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Introduction
Excitotoxicity, one important determinant in various diseases of the central nervous system (CNS), is involved in acute
ischemic brain injury[1_3] and can initiate postischemic inflammation by inducing the expression of pro-inflammatory
molecules/mediators[4_6]. Mediators in postischemic inflammation include 5-lipoxygenase (5-LOX) metabolites eg, cysteinyl
leukotrienes (CysLT, including LTC4,
LTD4 and
LTE4)[7_11]. We have recently indicated that in cultured rat primary neurons,
in vitro ischemic-like injury induces endo-genous excitatory amino acid (glutamate) release; the releas-ed glutamate activates
5-LOX via the N-methyl-D-aspartate (NMDA) receptor to produce CysLT, which then induce neuron
responses[12]. These findings show one aspect of the interaction between 5-LOX/CysLT and excitotoxicity. However, as another aspect, whether
the 5-LOX metabolites, CysLT, modulate excitotoxicity is still not clear.
The actions of CysLT are mediated by stimulating their receptors. The cloned CysLT receptors consist of 2 subtypes:
CysLT1 and CysLT2 receptors; both of them G-protein coupled
receptors[13]. The human
CysLT1 receptor is localized in the airway of smooth muscle cells, lung macrophages, mast cells, eosinophils and mononuclear cells as detected by
in situ hybridization or
immunohistochemistry[14,15]. We have recently reported that
CysLT1 receptor is primarily
expressed in cerebral microvascular endothelial cells, and the expression is induced in the neuron- and glial-appearing cells
after traumatic injury[16]. Moreover,
CysLT1 receptor antagonists, pranlukast (ONO-1078) and montelukast, possess
neuroprotective effects on focal cerebral ischemia in rats and
mice[17_20]. These findings indicate the involvement of the
CysLT1 receptor in brain injury. In addition, we found that pranlukast protected against global cerebral ischemia in rats and
inhibited the increased expression of the NMDA receptor subunit NR2A, suggesting an interaction between
CysLT1 and NMDA
receptors[19]. As indirect evidence, pranlukast attenuates brain injury induced by NMDA microinjection into rat
cortex, suggesting that the CysLT1 receptor may modulate NMDA-induced
neurotoxicity[21]. However, since the
CysLT1 receptor is not expressed in the neurons in a normal
brain[16], this modulation should be proven by
direct evidence.
To determine whether and how the
CysLT1 receptor is involved in excitotoxicity, we induced brain injury by NMDA (one
of the exogenous excitatory amino acids) microinjection in the cortex. Then we observed
CysLT1 receptor expression and the effect of pranlukast, a selective antagonist of
CysLT1 receptor, in mice. An NMDA receptor antagonist, ketamine, and an
antioxidant with neuroprotective effect for cerebral ischemia, edaravone (MCI-186,
3-methyl-1-phenyl-2-pyrazolin-5-one)[22,23]
, were used as controls.
Materials and methods
Materials Pranlukast (ONO-1078) was kindly provided by Dr Masami TSUBOSHIMA (Ono Pharmaceutical Co, Osaka,
Japan); NMDA and 2,3,5-triphenylterazolium chloride (TTC) were purchased from Sigma (St Louis, MO, USA); edaravone
was obtained from Hangzhou Conba Pharmaceutical Co (Hangzhou, China); ketamine was purchased from Shanghai
Bio-Chem Co (Shanghai, China); Trizol for extracting RNA was from Bio Basic Inc (Mississauga, Ontario, Canada); chemicals for
RT-PCR were from Takara Co (Kyoto, Japan); polyclonal rabbit anti-human
CysLT1 antibody was purchased from Cayman
Chemicals (Ann Arbor, MI, USA); mouse monoclonal antibodies against neuronal nuclei (NeuN) and glial fibrillary acidic
protein (GFAP) and FITC-conjugated goat anti-rabbit IgG and Cy3-conjugated goat anti-mouse IgG were from Chemicon
(Temecula, California, USA); cultured human umbilical vein endothelial cells (EA.hy926 cells) were provided by Dr Cora-Jean
S EDGELL (University of North Carolina, USA) and human neuroblastoma SK-N-SH cells were purchased from the Institute
of Cell Biology, Chinese Academy of Sciences (Shanghai, China); biotinyl-ated goat anti-rabbit IgG was purchased from
Zhongshan Biotech Co (Beijing, China). Other reagents were commercial products with analytic purity.
NMDA microinjection Male Kunming mice weighing 25_30 g were purchased from the Shanghai Experimental Animal
Center (Shanghai, China; Certificate No 22-001004).
The mice were housed under controlled temperature
(22±1 °C), 12 h light/12 h dark cycle and allowed free access to food and water. All the experiments were carried out in accordance with the
National Institute of Health Guide for the Care and Use of Laboratory Animals.
The mice were anesthetized with an intraperitoneal injection of chloral hydrate (400 mg/kg) and immobilized on a
stereotaxic frame (SR-5, Narishige, Tokyo, Japan). The dura overlying the parietal cortex was exposed, and NMDA
[50_150 nmol in 0.5 µLof sterile 0.1 mol/L phosphate buffered solution
(PBS), pH 7.4] or PBS (0.5 µL) alone was
injected with a microinjector into the parietal cortex at a site 1.5 mm caudal to the bregma, 4.0 mm from the midline and
0.8 mm below the dural surface[24]. Injections were made over a period of 8 min, and the microinjector was left in place for an
additional 10 min to minimize the back-flux of NMDA and
then removed. The rectal temperature was maintained at
37.0±0.5 °C with a heating pad and a heating lamp during the surgical procedure. After the surgery, the mice were kept in a recovery
box with heating lamps to maintain body temperature and then returned to their cages.
To observe the effects of the agents, the mice were intraperitoneally injected with pranlukast (0.01 and 0.1 mg/kg),
ketamine (30 mg/kg), edaravone (9 mg/kg), and saline (control) at 30 min before and 30 min after NMDA injection.
Histopathological
examination The mice were anesthetized with chloral hydrate and decapitated 24 h after NMDA or PBS
injection. The brains were quickly removed and cut into 1 mm-thick coronal slices. The slices were stained with 0.5%
2,3,5-triphenylterazolium chloride (TTC) at 37 °C for 30 min in the dark and then fixed by 10% buffered formalin. The stained slices
with the caudal facing upwards were photographed with a digital camera (Panasonic CP 230, Matsushita, Fukuoka, Japan)
and recorded in a computer. The regions completely lacking TTC-staining were defined as tissue lesions. The lesion and
hemisphere area of each slice were quantified using an image analysis program (AanlyPower
1.0, Zhejiang University, Hangzhou, China). The total lesion volume for each brain was calculated by summation of the
corrected lesion volumes [lesion area×thickness (1 mm)] of all slices as described by Lin
et al[25]. Hemispheric swelling
representing brain edema was indirectly determined as the percentage increase of the lesioned hemisphere volume.
In another series, the mice were anesthetized with chloral hydrate and then perfused transcardially with 4%
paraformaldehyde after pre-washing with saline. The brains were removed, post-fixed in the same fixative and embedded in paraffin; 5 µm
or 8 µm-thick coronal sections were cut by cryomicrotomy (CM1900, Leica,
Wetzlar, Germany). Then the 5 µm-thick sections
were stained with hematoxylin and eosin (H&E) for light microscopic examination. The densities of the neurons in the cortex
and hippocampal CA1 regions (1.8_2.0 mm caudal from bregma) were counted using the image analysis program described
above.
RT-PCR The brain tissues (from the region 0.5_2.5 mm caudal from bregma and the corresponding region of the
contralateral hemisphere) were dissected on ice and the total RNA was extracted from the tissue samples using Trizol
reagents according to the manufacture's protocol. RNA
purity and yield were determined by UV spectrophotometry (Bio-Rad Smart Spec 3000, Hercules, CA, USA). For 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. As a negative control, the reaction was performed with the
absence of the reverse transcriptase.
The RT-cDNA temple (1 µL) underwent PCR (Bio-Rad, USA) in a 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 of
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 pairs for the mouse
CysLT1 receptor were derived from the published cDNA
sequence[26] and synthesized by Sangon Biotech Co (Shanghai, China): 5'-CAA CGA ACT ATC CAC CTT CACC-3' as sense and 5'-AGC CTT
CTC CTA AAG TTT CCAC-3' as antisense. The primers for
b-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. The product sizes were 164 bp and 490 bp, respectively. The
PCR products in 10 µL 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, USA). The amount of
CysLT1 receptor mRNA was calculated as the ratio over
b-actin.
CysLT1 receptor specific immunohistochemical
analysis To confirm the specificity of the polyclonal rabbit anti-human
CysLT1 receptor antibody used in the immunohistochemical staining of mouse brain tissues, we collected protein samples
from normal mouse brains as well as from the cultured human umbilical vein endothelial cells (EA.hy926 cells) and human
neuroblastoma SK-N-SH cells for Western blotting analysis. The mouse brain samples were homogenized and cell samples
were sonicated in lysis buffer. The lysates were then centrifuged at 15
000×g at 4 °C for 30 min and the supernatant was used.
Protein samples (50 mg) were separated by 10% SDS-polyacrylamide gel electrophoresis and transferred to the nitrocellulose
membranes. Then, the membranes were blocked by 5% bovine serum albumin (BSA) and reacted with a rabbit polyclonal
antibody against the CysLT1 receptor (1:2000) and peroxidase-conjugated goat anti-rabbit IgG (1:2000) after repeated washing.
Finally, the protein bands were visualized by enhanced chemilumines-cence.
Immunohistochemical detection of the
CysLT1 receptor was performed on 8 µm-thick coronal sections (1.8_2.0 mm caudal
from bregma). After 3 washes with PBS, the sections were incubated with 0.3% hydrogen peroxide in methanol at room
temperature for 30 min to block the reactivity of endogenous peroxidase. The sections were washed several times in the PBS,
pre-incubated with 5% normal goat serum for 2 h to reduce non-specific staining, and then reacted with the
polyclonal rabbit anti-human CysLT1 receptor antibody
(1:150) overnight at 4 oC. Control sections were treated with normal goat serum
instead of the primary antibody. After repeated washing in PBS, the sections were reacted for 1 h with the secondary
antibody (1:200), biotinylated goat anti-rabbit IgG, followed by reaction for 1 h with avidin-biotin-horseradish peroxidase
complex (1:200). Finally, the sections were exposed for 2_5 min to 0.05% 3,3'-diaminobenzidine and 0.03% hydrogen peroxide
and examined by a light microscope (Olympus BX51, Olympus,
Tokyo, Japan).
To visualize the localization of the
CysLT1 receptor in different cell types, double immunofluorescence was employed.
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 (a specific marker of neurons) or GFAP (a specific marker of astrocytes). 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, Japan).
Statistical analysis All values are presented as mean±SD. One-way ANOVA (Student-Newman-Keuls) was performed for
statistical analysis using the SPSS software package (version 10.0 for Windows; SPSS, Chicago, Illinois, USA).
P<0.05 was considered statistically significant.
Results
Effect of pranlukast on NMDA-induced brain injury
To confirm the involvement of the
CysLT1 receptor in excitotoxicity, we observed the effect of its antagonist pranlukast, on NMDA-induced brain injury in comparison with ketamine and
edaravone. NMDA 50, 100, and 150 nmol dose-dependently increased lesion volume (TTC staining) and the lesioned
hemisphere volume (indicating brain edema) 24 h after microinjection
(P<0.01, Figure 1A_1C). Pranlukast 0.1 mg/kg, edaravone
9 mg/kg and ketamine 30 mg/kg significantly attenuated NMDA-induced (150 nmol) injury
(P<0.05 or 0.01, Figure 1D_1F). The histopathological examination showed that NMDA microinjection induced serious pyknotic nuclei and deeply stained
cells in the ipsilateral cortex and hippocampal CA1 [not CA3 and
dentate gyrus (DG)] region as detected by H&E staining
(Figure 2A,2B), and significantly reduced the density of neurons in the cortex (50_150 nmol; Figure 2C) and hippocampal CA1
region (100 and 150 nmol; Figure 2D). Pranlukast (0.1 mg/kg), edaravone
(9 mg/kg) and ketamine (30 mg/kg) significantly attenuated NMDA (150 nmol)-reduced density in the cortex (Figure 2E) or
hippocampal CA1 region (Figure 2F). These results indicates that the protective effect of pranlukast at 0.1 mg/kg on
NMDA-induced brain injury is similar to ketamine and edaravone.
CysLT1 receptor mRNA expression after NMDA
microinjection NMDA (100 and 150 nmol) significantly increased the
expression of the CysLT1 receptor mRNA, in the injured region of the mouse brain 24 h after NMDA microinjection
(P<0.05 or 0.01; Figure 3A, 3D), but NMDA at 50 nmol did not significantly affect the expression (data not shown). Pranlukast
(0.1 mg/kg) and ketamine (30 mg/kg) significantly inhibited NMDA (150 nmol)-increased expression of the
CysLT1 receptor mRNA (P<0.05) but edaravone did not show this effect
(P>0.05; Figure 3F). Otherwise, in the corresponding contralateral
region, the expression of the CysLT1 receptor mRNA was not changed (Figure 3E). This result indicated that NMDA
increased the expression of the CysLT1 receptor mRNA, which was inhibited by the NMDA receptor antagonist ketamine and
the CysLT1 receptor antagonist, pranlukast, but not by the antioxidant edaravone.
Distribution of the
CysLT1 receptor immunopositive cells after NMDA
microinjection Western blotting analysis
confirmed the specificity of a polyclonal rabbit anti-human
CysLT1 receptor antibody used in the mouse brain because the same
bands were found in the mouse brain samples and the samples from cultured human umbilical vein endothelial cells
(EA.hy926 cells) or human neuroblastoma SK-N-SH cells (Figure 4E). The band was closed to 43 kDa, which was consistent with
previously published results using the same polyclonal
antibody[27,28]. Using the antibody, we detected the distribution of
CysLT1 receptor protein 24 h after NMDA (150 nmol) microinjection by immunohistochemistry. The result showed that
CysLT1-positive cells were significantly increased in the cortex and hippocampal CA1 region after NMDA excitotoxic damage
(Figure 4A_4D), but not in the hippocampal CA3 or DG region. Pranlukast (0.1 mg/kg) and ketamine (30 mg/kg) reduced
CysLT1-positive cells, but edaravone (9 mg/kg) did not show this effect (Figure 4A_4D). To determine whether the increased
expression of the CysLT1 receptor is distributed in neurons or astrocytes, we performed double immunofluorescence. The
result showed that CysLT1 receptor immunoreactivity was mainly localized in NeuN-positive neurons in the NMDA (150
nmol)-injected cortex and hippocampal CA1 region (Figure 5). However, no apparent change was found in GFAP-positive
astrocytes; the CysLT1 receptor was much less expressed in the astrocytes (Figure 6).
Discussion
The most important finding in the present study is that the
CysLT1 receptor is involved in brain excitotoxicity. This
involvement is evidenced by the upregulation of the
CysLT1 receptor after NMDA microinjection and the attenuation of
NMDA insult by a CysLT1 receptor antagonist, pranlukast. Therefore, our study shows a possible interaction between the
excitotoxicity and the inflammation related to CysLT in the brain.
Our immunohistochemical results indicate that
CysLT1 receptor expression is induced by NMDA microinjection and
mainly localized in the neurons, but not in the astrocytes in the injured regions. This finding is consistent with those of our
recent studies. We found that the
CysLT1 receptor was primarily distributed in microvascular endothelial cells in the human
brain, and an inducible expression was detected in the neuron- and glial-appearing cells in the brain specimens from patients
with brain trauma or tumors[16]. In rats and mice with focal cerebral ischemia,
CysLT1 receptor expression was largely increased in the ischemic core 24 h after ischemia, and the increased expression was mainly localized in NeuN-positive
neurons and much less in GFAP-positive astrocytes (unpublished data). These findings suggest that the
CysLT1 receptor may mediate various brain injuries, such as trauma, ischemia and tumors, as well as chemically-induced excitotoxicity in the
present study.
Interestingly, the increased
CysLT1 receptor expression induced by NMDA is not only inhibited by the NMDA receptor
antagonist, ketamine, but also by the
CysLT1 receptor antagonist, pranlukast. Since none of the agents affect the expression
of a CysLT1 receptor mRNA, in the contralateral brain region from the NMDA-treated mice, it can be excluded that ketamine
or pranlukast directly inhibits the expression. Inhibition by ketamine reasonably results from the blockage of NMDA actions.
However, why pranlukast also inhibits
CysLT1 receptor expression is unclear. One possible explanation might be that
attenuation of brain
injury by pranlukast may secondarily reduce
CysLT1 receptor expression; however, this explanation is not supported by the
effect of edaravone that attenuated NMDA-induced injury, but did not inhibit the expression. Another explanation might be
that this phenomenon may be a special effect of
CysLT1 receptor antagonists. We have found that montelukast, another
CysLT1 receptor antagonist, also inhibited
CysLT1, but not CysLT2 receptor mRNA expression in the lungs with eosinophilic
inflammation from asthmatic mice[29]. Because interleukin-5 (IL-5) upregulates
CysLT1
receptor expression[30] and pranlukast inhibits IL-5 produc-
tion[29,31], inhibition of
CysLT1 receptor expression by pranlukast might result from its effect on upregulation by IL-5.
Among the agents used in the present study, ketamine is applied to confirm NMDA receptor activation, pranlukast is to
confirm CysLT1 receptor activation, and edaravone is to distinguish the differences from pranlukast. Ketamine is a potent
non-competitive NMDA receptor antagonist that has been shown to protect neurons from excitotoxic injury after
cerebral ischemia[32,33],
trauma[34] or injection of
excitotoxins[35,36]. In the present study, the inhibition of all the responses to NMDA by
ketamine confirmed that NMDA-induced
responses are mediated by NMDA receptor activation, similar to the reported
results[36,37]. For the effect of pranlukast, we
used 2 doses of pranlukast; 0.01 mg/kg was a nearly ineffective dose and 0.1 mg/kg was the most effective dose in the
experiments of cerebral
ischemia[17,18,20]. The results showed dose-dependency; only 0.1 mg/kg exerts effect on brain injury.
In addition, edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically available neuropro-tective agent for the
treatment of stroke with activity reducing free
radicals[22,23,38,39]. We found that edaravone had a different effect from pranlukast;
it attenuated NMDA-
induced brain injury, similar to its neuroprotective effect on cerebral
ischemia[23,38,39], but did not affect
CysLT1 receptor expression. Therefore, this difference supports that the
effect of pranlukast on CysLT1 receptor expression might be special.
Excitotoxicity is a common injurious factor involved in many CNS diseases including cerebral ischemia. The present
study indicates one aspect of the interaction between excitotoxicity and 5-LOX/CysLT pathway: the
CysLT1 receptor is upregulated and plays a role in excitotoxicity. As another aspect, we recently found that 5-LOX was upregulated by
excitotoxicity[12]. Taken together, excitotoxicity initiates post-injury inflammation by enhancing both pro-inflammatory
molecules (like 5-LOX) and inflammatory responses (like strengthening the action of CysLT).
Acknowledgments
We thank Dr Masami TSUBOSHIMA (Ono Pharmaceutical Co Ltd, Osaka, Japan) for providing us with pranlukast, Dr
Cora-Jean S EDGELL( Pathology Department, University of North Carolina) for providing EA.hy926 cells, and Professor
Jian-hong LUO, Department of Neurobiology, School of Medicine, Zhejiang University, for critically reading and commenting on
this manuscript.
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