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The Journal of Neuroscience, November 15, 2002, 22(22):9771-9775
Increased Severity of Stroke in CB1 Cannabinoid
Receptor Knock-Out Mice
Sophie
Parmentier-Batteur1,
Kunlin
Jin1,
Xiao Ou
Mao1,
Lin
Xie1, and
David A.
Greenberg1, 2
1 Buck Institute for Age Research, Novato, California
94945, and 2 Department of Neurology, University of
California, San Francisco, California 94143
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ABSTRACT |
Endogenous cannabinoid signaling pathways have been implicated in
protection of the brain from hypoxia, ischemia, and trauma, but the
mechanism for these protective effects is uncertain. We found that in
CB1 cannabinoid receptor knock-out mice, mortality from permanent focal
cerebral ischemia was increased, infarct size and neurological deficits
after transient focal cerebral ischemia were more severe, cerebral
blood flow in the ischemic penumbra during reperfusion was reduced, and
NMDA neurotoxicity was increased compared with wild-type littermates.
These findings indicate that endogenous cannabinoid signaling pathways
protect mice from ischemic stroke by a mechanism that involves CB1
receptors, and suggest that both blood vessels and neurons may be
targets of this protective effect.
Key words:
ischemia; cannabinoid; CB1 receptor; stroke; cerebral
blood flow; NMDA
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INTRODUCTION |
Cannabinoids, which include the
marijuana constituent
 9-tetrahydrocannabinol (Gaoni and
Mechoulam, 1964 ) and endogenous cannabinoids (endocannabinoids)
produced in the brain (Devane et al., 1992; Stella et al., 1997), exert
many of their effects through the G-protein-coupled CB1 receptor
(Matsuda et al., 1990). Cannabinoids reduce neuronal death from a
variety of insults, including excitotoxicity (Shen and Thayer, 1998),
oxidative stress (Hampson et al., 1998), hypoxia (Sinor et al., 2000),
ischemic stroke (Nagayama et al., 1999), and trauma (Panikashvili et
al., 2001), but the mechanism that underlies their neuroprotective
action is uncertain.
We reported previously that the cannabinoid agonist
R(+)- 2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4- benzoxazin-yl-1-naphthalenylmethanone
mesylate [R(+)-WIN 55212-2] decreased hippocampal
neuronal loss after transient global cerebral ischemia and reduced
infarct volume after permanent focal cerebral ischemia induced by
middle cerebral artery (MCA) occlusion in rats (Nagayama et al., 1999).
These effects were stereoselective for WIN 55212 isomers and were
inhibited by the CB1 cannabinoid receptor antagonist
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), consistent with CB1-mediated effects. Panikashvili et al. (2001) found that the endocannabinoid 2-arachidonoyl glycerol improved histological and functional outcome after closed head injury
in mice, including a reduction in the size of trauma-related cerebral
infarcts, and that these effects were also attenuated by SR141716A.
Although the pharmacological features of neuroprotection from cerebral
ischemia (Nagayama et al., 1999) and closed head trauma (Panikashvili
et al., 2001) are consistent with CB1 receptor-mediated effects, recent
evidence suggests that non-CB1 receptors with similar pharmacology may
exist in the brain. These include a G-protein-coupled receptor in mouse
brain membranes that is activated by R(+)-WIN 555212-2 and by the
endocannabinoid anandamide, but not by other CB1 agonists, and is
insensitive to SR141716A (Jarai et al., 1999; Breivogel et al., 2001),
and a presynaptic receptor in hippocampal slices from CB1 knock-out
mice that is activated by R(+)-WIN 555212-2 and blocked by SR141716A
and that inhibits glutamate release (Jarai et al., 1999; Breivogel et
al., 2001). The availability of CB1 receptor knock-out mice in which
numerous physiological effects of cannabinoids are absent (Ledent et
al., 1999) provides an opportunity to address directly whether the CB1
receptor mediates endogenous neuroprotection from ischemia and, if so,
to identify the cellular targets involved.
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MATERIALS AND METHODS |
Animals. CB1 knock-out, heterozygous, and wild-type
mice bred for at least five generations on a CD1 background were
provided by Ledent et al. (1999) and were used to breed the mice used
in his study. Experiments were approved by local committee review and
were conducted according to policies on the use of animals of the
Society for Neuroscience.
CB1 receptor expression. Genotyping was
performed according to the protocol of Ledent et al. (1999), using the
PCR primers 5'-CATCATCACAGATTTCTATGTAC-3' and
5'-GAGGTGCCAGGAGGGAACC-3', which amplify a 366 bp band from
the wild-type CB1 allele and 5'-GATCCAGAACATCAGGTAGG-3' and
5'-AAGGAAGGGTGAGAACAGAG-3', which amplify a 521 bp band from the
mutated CB1 allele. Western blotting and immunohistochemistry were
conducted as described in detail previously (Sun et al., 2001). For
Western blots, 25 µg of forebrain membrane protein was
electrophoresed and transferred to polyvinyldifluoridine membranes, which were blocked with 5% nonfat dried milk in PBS plus 0.1% Tween
20, and reacted with affinity-purified rabbit polyclonal anti-CB1
(1:100; Calbiochem, San Diego, CA) for 4 hr at room temperature. Blots
were incubated with biotinylated anti-rabbit IgG (1:2000; Santa Cruz
Biotechnology, Santa Cruz, CA) and streptavidin HRP-conjugated antibody
(Vector Laboratories, Burlingame, CA) for 1 hr in each and visualized
by chemiluminescence. For immunohistochemistry, the primary antibodies
were affinity-purified rabbit polyclonal anti-CB1 (1:200; Calbiochem),
mouse monoclonal anti-neuronal-specific nuclear protein (NeuN)
(1:500; Chemicon, Temecula, CA), mouse monoclonal
anti- 2- (vascular smooth muscle) actin (1:100;
Maine Biotechnology, Portland, ME), and affinity-purified goat
anti-E-selectin (1:100; Santa Cruz Biotechnology). The secondary
antibodies were FITC-conjugated goat anti-rabbit IgG (1:200; Vector
Laboratories) and rhodamine-conjugated donkey anti-mouse and anti-goat
IgG (1:200; Jackson ImmunoResearch, West Grove, PA). Controls included
omitting primary or secondary antibodies.
Ischemia model. Male mice (30-35 gm) were anesthetized with
1.5% isoflurane in 70% N2O/30%
O2. Rectal temperature was maintained at
37.0 ± 0.5°C with a thermostat-controlled heating blanket. The
left external carotid artery was ligated with 6-0 silk suture, and its
branches were electrocoagulated. A 5-0 monofilament surgical nylon
suture with a heat-blunted tip was introduced into the left internal
carotid artery through the stump of the external carotid and advanced
12 mm past the common carotid artery bifurcation to occlude the left
MCA. The left common carotid artery was also occluded during the
period of MCA occlusion. The filament was sutured in place (permanent
ischemia) or withdrawn 20 min later (transient ischemia). Regional
cerebral blood flow (rCBF) was measured by laser-Doppler flowmetry
with a probe (Vasamedic, St. Paul, MN) placed through a burr hole
drilled 1.5 mm lateral to the midline and 1.7 mm anterior to the
lambda. This location was based on previous reports (Iadecola et al.,
2001) and was confirmed in preliminary experiments to correspond to the
brain region that is recruited into infarction in CB1 knock-out mice.
Infarct area was measured on 2 mm coronal brain sections, which were
immersed in 2% 2,3,5-triphenyltetrazolium hydrochloride (TTC) in PBS
for 20 min at 37°C and then fixed overnight at 4°C in 4%
paraformaldehyde (Bederson et al., 1986b). Infarct volume was
calculated by integrating the infarction areas, corrected for edema
(Lin et al., 1993). Neurological function was assessed using a standard
scoring system: 0, no deficit; 1, failure to extend right forepaw; 2, circling to right; 3, falling to right; 4, inability to walk
spontaneously (Bederson et al., 1986a).
Intracerebral NMDA administration. Neuronal excitotoxicity
was induced in nonischemic animals by intracerebral injection of 20 nmol of NMDA in 200 nl of sterile PBS into the parietal cortex at a
site 1.5 mm caudal to bregma, 4.0 mm from the midline, and 0.8 mm below
the dural surface. After 24 hr, 30 µm coronal brain sections were
stained with hematoxylin to delineate the resulting lesion.
Data analysis. Quantitative data were expressed as mean ± SEM from at least three experiments. ANOVA and Student's
t test were used for statistical analysis, with p
values of <0.05 considered significant.
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RESULTS |
The brains of CB1 knock-out mice failed to express CB1 mRNA and
protein as measured by PCR genotyping and Western blotting, and
immunohistochemical analysis of cerebral cortical sections showed that
CB1 immunoreactivity, which was localized to neurons and blood vessels
of wild-type mouse brain, was absent from knock-out mice (Fig.
1). Nevertheless, the macroscopic anatomy
of the brain and major cerebral blood vessels was normal in knock-out
mice (data not shown).
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Figure 1.
Phenotypic features of CB1 receptor knock-out
mice. a, Genotype analysis documenting absence of the
wild-type (WT) CB1+/+ allele
(bottom arrow) and presence of the mutated [knock-out
(KO)] CB1 / allele (top
arrow) in CB1 knock-out mice. HZ,
Heterozygote. b, Western blots confirming the
absence of CB1 protein (Mr, ~53
kDa) in forebrains of knock-out mice. Each lane contains
a pooled protein sample from three mice. Blots were stripped and
rehybridized with anti- -actin (-Act) to control
for variations in protein application or transfer. c, Immunohistochemical localization of CB1
receptors to NeuN-labeled neurons, -actin-labeled vascular smooth
muscle (-Act) and E-selectin-labeled endothelium
(E-sel) of wild-type (top) but not
CB1 knock-out (bottom) mice. Data are representative
blots or fields from at least three independent experiments per
panel.
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In initial studies, permanent occlusion of the left MCA with a suture
was associated with a fivefold higher mortality at 24 hr in knock-out
mice (five of six mice; 83%) than in wild-type mice (one of six;
17%). To reduce mortality and better assess the effect of CB1
knock-out on the size of cerebral infarcts, we reduced the duration of
MCA occlusion to 20 min, followed by reperfusion for 24 hr. Under these
conditions, there was no difference between wild-type and knock-out
mice with regard to arterial blood gas measurements or temperature
(Table 1). Acute postischemic mortality
in knock-out mice was still approximately twice that seen in wild-type
mice, but a sufficient number of mice survived in whom to measure
infarct size. Infarct volume, determined using the vital dye TTC to
delineate surviving tissue (Bederson et al., 1986b) and confirmed by
cresyl violet staining of fixed sections (data not shown), was
increased 0.5-fold in CB1 heterozygotes and threefold in knock-out
mice, and we observed this difference throughout the linear extent of
the infarct (Fig. 2). Global neurological score, which reflects the severity of functional brain injury after
cerebral ischemia (Yang et al., 1994), was also more severely impaired
in knock-out compared with wild-type mice.
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Table 1.
Physiological and mortality measurements associated with
transient cerebral ischemia in wild-type and CB1 mutant mice
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Figure 2.
Brain infarct size and neurological deficit in
wild-type (WT), CB1+/
heterozygous (HZ), and CB1/
knock-out (KO) mice. The MCA was occluded for 20 min
followed by reperfusion for 24 hr, and infarct volume
(a) and infarct area (b) on
TTC-stained coronal brain sections taken at the indicated distances
from the frontal pole (c) were measured as
described in Materials and Methods, as was the neurological deficit
score (d). Data are means ± SEM from 8 to
12 animals. *p < 0.05; **p < 0.01 relative to wild type (a, d, ANOVA
followed by Fisher's PLSD test; b, Kruskal-Wallis test
followed by Mann-Whitney U test).
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The presence of vascular CB1 receptors in the brains of our wild-type
mice (Fig. 1) suggested the possibility that loss of these receptors in
CB1 knock-out mice might contribute to the increase in infarct size
that we observed. To test this possibility, we first compared
rCBF in the ischemic penumbra, or border zone, during temporary
MCA occlusion in wild-type and CB1 knock-out mice. During ischemia,
blood flow in the penumbra is reduced but not eliminated, and neuronal
dysfunction is potentially reversible; therefore, the ultimate fate of
neurons in the penumbra is a major determinant of infarct size and
neurological outcome after stroke (Sharp et al., 2000). After MCA
occlusion, rCBF in the ischemic penumbra was reduced to similar levels
in wild-type and CB1 knock-out mice; however, whereas rCBF was restored
to basal levels during reperfusion in wild-type mice, it remained low
in CB1 knock-out mice (Fig. 3). This
appeared to result from a direct effect on the cerebral vasculature,
and not from systemic hypotension, because mean arterial blood pressure
(MABP) was equivalent in wild-type and CB1 knock-out mice.
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Figure 3.
Vascular and neuronal basis for increased severity
of cerebral ischemia in CB1 receptor knock-out mice. The MCA was
occluded for 20 min (a, b,
bars), and rCBF (a) and MABP
(b) were monitored continuously in wild-type
(WT,  ), CB1+/ heterozygous
(HZ,  ), and CB1/ knock-out
(KO,  ) mice. c, NMDA (20 nmol) was
injected into the parietal cortex of WT ( ) and KO () mice; the
volume (left) and area at multiple coronal levels
(right) of the resulting excitotoxic lesion were
measured 24 hr later by staining with hematoxylin and measuring the
unstained region (outlined in d). Data
are means ± SEM from five (a, b) or
six (c) animals or representative sections from
six brains per condition (d).
*p < 0.05 for knock-out relative to wild type
(a, b, ANOVA followed by Fisher's PLSD
test; c, two-tailed Student's t
test).
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CB1 receptors are also found on neurons, where their expression is
increased in the ischemic penumbra after experimental stroke in rats
(Jin et al., 2000). To test whether the loss of neuronal CB1 receptors
also contributed to the more severe effects of cerebral ischemia in CB1
knock-out mice, we compared the extent of NMDA excitotoxicity, a lesion
that shares pathophysiological features with cerebral ischemia (Simon
et al., 1984) but which affects neurons directly, in wild-type and CB1
knock-out mice. Direct microinjection of 20 nmol of NMDA into the
cerebral cortex of CB1 knock-out mice produced excitotoxic lesions that
were approximately twice the size of lesions in nonischemic wild-type
mice. Therefore, the increased infarct size in CB1 knock-out mice may
result partly from enhanced sensitivity to neuronal excitotoxicity.
| |
DISCUSSION |
The major finding of this study is that cerebral ischemia has more
severe effects in CB1 knock-out than in wild-type mice, which appear to
be caused by the loss of both cerebral vascular and neuronal CB1 receptors.
The protective effects of cannabinoids against cerebral ischemia and
trauma in vivo have been thought to be mediated through CB1
receptors, because these effects are produced in a stereoselective manner by isomeric cannabinoid agonists and are blocked by CB1 antagonists (Nagayama et al., 1999; Panikashvili et al., 2001). However, additional classes of cannabinoid receptors with CB1-like pharmacology are likely to exist (Jarai et al., 1999; Breivogel et al.,
2001), and several studies of cannabinoid-induced neuroprotection in
in vitro cell-culture systems have reported effects that are not receptor-mediated (Hampson et al., 1998; Nagayama et al., 1999;
Sinor et al., 2000). The reason for this latter discrepancy is unclear,
but it could be related to the fact that cerebral CB1 receptors are
located not only on neurons but also on cerebrovascular smooth muscle
and endothelial cells (Hillard, 2000), where their activation promotes
vasodilation (Gebremedhin et al., 1999) and increases cerebral blood
flow (Hillard, 2000). Because blood vessels are absent from cortical
neuron cultures, a neuroprotective effect that was mediated partly
through vascular effects of cannabinoids (Hillard, 2000), such as an
increase in blood flow to ischemic tissue at risk for infarction, might
be less evident in such systems.
CB1 receptors were expressed by neurons, vascular smooth muscle cells,
and endothelial cells of our wild-type mice but were absent in CB1
knock-out mice, which developed approximately threefold larger cerebral
infarcts after transient occlusion of the MCA. These larger infarcts
were associated with correspondingly more severe functional deficits on
behavioral testing. The finding that cerebral ischemia is exacerbated
in CB1 receptor knock-out mice is consistent with an endogenous
neuroprotective role for the endocannabinoid signaling system in the
brain and with our previous finding that administration of exogenous
cannabinoids reduces ischemic neuronal injury after both global and
focal cerebral ischemia (Nagayama et al., 1999). In that study, the
pharmacological features of neuroprotection suggested a CB1
receptor-mediated effect, but the availability of CB1 receptor
knock-out mice provided an opportunity to test more directly whether
endocannabinoid-CB1 interactions mediate neuroprotection in ischemia.
The dysregulation of rCBF that we observed during reperfusion in the
ischemic penumbra of CB1 knock-out mice suggests that in the cerebral
vasculature after stroke, endogenous cannabinoid signaling through CB1
receptors normally acts to enhance blood flow and promote cell
survival. This is consistent with the ability of cannabinoids to
increase cerebral blood flow (Hillard, 2000) and with the proposed role
of vascular mechanisms in the protective effect of cannabinoids in head
trauma, which may involve antagonism of vasoconstriction induced by
endothelin-1 (Panikashvili et al., 2001). Nevertheless, caution is
warranted in the interpretation of these results insofar as absolute
values for rCBF in wild-type, heterozygous, and knock-out animals were
not measured. The observation that brain lesions induced by direct
injection of NMDA are more severe in CB1 knock-out mice suggests that
neuronal CB1 receptors may also be involved in protection from
ischemia, with the caveat that excitotoxic effects of NMDA can have a
vascular component as well (Dietrich et al., 1992; Globus et al.,
1995). In the absence of CB1 receptors, not only these direct
protective effects but also the ischemia-induced upregulation of
neuronal CB1 receptor expression (Jin et al., 2000) would be lost,
further compromising the capacity of the brain to adapt to and survive ischemia.
Neuronal CB1 receptors are thought to reside primarily on presynaptic
nerve terminals, where their activation inhibits voltage-gated calcium
channels, and their neuroprotective effect in ischemia could be
mediated partly through the inhibition of depolarization-induced glutamate release (Shen et al., 1996). How the absence of CB1 receptors
exacerbates the excitotoxicity of directly applied NMDA is unclear, but
the more severe NMDA-induced injury in CB1 knock-out mice suggests that
endogenous cannabinoid signaling can also regulate excitotoxicity at a
step beyond glutamate release. Because CB1 receptor activation is
coupled to a variety of effectors, including ion channels, adenylate
cyclase, and protein kinases (Pertwee, 1997), there are numerous
signaling pathways through which such an effect might occur.
Clinical stroke, which usually results from cerebral ischemia, is a
common and frequently incapacitating problem for which satisfactory
treatment is generally unavailable. Identifying new endogenous systems
that mitigate ischemic brain injury through effects on neurons, blood
vessels, or both (such as the endocannabinoid signaling pathway) may
help to guide the search for improved therapies.
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FOOTNOTES |
Received June 21, 2002; revised Sept. 3, 2002; accepted Sept. 9, 2002.
This work was supported by National Institutes of Health Grant NS39912
and by the Buck Institute for Age Research. We thank C. Ledent for
providing CB1 knock-out mice.
Correspondence should be addressed to Dr. David A. Greenberg,
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA
94945. E-mail: dgreenberg{at}buckinstitute.org.
| |
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Copyright © 2002 Society for Neuroscience 0270-6474/02/22229771-05$05.00/0
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TOP
ABSTRACT
INTRODUCTION
