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The Journal of Neuroscience, January 15, 2000, 20(2):763-770
Cyclooxygenase-2 Contributes to Functional Hyperemia in
Whisker-Barrel Cortex
Kiyoshi
Niwa1,
Eiichi
Araki1,
Scott G.
Morham2,
M. Elizabeth
Ross1, and
Costantino
Iadecola1
1 Center for Clinical and Molecular Neurobiology, Departments of
Neurology and Neuroscience, University of Minnesota Medical School,
Minneapolis, Minnesota 55455, and 2 Myriad Genetics, Salt
Lake City, Utah 84108
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ABSTRACT |
The prostanoid-synthesizing enzyme cyclooxygenase-2
(COX-2) is expressed in selected cerebral cortical neurons and is
involved in synaptic signaling. We sought to determine whether COX-2
participates in the increase in cerebral blood flow produced by
synaptic activity in the somatosensory cortex. In anesthetized mice,
the vibrissae were stimulated mechanically, and cerebral blood flow was
recorded in the contralateral somatosensory cortex by a laser-Doppler
probe. We found that the COX-2 inhibitor NS-398 attenuates the increase in somatosensory cortex blood flow produced by vibrissal stimulation. Furthermore, the flow response was impaired in mice lacking the COX-2
gene, whereas the associated increase in whisker-barrel cortex glucose
use was not affected. The increases in cerebral blood flow produced by
hypercapnia, acetylcholine, or bradykinin were not attenuated by
NS-398, nor did they differ between wild-type and COX-2 null mice. The
findings provide evidence for a previously unrecognized role of COX-2
in the mechanisms coupling synaptic activity to neocortical blood flow
and provide an insight into one of the functions of constitutive COX-2
in the CNS.
Key words:
cerebral blood flow; somatosensory activation; glucose
use; prostanoids; 2-deoxyglucose; COX-2 knock-out mice; NS-398
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INTRODUCTION |
Cyclooxygenase-2 (COX-2) is an
enzyme involved in the synthesis of prostaglandins and thromboxanes
from arachidonic acid (for review, see Vane et al., 1998 ). In some
organs, COX-2 is not present in the normal state, but its expression is
induced by inflammatory stimuli or mitogens (for review, see Dubois et
al., 1998). In brain, however, COX-2 is constitutively expressed and is
localized to a restricted population of excitatory neurons, wherein it
is enriched in dendritic arborizations and spines (Yamagata et al., 1993; Breder et al., 1995; Kaufmann et al., 1996). The role that COX-2
plays in normal brain function has yet to be elucidated. In the adult
cerebral cortex, neuronal COX-2 expression is upregulated by
synaptic activity (Yamagata et al., 1993) and, in the developing nervous system of the rat, COX-2 expression increases at a time when
activity-dependent synaptic remodeling occurs (Kaufmann et al., 1996).
These observations, in concert with its synaptic localization, have
suggested that COX-2 is involved in activity-dependent processes and
synaptic signaling (Kaufmann et al., 1996).
Synaptic activity is one of the critical factors controlling the
distribution of cerebral blood flow (CBF) among the different brain
regions. Thus, regional CBF is dynamically regulated to closely match
the changes in functional activity of each brain region (for review,
see Raichle, 1987; Woolsey et al., 1996). For example, when neural
activity increases in the somatosensory or visual cortex, the amount of
flow reaching these regions increases in proportion to the degree of
activation (Fox and Raichle, 1984; Ginsberg et al., 1987;
Greenberg et al., 1979) (for review, see Raichle, 1987). The spatial
and temporal correspondence between neural activity and CBF is so
accurate that changes in CBF are routinely used to map brain function
in humans (Raichle, 1998). Although the mechanisms that link synaptic
activity to local blood flow have been investigated for over a century,
they still remain to be elucidated in full (Lou et al., 1987; Iadecola,
1993; Woolsey et al., 1996). The observation that COX-2, an enzyme
whose reaction products are vasoactive (Ellis et al., 1979; Leffler and
Busija, 1987; Wei et al., 1996), is closely associated with
postsynaptic elements of excitatory neurons, raises the possibility
that COX-2 plays a role in the mechanisms coupling synaptic activity to
blood flow in brain.
In the present study, we sought to determine whether COX-2 is involved
in the increases in CBF that accompany neural activity. Using
activation of the rodent whisker-barrel cortex as a model of functional
hyperemia (Greenberg et al., 1979; Woolsey and Rovainen, 1991), we
found that the selective COX-2 inhibitor NS-398 attenuates the increase
in neocortical blood flow produced by vibrissal stimulation. Furthermore, the hyperemic response is impaired in mutant mice lacking
COX-2, whereas the associated increase in glucose use, a variable that
reflects neural activity, is not affected. The findings unveil a
previously unrecognized role of COX-2 in the mechanisms linking
synaptic activity to local blood flow in the somatosensory cortex and
provide an insight into one of the potential functions of COX-2 in the
normal brain.
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MATERIALS AND METHODS |
Animals
C57BL/6 mice were obtained from The Jackson Laboratory (Bar
Harbor, Maine). COX-2 null mice [homozygous ( /) mice and their wild-type (+/+) littermates] were obtained from a colony established at the University of Minnesota from breeding pairs provided by one of
the authors (S. Morham) (Morham et al., 1995). Mice were back-crossed
to C57BL/6 mice six to eight times and were studied at age 2-3 months.
Experiments were performed in age-matched littermates (COX-2 +/+ and
/) to minimize confounding effects deriving from the genetic
background of the mice. The genotype of all COX-2 mice was determined
by PCR (Morham et al., 1995). COX-2 mRNA is not detectable in the brain
of COX-2 / mice (C. Iadecola, S. Morham, and M. E. Ross,
unpublished observations).
Cerebral blood flow during vibrissal stimulation
Techniques used for studying the cerebral circulation in mice
were similar to those described previously (Zhang et al., 1997; Yang et
al., 1998; Iadecola et al., 1999). Mice were anesthetized with urethane
(750 mg/kg) and chloralose (50 mg/kg). The trachea was intubated, and
mice were artificially ventilated with an oxygen-nitrogen mixture. One
of the femoral arteries was cannulated for recording of arterial
pressure and collection of blood samples. Rectal temperature was
maintained at 37°C using a thermostatically controlled rectal probe
connected to a heating lamp. End-tidal CO2,
monitored by a CO2 analyzer (Capstar-100;
CWI Inc.), was maintained at 2.6-2.7% (pCO2 = 33-35 mmHg; dead-space ventilation
included) (Zhang et al., 1997) (Table 1).
A small craniotomy (2 × 2 mm) was performed to expose the
whisker-barrel area of the somatosensory cortex, the dura was removed,
and the site was superfused with Ringer's solution (37°C; pH
7.3-7.4) (Zhang et al., 1997). CBF was continuously monitored at the
site of superfusion with a laser-Doppler probe (Vasamedic, St. Paul,
MN) positioned stereotaxically on the cortical surface. The right
vibrissae were cut to a length of 5-10 mm and stimulated for 1 min by
gently stroking them (3-4 Hz) with a cotton-tipped applicator. The
left vibrissae were cut as short as possible to avoid unwanted
stimulation (Adachi et al., 1994). Vibrissal stimulation produced
increases in CBF that reached a stable plateau (Fig. 1). CBF increases, expressed as
percentage increase, were computed as the ratio of CBF at the
level of the plateau and baseline CBF before vibrissal stimulation
(Zhang et al., 1997; Yang et al., 1998; Iadecola et al., 1999). Two or
three vibrissal stimulation trials, separated by 10 min intervals, were
averaged for each experimental condition tested. Zero values for CBF
were obtained after the heart was stopped by an overdose of halothane
at the end of the experiment.
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Figure 1.
Time course of the increase in CBF produced by
vibrissal stimulation (Stim.) after topical application
of NS-398 (A) and in COX-2 null mice
(B). Vibrissal stimulation produces increases in
CBF that reach a plateau after 10-20 sec of stimulation. The increase
in CBF is attenuated by topical superfusion with NS-398 (100 µM) (A) or in COX-2 null mice
(B) (p < 0.05; t
test).
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Cerebral glucose use during vibrissal stimulation
Cerebral glucose use (CGU) was determined in awake, lightly
restrained COX-2 +/+ and / mice by a modification of the
14C-2-deoxyglucose (2-DG) method (Sokoloff
et al., 1977; Meibach et al., 1980). Under halothane anesthesia, one of
the femoral arteries was cannulated and used for recording of arterial
pressure (Table 1) and collection of blood samples. Wounds were treated with a 2% lidocaine ointment and sutured. Mice were allowed to recover
from anesthesia for 3-4 hr and placed in a loosely fitting restraining
cylinder with an anterior opening to expose the face and whiskers. The
right vibrissae were stroked for 1 min before 2-DG injection. Vibrissal
stimulation continued throughout the 45 min measurement period.
14C-labeled 2-DG (20 µCi/100 gm in 1 ml
of 0.9% NaCl; NEN, Boston, MA) was injected intraperitoneally,
and ~60 µl of arterial blood were collected 1, 5, 7, 10, 15, 20, 25, 35, and 45 min later. One blood sample was taken before injection
of 2-DG. These sampling times were selected in preliminary experiments
to accurately resolve the arterial concentration time course of the
tracer. Blood samples were centrifuged and stored on ice. The volume of
blood removed was replaced with normal saline. Blood sampling reduced
mean arterial pressure from 101 ± 4 mmHg to 70 ± 6 in COX-2
+/+ mice and from 106 ± 4 to 68 ± 4 in COX-2 / mice
(p < 0.05). However, such hypotension is
unlikely to lead to cerebral hypoperfusion because arterial pressure is
still within the autoregulated range of CBF in this preparation (Niwa
et al., 1999).
Techniques for determination of tissue 2-DG concentration by
quantitative autoradiography have been described previously (Iadecola and Xu, 1994) and are only summarized. After collection of the last
blood sample, mice were deeply anesthetized with halothane and
decapitated. Brains were rapidly removed and frozen in isopentane cooled to 30°C. Serial sections (20 µm) were cut through the brain using a cryostat (Hacker-Bright; Hacker Instruments, Fairfield, NJ), mounted on glass slides, and apposed to x-ray film (Sterling Diagnostic Imaging Inc., Newark, DE) together with calibrated 14C standards (Iadecola et al., 1996).
Fourteen days later, the film was developed, and the optical density
(OD) of regions of interest was determined bilaterally on four adjacent
sections using a computerized image analyzer (MCID system; Imaging
Research Inc., St. Catharines, Ontario, Canada). OD was transformed in 14C concentration (nanocuries per gram)
using the standards on the film (Iadecola and Xu, 1994). Radioactivity
(nanocuries per gram) of plasma samples was determined by liquid
scintillation counting (Iadecola and Xu, 1994). Plasma glucose was
measured using a glucose analyzer (Beckman Instruments, Fullerton, CA)
(Table 1). CGU (µmol/100 gm/min) was calculated from the OD of the
regions of interest and the arterial time course of 2-DG using the
equation developed by Sokoloff et al. (1977).
Experimental protocol for CBF studies
Effect of NS-398 on the increase in CBF produced by
vibrissal stimulation in C57BL/6 mice. The cranial window was
superfused with Ringer's, and baseline CBF responses to vibrissal
activation were obtained. The superfusion solution was then changed to
Ringer's containing increasing concentrations of the COX-2 inhibitor
NS-398 (10-300 µM; Cayman Chemicals, Ann
Arbor, MI) (Futaki et al., 1993; Seibert et al., 1994). Responses to
whisker stimulation were tested after each concentration of NS-398 was
applied for 40 min. This time point was selected on the basis of
preliminary experiments in which the time course of the effect of
NS-398 on CBF responses to vibrissal stimulation was studied (data not shown).
Effect of NS-398 on the increase in CBF produced by other
vasodilators in C57BL/6 mice. The cranial window was superfused with Ringer's, and baseline CBF responses to topical application of
acetylcholine (ACh) (10 µM; Sigma, St. Louis,
MO) or bradykinin (BK) (50 µM; Sigma) were
tested. Agents were superfused on the cerebral cortex for 3-5 min at
concentrations that produce 50% of maximal responses (Iadecola et al.,
1999). The vasodilation produced by arterial hypercapnia was also
tested. Hypercapnia (pCO2 = 50-60 mmHg) was
produced by introducing CO2 through the circuit
of the ventilator and was induced for 2-3 min. After the hypercapnia
challenge was completed, pCO2 was returned to normocapnia.
Increases in CBF produced by vibrissal stimulation in COX-2 null
mice. In these experiments, the vibrissae were stimulated in COX-2
/ and COX-2 +/+ mice, and the evoked changes in CBF were recorded.
CBF responses to topical application of ACh or BK or to arterial
hypercapnia were studied using methods described above. In some
experiments, the effect of NS-398 on the CBF response evoked by
vibrissal stimulation was tested in COX-2 +/+ and / mice. NS-398
was applied for 40 min at a concentration of 100 µM.
Data analysis
Data in text and figures are expressed as means ± SE.
Two-group comparisons were analyzed by the two-tailed t test
for independent samples. Multiple comparisons were evaluated by the
ANOVA and Tukey's test. p < 0.05 was
considered statistically significant.
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RESULTS |
Effect of NS-398 on the increase in CBF produced by
vibrissal stimulation
In these experiments, we studied the effect of the COX-2 inhibitor
NS-398 on the increases in CBF produced by vibrissal stimulation in
C57BL/6 mice. During superfusion with Ringer's, vibrissal stimulation increased CBF in the contralateral somatosensory cortex by 30 ± 1% (n = 6), an increase comparable with that reported
previously in this preparation (Ma et al., 1996). The increases in CBF
reached a stable plateau within 10-20 sec of stimulation (Fig. 1).
Superfusion with NS-398 (10-300 µM) did not
influence resting CBF [before NS-398 (100 µM),
20.7 ± 0.5 perfusion units; after NS-398, 20.6 ± 0.7;
p > 0.05], but it attenuated the increase in CBF
produced by vibrissal stimulation substantially (Figs. 1,
2). The effect of NS-398 was
dose-dependent and reached a maximum at 100 µM
(47 ± 7%; p < 0.01). In contrast, NS-398 did
not alter the flow increase produced by hypercapnia
(p > 0.05) (Fig. 2) or by topical application of ACh and BK (p > 0.05) (Fig.
3).
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Figure 2.
Effect of the COX-2 inhibitor NS-398 on the
increases in neocortical CBF produced by vibrissal stimulation
(A) or hypercapnia (B).
NS-398 was topically superfused on the exposed somatosensory cortex,
and CBF was recorded by laser-Doppler flowmetry. NS-398 attenuates the
increase in CBF produced by vibrissal stimulation
(A) (p < 0.01; ANOVA
and Tukey's test) but does not affect the response to hypercapnia
(B) (p > 0.05).
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Figure 3.
Effect of NS-398 on the increase in CBF produced
by topical application of the endothelial-dependent vasodilators
acetylcholine (A) or bradykinin
(B).
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Effect of vibrissal stimulation on CBF in COX-2 null mice
To provide additional evidence that COX-2 is involved in the flow
response evoked by somatosensory activation, COX-2 null mice were
studied. In COX-2 / mice, the increase in CBF produced by vibrissal
stimulation was markedly reduced compared with COX-2 +/+ littermates
(37 ± 2%) (Figs. 1, 4). However,
the increases in CBF produced by hypercapnia or topical application of
ACh and BK were not affected (Figs. 4,
5). In COX-2 +/+, topical superfusion of
NS-398 (100 µM) reduced the CBF response to vibrissal
stimulation (37 ± 1%; p < 0.01) (Fig. 4)
without attenuating responses to hypercapnia, ACh, or BK (Figs. 4, 5)
(p > 0.05). However, in COX-2 / mice,
NS-398 failed to influence the CBF response to somatosensory activation
(Fig. 4).
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Figure 4.
Effect of NS-398 on the increases in CBF produced
by vibrissal stimulation (A) or hypercapnia
(B) in homozygous COX-2 null mice (/) or in
wild-type littermates (+/+). The response to whisker stimulation is
attenuated in COX-2 null mice (p < 0.01).
Furthermore, NS-398 (100 µM) attenuated the response in
COX-2 +/+ but not in COX-2 / mice. The response to hypercapnia
(B) is not affected in COX-2 / null mice and
is not attenuated by NS-398 in either COX-2 / or +/+ mice
(p > 0.05).
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Figure 5.
Effect of NS-398 on the increases in CBF produced
by acetylcholine (A) or bradykinin
(B) in homozygous COX-2 null mice (/) or in
wild-type littermates. These responses are not affected in COX-2 /
null mice and are not attenuated by NS-398 (100 µM) in
either COX-2 / or +/+ mice (p > 0.05).
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Effect of vibrissal stimulation on CGU in COX-2 null mice
In COX-2 +/+ mice, CGU ranged from 64 ± 7 µmol/100 gm/min
in the left corpus callosum to 260 ± 38 in the left inferior
colliculus (Table 2, COX-2 +/+
column). Vibrissal stimulation increased CGU selectively in the
contralateral somatosensory cortex (+39 ± 5%), contralateral
ventrobasal thalamus (+41 ± 11%), and ipsilateral trigeminal
nucleus (+54 ± 15%) (p < 0.01) (Table
2). In COX-2 / mice, resting CGU was not different from that of
COX-2 +/+ mice in any of the brain regions studied (Fig.
6, Table 2) (p > 0.05). Furthermore, the increases in CGU in somatosensory relay nuclei
were similar to those observed in COX-2 +/+ mice (Table 2).
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Figure 6.
Effect of vibrissal stimulation on CGU in the
somatosensory cortex of COX-2 null mice. Vibrissal stimulation produces
comparable increases in CGU in COX-2 wild-type (+/+) and null (/)
mice. See Table 2 for group values.
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DISCUSSION |
We sought to determine whether the prostanoid-synthesizing enzyme
COX-2 is involved in the increases in CBF produced by functional activation. Using a mouse model of somatosensory activation, we found
that the COX-2 inhibitor NS-398 attenuates the increase in
somatosensory cortex blood flow produced by vibrissal stimulation. The
attenuation is related to the concentration of the inhibitor and is
independent of effects on resting CBF. Interestingly, NS-398 did not
attenuate the increase in CBF produced by hypercapnia, a response that
is not linked to neural activity (Iadecola et al., 1987; Fabricius and
Lauritzen, 1994). Furthermore, NS-398 did not alter the increase in CBF
produced by topical application of ACh or BK, vasodilators that act by
releasing vasoactive factors from the endothelium (Rosenblum, 1986;
Mayhan, 1996; Sobey and Faraci, 1997; Sobey et al., 1997). The findings
indicate that NS-398 attenuates vasodilator responses mediated by
neural activation, and they are consistent with the exclusive neuronal
localization of COX-2 in the normal brain (Yamagata et al., 1993;
Breder et al., 1995; Kaufmann et al., 1996).
To provide independent evidence that COX-2 is involved in the
mechanisms of functional hyperemia, mice with a null mutation of the
COX-2 gene were studied (Morham et al., 1995). We found that the
increase in CBF produced by vibrissal stimulation is attenuated in
COX-2 / mice, whereas responses to hypercapnia and to topical
application of ACh or BK were preserved. To rule out the possibility
that the attenuation in functional hyperemia resulted from a reduction
in neural activation during vibrissal stimulation, we studied the
effect of vibrissal stimulation on CGU, a reliable marker of synaptic
activity (Yarowsky et al., 1983). It was found that the increase in CGU
in the whisker-barrel cortex and in other somatosensory relay stations
did not differ between COX-2 +/+ and / mice. Therefore, the
attenuation in functional hyperemia in COX-2 / mice cannot be
attributed to a reduction in the intensity of neural
activation. However, the possibility that the time course of
the activation differs between COX-2 +/+ and / mice cannot be ruled
out, because the 2-DG method has a limited temporal resolution. Thus,
the 2-DG method provides an average of CGU during the 45 min
measurement period, albeit heavily weighted toward the first 10 min
(Sokoloff et al., 1977). The findings in COX-2 null mice, in concert
with the pharmacological data with NS-398, provide strong evidence that
COX-2 is involved in the mechanisms coupling synaptic activity to blood
flow in brain.
The findings of the present study cannot be attributed to secondary
effects on CBF resulting from differences in physiological variables.
Arterial pressure and blood gases were carefully monitored and did not
differ among the groups of mice studied. In addition, the effect of
NS-398 is unlikely to result from a nonspecific blockade of all
vasodilator responses, because this inhibitor did not attenuate the CBF
response to hypercapnia, ACh, or BK. Furthermore, the observation that
NS-398 does not alter the increase in CBF produced by vibrissal
stimulation in COX-2 null mice supports the selectivity and specificity
of the effects of NS-398 in this model. A major drawback of studies
using null mice is that compensatory changes initiated by the missing
gene product may alter the normal physiology of the mouse (Gerlai,
1996). Furthermore, because most null mice have a mixed genetic
background (C57BL/6 and SV129), the possibility that the observed
effects result from strain differences cannot be ruled out (Choi,
1997). However, these concerns do not apply to the present study,
because acute pharmacological inhibition of COX-2 reproduced in full
the cerebrovascular "phenotype" of the COX-2 null mice. Therefore,
the reduced CBF response to vibrissal stimulation in COX-2 null mice
cannot be attributed to heterogeneity of the genetic background or to
compensatory changes in cerebrovascular physiology resulting from COX-2
deletion. In addition, the fact that acute COX-2 inhibition with NS-398
reproduces the cerebrovascular effects of COX-2 deletion rules out the
possibility that alterations in neuronal development resulting from
lack of COX-2 are responsible for the reduction in the hyperemic response.
The mechanisms regulating the cerebral circulation during synaptic
activity have been investigated extensively over the past century. The
prevailing view is that working brain cells release vasoactive agents
that spread to local blood vessels and produce vasodilation (Iadecola,
1993; Woolsey et al., 1996). Over the years, a wide variety of factors,
including H+ and K+ ions,
CO2, hypoxia, adenosine, neurotransmitters, and
neuropeptides, have been proposed to play a role in the coupling
between synaptic activity and blood flow (Kuschinsky et al., 1972;
Leniger-Follert, 1984; Yaksh et al., 1987; Ko et al., 1990) (for
review, see Edvinsson et al., 1993). However, as discussed in detail
previously (Edvinsson et al., 1993; Iadecola, 1993; Lou et al., 1987),
conclusive evidence that these agents are involved in the vasodilation
initiated by functional activity is lacking. Recently, neurons
containing nitric oxide synthase (NOS) have been proposed to be
involved in the mechanisms coupling synaptic activity to blood flow
(Gally et al., 1990; Iadecola, 1993). Initial observations supported
this hypothesis by demonstrating that pharmacological inhibition of NOS
in somatosensory cortex attenuates the increase in CBF produced by
vibrissal stimulation (Northington et al., 1992; Dirnagl et al., 1993;
Irikura et al., 1994). However, subsequent findings have challenged
this idea. Mutant mice lacking neuronal NOS (nNOS) have a normal
neocortical flow increase in response to vibrissal stimulation (Ma et
al., 1996), suggesting that nNOS is not required for the hyperemic
response. Furthermore, other studies have indicated that NO acts more
as a "permissive" factor, facilitating the action of other
vasodilators, than as the mediator of vasodilation (Niwa et al., 1993;
Lindauer et al., 1999) (for review, see Iadecola, 1999). Therefore, the
presence of NO is not an absolute requirement for the CBF increases
evoked by synaptic activity.
In contrast, we have shown here that acute inhibition of COX-2 by
NS-398 and deletion of COX-2 by gene-targeting approaches produce
comparable attenuations of the increase in CBF evoked by somatosensory
activation. Therefore, the presence of COX-2 is absolutely required for
the full expression of the vasodilation. These data demonstrate that
COX-2 plays a critical role in the mechanisms coupling synaptic
activity to blood flow and provide functional evidence for a
participation of COX-2 in activity-dependent processes in the CNS.
The mechanisms by which COX-2 influences CBF during neural activity
remain to be defined. In the normal rodent brain, COX-2 is expressed
exclusively in neurons (Yamagata et al., 1993; Breder et al., 1995;
Kaufmann et al., 1996). It is, therefore, likely that neuronal COX-2 is
involved in the coupling between synaptic activity and blood flow. One
possibility is that COX-2 is activated during neuronal depolarization
and that COX-2 reaction products, either directly or through another
agent, influence vascular tone and produce vasodilation. Prostaglandin
E2 and prostacyclin, metabolites of the COX-2 reaction product
prostaglandin H2 (Brock et al., 1999), or superoxide, the other
product of COX-2, are potent cerebrovasodilators (Ellis et al., 1979;
Leffler and Busija, 1987; Wei et al., 1996). It would also be of
interest to determine whether neurons containing COX-2 have close
associations with cerebral blood vessels. For example, central neurons
containing NOS, dopamine, ACh, and vasoactive intestinal polypeptide
have processes closely apposed to cerebral blood vessels (Eckenstein
and Baughman, 1984; Iadecola et al., 1993; Vaucher and Hamel, 1995;
Krimer et al., 1998). However, most morphological data on the
localization of COX-2 in neurons were obtained in rats, and it would be
important to determine whether a similar localization is present also
in other species. Irrespective of the specific COX-2 reaction
product(s) involved in the vasodilation and the relationships of COX-2
neurons to blood vessels, the present results are noteworthy because
they provide, for the first time, evidence that COX-2 is involved in the mechanisms regulating CBF during synaptic activity.
In conclusion, we have demonstrated that pharmacological inhibition of
COX-2 with NS-398 attenuates the increase in CBF produced by
somatosensory activation. The increase in CBF is also attenuated in
mice lacking COX-2. Vasodilator responses of the cerebral circulation that do not depend on neuronal activity were not influenced by NS-398
and were preserved in COX-2 null mice. The attenuation of the CBF
response in null mice cannot be attributed entirely to a reduction in
the intensity of activation produced by vibrissal stimulation. The
findings unveil a critical role of COX-2 in the mechanisms coupling
synaptic activity to neocortical blood flow and provide an insight into
one of the functions of constitutive COX-2 in the CNS.
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FOOTNOTES |
Received Sept. 13, 1999; revised Oct. 14, 1999; accepted Nov. 1, 1999.
This work was supported by National Institutes of Health Grants NS35806
and NS38252. C.I. is the recipient of a Javits Award from National
Institutes of Health/National Institute of Neurological Disorders and
Stroke. The editorial assistance of Deborah Kabes is gratefully acknowledged.
Correspondence should be addressed to Dr. C. Iadecola, Department of
Neurology, University of Minnesota, Box 295, University of Minnesota
Health Center, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail:
iadec001{at}tc.umn.edu.
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TOP
ABSTRACT
INTRODUCTION
