenase ICH model,
EBA immunohistochemical staining provides a sensitive
and reliable index for cerebral vessels [20]. Angiogenesis
was observed after brain injury, and characterized by
enlarged vascular perimeters and capillaries sprouting
from preexisting blood vessels as well as increased mi-
crovessel density and newly formed endothelial cells. In
the current study, the boundary area around the hema-
toma in both statin-treated groups showed an up-regula-
tion in the intensity of immunoreactivity to EBA (Figure
5). The distribution of EBA immunoreactivity in other
regions of statin-treated brain tissue appeared similar to
that of control animals. A significant increase in the
number of cells co-stained with EBA and BrdU was also
observed in the same area in statin-treated animals, when
compared to control animals (Figure 6).
4. Discussion
2 T
The present study demonstrates that simvastatin treat-
ment significantly protects BBB integrity, reduces edema
and improves CBF as measured by MRI during the acute
phase after experimental ICH. Atorvastatin showed a
non-significant trend by MRI measurement, although
both statins induced increased expression of the tight
junction protein occludin in the boundary zone. This
Figure 2. Plots of ipsilateral/contralateral ratio values for
cerebral blood flow (CBF), T1sat and T2 at 4 days after
intracerebral hemorrhage (ICH) for control, atorvastatin-
and simvastatin-treated rats. The data indicate that treat-
ment with simvastatin significantly increased CBF, and de-
creased T1sat and T2 values in the rim compared with the
control group. *P < 0.05.
Figure 3. Effects of statin on the tight junction protein occludin. The left and middle panels show occludin immuno-reactivity
in the ICH boundary are a of representative rats treate d with PBS and simvastatin, respec tively. The r ight panel show s quan-
titative estimates of occluding-positive cells expressed as a percentage of area in the ICH boundary (mean ± SEM) zone for all
three groups. Both statin-treated groups showed significant increases in occludin expression compared to controls (*P < 0.05).
Figure 4. Western blot data are shown for tissue samples taken from the ICH border zone of c ontrol and statin-treated ani-
mals. Occludin protein expression in the hemorrhagic brain tissue endothelial cells was increased in the statin-treated rats
ompared to controls. c
Jung et al., found that 1 mg/kg or 10 mg/kg atorvastatin
promoted sensorimotor recovery after 2 weeks and the
effects persisted up to 4 weeks [21]. Several retrospective
and prospective studies indicated that the ICH patients on
statins had better outcome in comparison to those with-
out statins [22-26]. While the study of the Stroke Preven-
tion by Aggressive Reduction in Cholesterol Levels
(SPARCL) demonstrated an increased risk of ICH in pa-
tients treated with high doses of atorvastatin, the overall
effect was deemed to be one of clinical benefit [27]. Our
present result shows that treatment with 2 mg/kg/day
statin for 4 days protected the BBB after ICH, while ex-
pansion of the hematoma was not observed by either
MRI or histology. These data suggest that a low dose of
statin during the acute phase of ICH might be optimal to
achieve therapeutic effects without secondary hemor-
The BBB after ICH is disrupted by perihematomal in-
jury and the subsequent inflammatory cascades initiated
by coagulation products and toxic blood breakdown pro-
ducts [1]. The autologous whole blood ICH model has
been shown to mimic the mechanism of BBB disruption
[28]. The onset of BBB dysfunction was observed to oc-
cur at 12 h to 48 h after ICH in this model [2]. The cur-
rent study demonstrated that statin treatment starting 24 h
post-ICH and persisting through Day 4 attenuated brain
edema formation and BBB permeability. The post-ICH
intervention with statins provided rapid BBB protection;
this ultimately may alleviate intracranial complications
and promote the improved functional outcome which is
observed in these experimental models.
The immunohistochemistry portion of the study sup-
ports the concept of endothelial cell-mediated function of
the BBB integrity. Tight junctions linking the cerebral
endothelial cells play a vital role in BBB function by
limiting diffusion of compounds from the systemic cir-
culation to brain parenchyma [29]. Occludin is one of the
important transmembrane proteins of tight junctions that
are essential for maintenance of the BBB integrity [30].
Decreased expression of occludin correlated with disru-
pted BBB function in neurological injuries [31,32]. Our
results indicated that animals treated with statins after
ICH have elevated occludin protein levels relative to
controls, which is associated with improved BBB in-
tegrity. It is unclear, however, whether the increased pro-
tein level is due to enhanced occludin synthesis or its
protection from breakdown.
Angiogenesis can begin at 12 h to 24 h after experi-
mental ischemic stroke, and clinical data suggest that it is
present three to four days after ischemic stroke [33,34].
In parallel, our study showed that after 4 days of statin
treatment the number of vessels and proliferating endo-
thelial cells were increased in the boundary zone around
Figure 5. Analysis for proliferating endothelial cells. The
upper panels show BrdU (left) and EBA (right) immu-
nostaining. Merged BrdU and EBA images are presented in
the lower left panel, showing colocalization of BrdU-EBA
for a subpopulation of cells located near the injured site for
a simvastatin-treated animal. Arrows indicate the cells that
stained positively for both BrdU and EBA. Quantitative
measures of the percentage of BrdU-positive endothelial
cells (mean ± SEM) are presented as bar graphs in the
lower right panel. The statin-treated rats showed significant
increases in BrdU expression compared to controls (*P <
Figure 6. Effects of simvastatin on the blood-brain barrier in the ICH boundary zone. The left and middle panels show EBA
immunoreactivity in the ICH boundary are a of representative rats treated with PBS and simvastatin, respectively. The right
panel shows quantitative measures of EBA immunoreactive vessels for all three groups with significant increases in EBA
expression in the statin-treated animals as compared to controls (*P < 0.05).
Copyright © 2013 SciRes. JBBS
D. M. YANG ET AL. 105
the hematoma suggesting that angiogenesis can occur as
early as 4 days after ICH. We reason that these increased
CBF levels observed by MRI may be attributed partially
to ongoing angiogenesis.
Our previous study demonstrated that both simvastatin
and atorvastatin provided similar neuroprotective and
neurorestorative effects at 4 weeks post-ICH [12]. Never-
theless, current MRI studies suggest that at the same dose
simvastatin-based therapy was more effective than ator-
vastatin-based therapy in achieving acute efficacy via
BBB protection or improving CBF at 4 days post-ICH.
The differences between the two statins could be due to
their intrinsic differences in plasma life and permeability
across the BBB with simvastatin having greater lipo-
philic properties [35,36]. Whether higher doses or longer
administration times would render atorvastatin as effec-
tive as simvastatin is unknown and requires further study.
In conclusion, simvastatin demonstrated therapeutic
potential in acute treatment of ICH as seen in this ex-
perimental model. Increased expression of tight junction
proteins and the early observation of angiogenesis may
represent important mechanisms for the efficacy of sim-
vastatin in ICH.
5. Acknowledgements
We would like to thank Susan E. MacPhee-Gray for edi-
torial assistance.
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