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Introduction
Cysteinyl leukotrienes (CysLT, including leukotriene
C4 [LTC4], LTD4, and
LTE4), 5-lipoxygenase metabolites of
arachidonic acid, are potent inflammatory mediators and are involved in cerebral
ischemia[1,2] and brain
trauma[3]. The actions of CysLT are mediated by G protein-coupled receptors, namely the
CysLT1 and CysLT2
receptors[4]. Recently, we reported that
the pre-ischemic or postischemic treatment with the
CysLT1 receptor antagonists, pranlukast
and monte-lukast, protect against cerebral ischemia in rats and
mice[5_8]. Pranlukast also exerts a protective effect on
N-methyl-D-aspartate (NMDA)-induced brain injury in
mice[9]. Moreover, we have found that the expression of the
CysLT1 receptor is increased in the brain
after focal cerebral ischemia in rats and
mice[10,11] or NMDA injury in
mice[9]. The expression of the
CysLT1 receptor is induced in the neuron- and glial-appearing cells in the human brain by traumatic
injury[12]. These findings indicate that the
CysLT1 receptor mediates brain injury. However, the exact changes in the
CysLT1 receptor expression in the brain with traumatic
injury are still unknown.
To clarify the role of the CysLT1 receptor in traumatic
brain injury (TBI), we recently investigated the effect of
pranlukast on brain cryoinjury. Brain cryoinjury (also called
cold injury) is a well-established model that can mimic some
of the characteristics of TBI and the related repair responses;
for example, vasogenic brain
edema[13,14],
inflammation[15_19], and the disruption of the blood-brain barrier
(BBB)[20,21]. We found that pre-injury treatment with pranlukast
dose-dependently protected mouse brain from cryoinjury, suggesting
that the CysLT1 receptor might mediate
TBI[22]. However, it is not known whether pranlukast exerts protective effects
when it is administered after cryoinjury, and how the
CysLT1 receptor expression changes after cryoinjury. Because most
pathophysiological changes of TBI are similar to those of
cerebral ischemia[23], we hypothesize that the
CysLT1 receptor may have changes after TBI, similar to those after
cerebral ischemia, and postinjury treatment with pranlukast may
have protective effects on TBI.
To test this hypothesis, in the present study we observed
the expression and localization of the
CysLT1 receptor in the mouse brain, and further investigated the time-dependent
effect of pranlukast on cryoinjury. As a positive control,
minocycline, a semi-synthetic tetracycline with central
anti-inflammatory activity[24,25], was used in this study because it
can protect mice against TBI[26].
Materials and methods
Materials Pranlukast was a gift from Dr Masami
TSUBOSHIMA (Ono Pharmaceutical Co, Osaka, Japan).
Minocycline was purchased from Syowa Hakko (Tokyo,
Japan). Chloral hydrate, biotinylated anti-mouse IgG
antibody, and 2,3,5-triphenylterazolium chloride (TTC) were
from Sigma (St Louis, MO, USA). The reagents for RT-PCR
were from TaKaRa (Kyoto, Japan). The polyclonal rabbit
anti-human CysLT1 antibody was from Cayman Chemicals
(Ann Arbor, MI, USA). The mouse monoclonal antibodies
against neuronal nuclei (NeuN), glial fibrillary acidic protein
(GFAP) and CD11b, GAPDH, fluorescein isothiocyanate
(FITC)-conjugated goat anti-rabbit IgG, and Cy3-conjugated
goat anti-mouse IgG were from Chemicon International
(Temecula, CA, USA). Biotinylated goat anti-rabbit IgG,
horseradish peroxidase streptavidin and
3,3'-diaminobenzi-dine (DAB) were from Zhongshan Biotechnology (Beijing,
China).
Animals Male Kunming mice weighting 25_30 g
(Shang-hai Experimental Animal Center, China, Certificate
No 22-001004) were used in this study. All experiments were
carried out in accordance with the National Institute of Health
Guide for the Care and Use of Laboratory Animals. The mice
were housed under a controlled temperature (22±1 °C), 12 h
light/dark cycle, and allowed free access to food and water.
Cryoinjury and drug treatment The mice were
anesthetized with an ip injection of chloral hydrate (400 mg/kg) and
placed on a stereotaxic frame (SR-5, Narishige, Tokyo, Japan).
Brain cryoinjury was induced according to a reported
method[18] with modifications. Briefly, the scalp was incised
on the midline to expose the skull. A metal probe (100 g in
weight, 3 mm tip diameter) cooled in liquid nitrogen was
applied to the surface of the intact skull above the right parietal
lobe (1.5 mm lateral to the midline, -3 mm from the bregma) for
30 s. The rectal temperature was measured and maintained
at 37±0.5 °C with a heating pad and a heating lamp during the
surgery. Incisions were sutured after cryoinjury, and the
mice were kept in a recovery box with heating lamps to
maintain body temperature and then returned to their cages.
In the multidose group, the mice were pretreated by ip
injections of pranlukast (0.01 and 0.1 mg/kg) or minocycline
(45 mg/kg) once a day for 3 consecutive days before
cryoinjury; the last doses were given 30 min before cryoinjury
(total of 4 doses). In the single dose groups, the mice were
pretreated 30 min before cryoinjury or post-treated 30 min or
1 h after cryoinjury with the same doses of both drugs. In
the control groups, saline (5 mL/kg) was ip injected at the
same time as the drug treatment groups.
Determination of lesion volume and brain edema
The mice were anesthetized with chloral hydrate and decapitated
24 h after cryoinjury. The brains were quickly removed and
dissected into 1 mm-thick coronal slices. The slices were
stained with 0.5% TTC at 37 °C for 30 min, and then fixed in
a 10% buffered formalin solution. The stained slices, with
the caudal facing upwards, were photographed with a digital
camera (FinePix S602 Zoom, Fuji, Tokyo, Japan) and recorded
on a computer. The lesion and hemisphere area of each slice
were determined by an image analysis program
(AnalyPower1.0, Zhejiang University, Hangzhou, China). The lesion volume
was calculated as follows: lesion volume=lesion area×
thickness (1 mm), and the summation of the lesion volumes of all
brain slices was the total lesion volume. Brain edema was
indirectly evaluated as a percentage increase of the lesioned
hemisphere volume.
Pathohistological examination In another series, the mice
were anaesthetized with chloral hydrate and then perfused
transcardially with 4% paraformaldehyde after a saline
prewash. The brains were removed, postfixed in 4%
paraformaldehyde overnight, and then transferred to 30% sucrose
and submerged for 3_7 d. Serial 10 µm-thick coronal
sections were cut by cryomicrotomy (CM1900, Leica, Wezlar,
Germany). The sections were immunostained with a mouse
monoclonal antibody against NeuN (a specific marker of
neurons) to detect neuron density as described later. Since
the neurons in the lesion core almost completely disappeared
(data not shown), we observed the neurons in the periphery
of the lesion, neocortex layers III and IV (1.8_2.0 mm caudal
from bregma). Endogenous IgG immunostaining was
performed to detect the disruption of the
BBB[27]. The brain sections were sequentially reacted with biotinylated
anti-mouse IgG antibody (1:500), horseradish peroxidase
streptavidin (1:200), and DAB. The optical gray scales in the
immunostained sections were detected with an image
analyzer (Imagetool 2.0, University of Texas, Health Science
Center, San Antonio, TX, USA). IgG exudation was
evaluated as the percentage increase of the gray scales of the
injured hemisphere,
IgG%=(Gi-G0)/G0×l00%. Here,
Gi=the gray scale of the injured hemisphere and
G0=the gray scales of the contralateral hemisphere.
RT-PCR The mouse cerebral cortex from the injured
hemisphere and the contralateral cortex were dissected on ice at
the indicated time points, and stored at -70 °C until use. The
total RNA was extracted from the tissue samples using Trizol
reagents (Invitrogen, Calsbad, CA, USA) according to the
manufacture's protocol. For the cDNA synthesis, aliquots
of total RNA (2 µg) were mixed with 0.2 µg random hexamer
primer, 20 U RNasin, 1 mmol/L dNTP, and 200 U M-MuLV
reverse transcriptase in 20 µL of the reverse reaction buffer.
The mixture was incubated at 42 °C for 60 min, and then at
72 °C for 10 min to inactivate the reverse transcriptase.
PCR was performed on an Eppendorf Master Cycler
(Eppendorf, Hamburg, Germany). The mixture was as follows:
1 µL RT-cDNA temple was dissolved in 20 µL reaction
mixture containing 1×PCR buffer, 200 µmol/L dNTP, 1.5 mmol/L
MgCl2, 20 pmol of each primer, and 0.5 U
Taq DNA polymerase. Cycling parameters were as follows: 94
°C for 2 min, followed by 33 cycles of 94
°C for 30 s, 63 °C for 30 s, and 72
°C for 30 s, with a final extension step of 72 C for 10 min.
The primer sequences for the mouse
CysLT1 receptor were derived from the published cDNA
sequence[28]: 5'-CAA CGA ACT ATC CAC CTT CACC-3' as sense, and 5'-AGC CTT
CTC CTA AAG TTT CCAC-3' as antisense (product size 164
bp). The primers for β-actin were 5'-GTC GTA CCA CAG
GCA TTG TGA TGG-3' as sense, and 5'-GCA ATG CCT GGG
TAC ATG GTG-3' as antisense (product size 490 bp). The
amplification products were separated by electrophoresis
on a 2% agarose gel containing ethidium bromide and
photographed. The optical density of the bands was
determined by an image analysis system (Bio-Rad, Richmond, CA,
USA). The amounts of the CysLT1 receptor mRNA were
calculated as the ratios of the
CysLT1/β-actin.
Immunoblotting analysis The mice were sacrificed and
the cerebral cortex of the injured hemisphere were quickly
dissected on ice at the indicated time points, then stored at
-70 °C until use. The brain samples were homogenized; the
homogenates were then centrifuged at 15
000×g at 4 °C for 30 min and the supernatant was harvested. The protein
samples (80 µg) were separated by 12% SDS-PAGE and
transferred to nitrocellulose membranes. The membranes were
blocked with 5% bovine serum albumin and then incubated
with a rabbit polyclonal antibody against the human
CysLT1 receptor (1:2000) or the mouse monoclonal antibody against
GAPDH (1:5000) at 4 °C overnight. After repeated washing,
the membranes were incubated with peroxidase-conjugated
goat anti-rabbit IgG (1:2000). Finally, the protein bands were
visualized by enhanced chemiluminescence. The protein
bands were scanned by a Laser Densitometer and analyzed
by Met Imaging Series 5.0 (Bio-Rad, USA). The amounts of
the CysLT1 receptor protein were calculated as the ratios of
the CysLT1/GAPDH. The antibody against the human
CysLT1 receptor had been confirmed to be specific for mouse
brain tissue[9].
CysLT1 receptor specific immunohistochemical
analysis To visualize the localization of the
CysLT1 receptor in different cell types, double immunofluorescence was
employed on the 10 µm-thick sections. Briefly, non-specific
binding of IgG was blocked with 5% normal goat serum for
2 h at room temperature. Each section was incubated
overnight at 4 °C with a mixture of rabbit polyclonal antibody
against the CysLT1 receptor and mouse monoclonal
antibodies against NeuN, GFAP (a specific marker of astrocytes)
or CD11b (a specific marker of microglia). Then the sections
were incubated with the mixture of FITC-conjugated goat
anti-rabbit IgG and Cy3-conjugated goat anti-mouse IgG and
observed under a fluorescence microscope (Olympus BX51,
Tokyo, Japan).
Statistical analysis All values are presented as mean±SD.
One-way ANOVA (Student-Newman-Keuls) was performed
for statistical analysis using the SPSS 10.0 software package
for Windows (SPSS, Chicago, IL, USA). P<0.05 was
considered statistically significant.
Results
Brain injury Pretreatments for 3 d before cryoinjury
with multidoses of pranlukast (0.1 mg/kg) and minocycline
(45 mg/kg) significantly reduced the lesion volume and brain
edema 24 h after cryoinjury. In the single dose groups with
the 2 drugs, pretreatment at 30 min before cryoinjury or
post-treatment at 30 min after cryoinjury had protective effects as
well. However, post-treatment with pranlukast at 1 h after
cryoinjury did not show any significant protective effects,
but minocycline was still effective. Pranlukast 0.01 mg/kg
was not effective at any dosing regimen (Figure 1). We then
administered single doses of these agents 30 min after
cryoinjury in the following experiments.
The density of the NeuN-positive neurons was
substantially decreased in the periphery of the lesion 24 h after
cryoinjury. Pranlukast (0.1 mg/kg) and minocycline (45
mg/kg) significantly attenuated the neuron loss
(P<0.01, Figure 2). The endogenous IgG exudation was found in the injured
cortexes, indicating BBB disruption. Pranlukast (0.1 mg/kg)
and minocycline (45 mg/kg) significantly reduced IgG
exudation (P<0.01, Figure 3).
Expression of the CysLT1
receptor The expression of the
CysLT1 receptor in the injured cortexes was significantly
increased at 6, 12, and 24 h, and then recovered 48 h after
cryoinjury (Figure 4B). The expression in the contralateral
cortexes was not changed 48 h after cryoinjury (Figure 4A).
The expression of the CysLT1 receptor protein in the injured
cortexes was also significantly increased 6, 12, and 24 h after
cryoinjury (Figure 4C). Minocycline (45 mg/kg), not
pranlukast (0.01 and 0.1 mg/kg), significantly inhibited the
increased expression (P<0.05, Figure 5). The double
immunofluorescence showed that the
CysLT1 receptor immunoreactivity was primarily localized in the NeuN-positive
neurons (Figure 6A), but less in the GFAP-positive astrocytes in
the periphery of the lesion 24 h after cryoinjury (Figure 6B).
Moreover, the amount of CD11b-positive microglia was
increased, but they expressed less of the
CysLT1 receptor (Figure 6C).
Discussion
The present study indicates that the
CysLT1 receptor mediates brain cryoinjury. This mediation is evidenced by
the fact that the CysLT1 receptor expression is enhanced
after cryoinjury, and its antagonist pranlukast exerts a
protective effect on cryoinjury. These findings further confirm
that the CysLT1 receptor mediates not only ischemic brain
injury, but also traumatic brain injury.
The most important finding is that transcription and the
protein expression of the CysLT1 receptor in the brain are
enhanced 6_24 h after cryoinjury, and the increased
CysLT1 receptor is primarily localized in the neurons. This result is
similar to, but somewhat different from that found in focal
cerebral ischemia in mice[10]. Focal cerebral
ischemia-increased expression of the
CysLT1 receptor peaked at 24 h and was maintained for 48
h[10], while cryoinjury-increased expression was limited to 6_24 h. This difference may be due
to the smaller lesion induced by cryoinjury than that by
focal cerebral ischemia. However, the increased
CysLT1 receptor was similarly localized in the neurons, not in the
astrocytes and microglia, in the periphery of the lesion 24 h after
focal cerebral ischemia and cryoinjury. This finding
indicates that the CysLT1 receptor plays a role in neuronal
damage in the acute phase of injury as we reported in rat focal
cerebral ischemia[11].
We can not exactly explain why the
CysLT1 receptor is upregulated after cryoinjury. However, 1 possible
mechanism may be excitotoxicity after cryoinjury. Cryoinjury can
induce the endogenous excitatory acid glutamate
release[29]. The released glutamate might activate the NMDA receptor
and produce the resultant damage because the NMDA
receptor antagonist dizocilpine (MK-801) can reduce cryo-
injury[30]. Moreover, we found that NMDA microinjection
induced the upregulation of the CysLT1 receptor, and the
increased receptor was localized in the
neurons[9]. Therefore, NMDA receptor activation (excitotoxicity) may be an
intermediate triggering step of the cryoinjury-induced
CysLT1 receptor expression. Since ischemic brain injury is also
evoked by excitotoxicity[31], the enhanced
CysLT1 receptor expression might be a common consequence in both ischemic
and traumatic brain injury. Of course, postinjury upregulation
of the CysLT1 receptor may be also induced by various
unknown factors secondary to cryoinjury.
Another finding is that pranlukast, a selective
antagonist of the CysLT1 receptor, exerts protective effects on
cryoinjury with a therapeutic window of 30 min. We found
dose-dependent protective effects of pretreatment with
multidoses of pranlukast on cryoinjury in mice, and the most
effective dose was 0.1 mg/kg[22]. The present study further
reveals its effect of post-treatment with a single dose of
pranlukast; the therapeutic window (30 min) is the same as
that found in focal cerebral ischemia in
mice[5]. Because postinjury treatments are clinically important, pranlukast
administered in a short duration after brain injury may be an
effective treatment of brain injury. However, pranlukast did
not inhibit the expression of the
CysLT1 receptor in the brain after cryoinjury, which was inhibited after NMDA
injury[9].
The control agent minocycline exerts the protective
effect on cryoinjury with a wider therapeutic window of at
least 1 h, which is consistent with that (4 h) in focal cerebral
ischemia in rats[25]. Interestingly, minocycline inhibited the
increased expression of the CysLT1 receptor, suggesting a
new aspect of its anti-inflammatory ability in addition to the
inhibition of microglial cell
activation[32], apoptotic cascades in
neurons[33,34], 5-lipoxygenase activation in rat
pheochromocytoma PC12 cells[35,36], and the activated p38
mitogen-activated protein kinase in microglial
cells[37].
In summary, we found that CysLT1 receptor is
up-regulated in the brain and localized in neurons after cryoinjury in
mice, and the postinjury treatment with
CysLT1 receptor antagonist pranlukast exerts protective effects with a
therapeutic window of 30 min. These findings indicate that the
CysLT1 receptor modulates cryoinjury at least partly, and
CysLT1 receptor antagonist(s) may possess therapeutic
potential in the treatment of brain injury, including ischemic
and traumatic brain injury.
Acknowledgments
We thank Dr Masami TSBOSHIMA, (Ono Pharmaceutical Co, Osaka, Japan) for supplying pranlukast, and Prof
Jian-hong LUO (Department of Neurobiology, School of
Medicine, Zhejiang University, Hangzhou, China) for
critically reading and commenting on this manuscript.
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