1259
Effect of Indomethacin on Edema
Following Single and Repetitive
Cerebral Ischemia in the Gerbil
Karl S. Deluga, MD; Frans B. Plotz, MD; and A. Lorris Betz, MD, PhD
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Background and Purpose: Repetitive periods of cerebral ischemia result in more severe injury
than a single period of ischemia of similar total duration. We investigated the possibility of
prostaglandin mediation of this increased injury by attempting to modify brain edema
formation with indomethacin pretreatment
Methods: Under halothane/NjO anesthesia, groups of gerbils underwent bilateral carotid
occlusion to induce forebrain ischemia. Group I underwent a single 15-minute period of carotid
occlusion. Group II underwent three 5-minute periods of occlusion at hourly intervals. Groups
III and IV were similar to groups I and II, respectively, but received 0.2 mg/kg indomethacin
before carotid occlusion. Cortical and ccrebellar water and sodium contents were determined
in control animals (n=6) at time zero and in experimental animals 24, 48, and 72 hours after
ischemia (n=6-10 gerbils/group at each time point).
Results: Cortical water and sodium contents in group II peaked 48 hours after insult
(82.15±0_31% and 420±14 meq/kg dry wt, respectively) and were significantly higher than
control and group I values at both 24 and 48 hours. Cortical water did not change from control
in group I animals. Indomethacin pretreatment significantly attenuated increases in water and
sodium content seen at 48 hours in gerbils undergoing repetitive ischemia (peak 80.02 ±0.45%
and 300±39 meq/kg dry wt), but did not affect mortality.
Conclusions: Indomethacin lessens edema after repetitive cerebral ischemia, suggesting that
elevations of cyclooxygenase products are responsible, at least in part, for severe brain edema
following repetitive ischemia. (Stroke 1991^2:1259-1264)
M
ultiple, repetitive hypoxic or ischemic brain
insults may occur in a variety of clinical
circumstances such as transient ischemic
attacks, surgical procedures, arrhythmias, or during
the intrapartum period. In experimental models,
brief repetitive periods of cerebral ischemia have
been shown to be more damaging than a single
period of cerebral ischemia of similar total duration.1
The mechanism(s) responsible for this exacerbation
of cerebral injury is unknown; however, several possibilities exist, including progressive accumulation of
cytotoxic substances such as free radicals, prostaglandins, and excitatory neurotransmitters or exaggerated
alterations of cerebral blood flow.
Although it is known that prostaglandins accumulate during ischemia and reperfusion,2"5 the signifiFrom the Departments of Pediatrics (K.S.D., F.B.P., A.L.B.),
Surgery (A.L.B.), and Neurology (A.L.B.), University of Michigan,
Ann Arbor.
Address for reprints: Karl S. Deluga, MD, L3023 Women's
Hospital/0254, University of Michigan Medical Center, 1500 E.
Medical Center Drive, Ann Arbor, Ml 48109-0254.
Received April 12, 1991; accepted June 11, 1991.
cance of these changes is unknown. In an effort to
further characterize the model of repetitive ischemia
we documented the time course of changes in brain
water and sodium caused by single and repetitive
periods of cerebral ischemia and also compared the
degree of edema caused by each type of insult. In
addition, some animals were pretreated with the
cyclooxygenase inhibitor indomethacin in an attempt
to determine if excessive accumulations of prostaglandins might mediate the more severe edema seen
after repetitive ischemia.
Materials and Methods
One hundred fifteen adult male gerbils (Meriones
unguiculatus), mean weight (±SEM) 74 ±1 g (Tumblebrook Farms, West Brookfield, Mass.), were used
in the study. Surgical procedures and general care
were conducted in accordance with the University of
Michigan principles for the care and use of laboratory animals.
The gerbils were divided into one control group
and four experimental groups. Control animals
(n=6) were killed and processed as described below,
1260
Stroke Vol 22, No 10 October 1991
immediately after induction of anesthesia, without
femoral or neck surgery. The experimental groups
I-IV were treated as follows: group I received a
single 15-minute period of bilateral carotid occlusion
after pretreatment with 0.9% saline, group II underwent three 5-minute periods of bilateral carotid
occlusion at hourly intervals after pretreatment with
0.9% saline, group III received a single 15-minute
period of bilateral carotid occlusion after pretreatment with 0.2 mg/kg i.v. indomethacin (Merck Sharp
& Dohme) dissolved in 0.9% saline 15-20 minutes
before ischemia, and group IV underwent three
5-minute periods of bilateral carotid occlusion at
hourly intervals after pretreatment with 0.2 mg/kg
i.v. indomethacin in 0.9% saline 15-20 minutes before ischemia.
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After weighing, anesthesia was induced by 2%
halothane with 70% N2O/30% O2. Previous experiments had documented that this level of anesthesia
did not result in hypotension. Body temperature
was maintained between 36-38°C using a servocontrolled warming pad and rectal temperature
probe. In experimental gerbils, the left femoral vein
was cannulated with PE-10 tubing followed by injection of saline or indomethacin (0.2 mg/kg) each at a
volume of 2 ml/kg body wt. The catheter was then
removed, the femoral vein cauterized, and the incision sutured. After completion of the femoral surgery, the anesthesia was decreased to 0.5% halothane
and 70% N2O/30% O2.
The carotid arteries were approached by a midline
anterior cervical incision. Each carotid artery was
carefully isolated from surrounding nerves and veins.
After isolation, a loose 5-0 ligature was placed
around each vessel for ease in handling. Week microaneurysm clips were placed on the left carotid and
then the right. The interval between occlusion of the
left and right carotid arteries ranged from 5 to 15
seconds. Cessation of blood flow was visually confirmed in all cases. After the specified time, the clips
were removed and reestablishment of flow was confirmed visually. The skin incision was sutured and the
anesthesia was stopped. The gerbil remained supine
on the warming blanket until awake enough to right
itself, at which time it was placed in a cage.
Gerbils requiring multiple carotid occlusions were
reanesthetized with halothane/N2O/O2 just before
carotid reocclusion. The carotids were occluded in a
similar fashion 1 hour after the previous occlusion.
Animals in groups requiring only a single 15-minute
carotid occlusion underwent two further periods of
anesthesia at hourly intervals but without carotid
occlusion to control for possible effects of repeated
anesthesia.
Nine gerbils underwent sham surgery to mimic
repetitive occlusion. After femoral vein cannulation,
neck surgery was performed. The carotid arteries
were isolated and manipulated, but no occlusion was
performed. This was repeated along with anesthesia
a total of three times. Five animals were pretreated
with saline and four with indomethacin. All were
killed 48 hours after surgery.
Experimental animals (groups I-IV) were killed by
decapitation 24,48, or 72 hours after the final carotid
occlusion. Each gerbil was placed in an ether jar for
30-45 seconds before being killed. Control gerbils
were decapitated immediately after induction of anesthesia. Each brain was removed from the cranium,
and the brain stem was removed and discarded. The
cerebellum was removed and placed in a preweighed
crucible. The cerebral hemispheres were divided in
the saggital plane, and the cortex was separated from
the deep white matter with curved forceps. Each
cortex was placed in a preweighed crucible. After
determination of the wet weights, each sample was
baked at 100°C for 24 hours and the dry weight
measured. Percent tissue water was then calculated
for the cortex and nonischemic cerebellum. The
dessicated tissue was then ashed at 400°C for 16
hours, and the sodium content of each tissue region
was determined by flame photometry. After determination of percent tissue water and sodium content,
the results obtained from each hemicortex of an
individual gerbil were combined before statistical
analysis.
After the brain water and sodium contents of each
brain region at 24,48, and 72 hours were determined,
single-factor analysis of variance was used to compare results of each group to control values. A value
of p=0.05 was used to assign significance. Two-tailed
Student's t tests with Bonferroni's correction were
used to compare given parameters between different
experimental groups at 24-, 48-, and 72-hour time
points (group I versus II, group I versus III, and
group II versus IV). Fisher's exact test was used to
compare mortality related to type of ischemic insult
and type of pretreatment.
Results
Following a single 15-minute period of ischemia
after saline pretreatment (group I), the percent
water (±SEM) of the cortex increased from
79.10±0.22% (control) to a maximum of
80.14±0.46% at 48 hours, a change that did not reach
statistical significance. Cortical sodium content after
this insult increased significantly from 206 ±2 in
control cortices to 258±11 meq/kg dry wt at 48 hours
)
In contrast to single ischemia, a marked increase in
both cortical water and sodium content occurred in
gerbils after multiple periods of ischemia (group II)
as compared with control values, with cortical brain
water reaching a maximum of 82.15±0.31%
(p^0.0001) and cortical sodium content reaching
420±14 meq/kg dry wt (/?<;0.0001). The peak of each
measurement occurred 48 hours after the insult in
both groups.
Gerbils undergoing a single period of ischemia and
that were pretreated with indomethacin (group III)
showed changes in cortical water and sodium content
Deluga et al
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that were similar to those seen in gerbils undergoing
a similar insult but that were pretreated only with
saline (group I). Group III gerbils did not show an
increase in brain water compared with control values
(peak value, 79.70±0.18%), but had significantly
increased cortical sodium content (peak value,
242±7 meq/kg dry wt,/>=0.026).
Gerbils undergoing repetitive ischemia after pretreatment with indomethacin (group IV) showed
significant increases in both cortical water (peak
value, 80.90±0.36%, p=0.005) and sodium content
(peak value, 335±36 meq/kg dry wt, />=0.03) compared with control values. The values for these
measurements changed minimally from 24 to 72
hours after insult.
Sham-operated gerbils pretreated with saline or
indomethacin and killed 48 hours after surgery
showed no change in cortical water content
(79.05+0.07% and 79.07±0.07%, respectively, versus
79.10±0.22%, control). No change was noted in
cortical sodium content of saline pretreated shamoperated gerbils (216±4 meq/kg dry wt), and a
modest, but significant, increase was seen in indomethacin-treated, sham-operated gerbils (225 ±7 versus 206±2 meq/kg dry wt, control,/?=0.01).
Comparisons at individual time points between
groups undergoing single and repetitive ischemia
after saline pretreatment (Figure 1A) showed that
brain water was significantly higher after multiple
ischemic periods (group II) than after a single ischemic period (group I) both 24 and 48 hours after the
insult (/>=0.008 and 0.005, respectively). There was
no significant difference in brain water between
groups I and II at 72 hours. Similarly, cortical sodium
content (Figure IB) was significantly higher in gerbils
that underwent three 5-minute periods of ischemia
(group II) rather than a single 15-minute period of
ischemia (group I) both 24 and 48 hours after ischemia (p=0.002 and 0.0001, respectively).
The cerebellum, which is not made ischemic in the
gerbil model of bilateral carotid occlusion,6 had
water contents ranging from 76.28% to 77.20% and
sodium contents ranging from 177 to 194 meq/kg dry
wt in groups I and II (Table 1). None of these values
differed significantly from the control values of
76.70 ±0.26% and 181 ±3 meq/kg dry wt, nor were
there differences between groups at any time point
after ischemia.
As previously stated, single ischemia with saline
pretreatment resulted in no significant change from
control in cortical water content, but a modest,
though significant, increase in cortical sodium content. Comparison of groups receiving saline or indomethacin before a single 15-minute period of ischemia revealed no significant differences between
groups I and III in either cortical water or sodium
content at any time point after ischemia (Figure 1).
There were no differences in cerebellar water
content between group I and group HI gerbils at any
time point after ischemia, nor did any of these values
differ from control. As noted, the sodium content of
Edema After Repetitive Cerebral Ischemia
1261
Q15UkVS*ln>
77
—D-
ID) 1 5 1 * * * .
—•*-
IV)3i5UW1ndD.
75
24
48
72
48
72
TIME (hrs)
l)15MWSalna
II) 3 x 5 Mn/Saln»
450
lll)15MWlndo.
IV) 3 x 5 MWIndo.
1
I
350
250
150
0
24
TIME (hrs)
FIGURE 1. Cortical water (A) and sodium (B) contents at
various times after ischemia. Each point is mean±SEM of six
to 10 animals. (*p^0.008, **ps0.005, group I vs. II and
tp«S0.00J, ftp 50.076, group II vs. IV using two-tailed Student's t test with Bonferroni's correction at individual time
points.)
the cerebellums of group I gerbils did not differ from
control. Sodium content of the cerebellums of group
III gerbils differed from control values (Table 1) only
at the 24-hour time point (p=0.01). This value was
also significantly higher than the corresponding value
in group I (220±9 versus 194±2 meq/kg dry wt,
p=0.015).
Comparison of gerbils undergoing repetitive ischemia (Figure 1) that received indomethacin (group
IV) to those pretreated with saline (group II) revealed
significantly less brain water (80.02 ±0.45 versus
82.15±0.31%, />=0.003) and lower sodium content
(300±39 versus 420±14 meq/kg dry wt, p=0.016) 48
hours after the insult in the gerbils pretreated with
indomethacin. Differences at 24 and 72 hours were
not significant.
The values for cerebellar water and sodium content (Table 1) in gerbils from groups II and IV did
not differ from control values, nor were there significant differences between the two groups at any time
point.
Cerebellar water content of animals undergoing
sham surgery after saline or indomethacin treatment
showed no change in water content (76.99±0.20 and
76.80±0.09, respectively, versus 76.70±0.26, control).
1262
Stroke Vol 22, No 10 October 1991
TABLE 1.
Cerebellar Water and Sodium Contents of Control and Experimental Gerblls at Individual Time Points
Time (hrs)
% Water
Control 76.70±0.26 (6)
I) 15 minutes/saline
II) 3x5 minutes/saline
III) 15 minutes/indo
XV) 3x5 minutes/indo
Sodium (meq/kg dry wt)
Control 181 ±3 (6)
I) 15 minutes/saline
II) 3x5 minutes/saline
III) 15 minutes/indo
XV) 3x5 minutes/indo
24
48
72
76.52±0.32 (9)
76.28±0.16 (10)
76.69±0.91 (7)
77.59±0.51 (10)
77.00±0.18 (6)
77.20±0.27 (6)
76.57±0.50 (6)
76.12±037 (6)
76.45±0.16(6)
76.94±0.27 (6)
76.66+0.27 (9)
76.84+0.25 (8)
194±2(9)
193±6 (10)
220±9' (7)
182±9 (9)
182±10(6)
177±13 (6)
198±10(6)
178±10(6)
180+7 (6)
178±3 (6)
194±6 (9)
2O0±8 (9)
Values are mean±SEM. Indo, indomethacin. Number in parentheses after each value represents number of animals
at given time point (*ps0.015 compared with control value and group I animals at same time point).
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Cerebellar sodium content was slightly elevated in
both these groups of gerbils (202 ±7 and 203 ±8,
respectively, versus 181 ±3 meq/kg dry wt, control,
/7<;O.O2).
Mortality after a single 15-minute ischemic insult
(those dying before the 48- or 72-hour time point)
was 6.9% (two of 29 animals). There was no difference based on pretreatment with saline or indomethacin (zero of 12 versus two of 17, p=0.34, Fisher's
exact test). Mortality after repetitive ischemia was
25% (nine of 36), also with no significant difference
noted after saline or indomethacin pretreatment
(three of 15 versus six of 21, p=0A3, Fisher's exact
test). The difference in mortality between gerbils
undergoing single or repetitive ischemia (combining
saline- and indomethacin-treated gerbils) was significant (two of 29 versus nine of 36, p=0.05, Fisher's
exact test). Comparison of mortality based only on
treatment with saline or indomethacin showed no
significant difference (three of 27 versus eight of 38,
respectively, p=0.24, Fisher's exact test).
Discussion
Our results indicate that brain edema resulting
from three 5-minute periods of cerebral ischemia
spaced at hourly intervals peaks approximately 48
hours after the insult. The time course of edema seen
after a single 15-minute period of cerebral ischemia is
similar, but the change in the percentage of cortical
water did not reach statistical significance and thus the
presence of edema is not clearly documented. However, the increased sodium content in the cortex after
a single ischemic insult was significant and paralleled
the increase in water content, suggesting that edema
was present after 15 minutes of ischemia. Both water
content and sodium accumulation in the cortex were
significantly greater after repetitive ischemia.
Although cortical sodium and water content
peaked 48 hours after the ischemic insult, the level
and timing of the peak may be misleading. After
repetitive ischemia, 25% of the gerbils died before 48
or 72 hours and thus were not included in the
determination of edema or sodium content. Animals
that died after an ischemic insult might reasonably be
expected to be more severely affected than the
survivors. Thus, the peak in edema and sodium
content seen at 48 hours might have been higher and
the subsequent decline less rapid after repetitive
ischemia if the values for brain water and sodium
content of gerbils that died could have been included.
Similarly, higher mortality in the gerbils undergoing repetitive ischemia that received indomethacin
could artificially lower the mean values for brain
water and sodium content compared with repetitive
ischemia animals pretreated with saline. As noted
above, mortality was not significantly different in the
repetitive ischemia gerbils based on saline or indomethacin pretreatment. Nonetheless, the fact that
the mortality was slightly higher after indomethacin
pretreatment (28.6% versus 20%) may have lowered
the mean values for water and sodium content in
these gerbils to some degree.
As expected, the nonischemic cerebellum did not
show significant water accumulation at any time point
in any group. The magnitude of the increase in the
cerebellar sodium content at 24 hours in gerbils
subjected to 15 minutes of ischemia after indomethacin pretreatment (group III) was small in comparison to changes in the cortex. Similarly, gerbils that
underwent sham surgery showed no changes in cortical or cerebellar water content but tended to show
slight increases in sodium content. These were small
in comparison to cortical changes after repetitive
ischemia. We believe these to be of unlikely biological significance despite their statistical significance;
however, a minor effect of surgery or anesthesia is
also possible.
These data confirm and expand on data reported
previously. Tomida et al1 documented greater damage histologically, lower tissue specific gravity, and
higher mortality 24 hours after insult in animals that
underwent repetitive ischemia as opposed to a single
Deluga et al
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period of ischemia. Our data confirm that there is
increased brain edema in animals that persists beyond 24 hours after repetitive ischemia. The most
severe edema occurs 48 hours after insult.
Gerbils subjected to 15 minutes of ischemia and
pretreated with saline or indomethacin had no notable differences in cortical edema or sodium content.
Both groups had insignificant elevations of cortical
water, but significant increases in cortical sodium
content. In view of the marginal degree of edema, it
is perhaps not surprising that no discernable effect
was found with indomethacin pretreatment. In contrast, in gerbils subjected to repetitive ischemia,
indomethacin pretreatment resulted in a marked
decrease in the amount of edema and sodium accumulation at the 48-hour time point in comparison to
saline-treated gerbils.
The mechanism by which indomethacin lessens
cerebral edema after repetitive ischemia is unclear.
Indomethacin has been used to lessen postischemic
cerebral edema in other animal models7"9 where it
has been effective during partial ischemia and ischemia with reperfusion, suggesting that arachidonic
acid and prostaglandins are at least partially responsible for edema seen after ischemia. The level of
arachidonic acid, the major substrate for prostaglandin synthesis, increases during brain ischemia,10 and
several prostaglandins have been shown to increase
during postischemic reperfusion.4-5 Prostaglandins,
particularly of the E and I series, are well known to
affect capillary permeability and cause vascular dilation.11 Thus, increases in the levels of these prostaglandins may lead to capillary leakage and edema.
These parameters have not been studied in the
context of repetitive ischemia; however, the effect of
indomethacin on edema after repetitive ischemia
suggests that prostaglandins are involved.
Mechanisms involving prostaglandins by which repetitive ischemia could cause increased brain injury
are speculative. As suggested by Tomida et al,1
repetitive periods of ischemia that occur during
postischemic hypoperfusion may be a critical prerequisite for aggravated cerebral injury. The levels of
some prostaglandins appear to peak in brain tissue
after only a few minutes of reperfusion and to
decrease within 15 minutes after ischemia.4 Levels in
the cerebrospinal fluid peak at varying times with
dilator prostaglandins peaking early in reperfusion
and constrictors later,2 resulting in a predominance
of constrictor prostaglandins. This may be significant
with repetitive ischemia. Ischemia occurring at the
time of constrictor prostaglandin predominance may
further aggravate this imbalance between constrictor
and dilator prostaglandins. Ischemic periods at
hourly intervals occur during the hypoperfusion or
presumed constrictor predominance period.
Conversely, a balance between dilator and constrictor prostaglandins may also explain why repetitive ischemia with short interischemic periods (i.e.,
3-10 minutes) does not appear to cause damage as
severe as that seen with interischemic intervals of 60
Edema After Repetitive Cerebral Ischemia
1263
minutes.1 Ischemia commencing during the vasodilator prostaglandin predominance phase (hyperemic
phase) might have a different effect on the relationship of constrictor and dilator prostaglandins. To our
knowledge, these possibilities have not been examined in the model of repetitive cerebral ischemia.
Based on the scheme outlined above, one might
expect that indomethacin treatment before ischemia
may affect postischemic cerebral hemodynamics. Indomethacin has been used in animal models to
ameliorate postischemic hypoperfusion.12-14 Repetitive ischemia results in hypoperfusion after each
period of cerebral ischemia1 that does not appear to
be more severe than that seen after a single equivalent period of ischemia; however, the reactive hyperemia seen immediately after each successive period
of ischemia appears less pronounced. The lessened
hyperemia may impede the reestablishment offlowin
previously ischemic areas that are blocked because of
platelet clumps or swelling of capillary endothelium.
The successively lower degree of reperfusion might
result in progressively enlarging areas of no-reflow
and presumed continued microvascular ischemia.
Vass et al15 correlated abnormalities of the microcirculation after repetitive ischemia with brain tissue
edema. Thus, if indomethacin improves reflow during
the hyperemic phase or lessens the degree of later
hypoperfusion, this later persistent and widening
area of ischemia after repetitive ischemia may be
prevented.
Other mechanisms not directly dependent on prostaglandin levels may be involved. Free radicals, which
have been implicated in the development of ischemic
brain edema,16 are generated via the cyclooxygenase
pathway.17 If arachidonic acid is released with each
successive ischemic insult, further generation of free
radicals will occur as arachidonic acid is removed via
the cyclooxygenase pathway, possibly inducing further damage. Prevention of repetitive release of
these reactive molecules by cyclooxygenase inhibition
may account for the effects of indomethacin.14
Indomethacin might also exert effects by affecting
brain temperature in the peri-ischemic period. Small
differences in brain temperature are known to affect
the extent of cerebral injury after ischemia18 and
transient hyperthermia has been noted to occur in
animals after cerebral ischemia.19 Repeated bouts of
cerebral hyperthermia after ischemia, which were
undetected by core temperature monitoring, could
account for more severe damage occurring after
repetitive ischemia. Indomethacin has known antipyretic effects and by suppressing temperature elevations might decrease cerebral injury. This possibility, along with those previously mentioned, will
require further investigation, both to delineate the
mechanism(s) of increased injury with repetitive ischemia and of its amelioration by indomethacin.
In summary, our results indicate that edema after
repetitive cerebral ischemia may be secondary to
changes in prostaglandin metabolism and suggest
that differences in prostaglandin metabolism are
1264
Stroke Vol 22, No 10 October 1991
responsible for the differences in edema seen after
single or repetitive cerebral ischemia. Other mechanisms are also possible, thus comparison of prostaglandin levels and the effects of indomethacin on
postischemic perfusion and brain temperature in
this repetitive ischemia model may provide important information concerning the mechanisms of
ischemic brain injury.
References
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KEY WORDS • indomethacin • cerebral ischemia • brain
edema • gerbils
Effect of indomethacin on edema following single and repetitive cerebral ischemia in the
gerbil.
K S Deluga, F B Plötz and A L Betz
Stroke. 1991;22:1259-1264
doi: 10.1161/01.STR.22.10.1259
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Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
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