(Stroke. 1997;28:2238-2243.)
© 1997 American Heart Association, Inc.
Articles |
Hypothermic Neuroprotection
A Global Ischemia Study Using 18- to 20-Month-Old Gerbils
From the Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's (D.C.); Centre de Recherche en Sciences Neurologiques et Département de Physiologie, Université de Montréal, Québec (S.N.); and Department of Neurosciences, Faculty of Medicine, University of Calgary (Canada) (F.C.).
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Abstract |
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Background and Purpose Previous studies from this laboratory have shown that mild intraischemic or prolonged (ie, 12 to 24 hours) postischemic hypothermia conveys long-lasting (1 to 6 months) protection against CA1 injury. However, these studies have used young animals (aged
3 to 5 months). Stroke
incidence rises sharply in late middle age at a time when changes in
brain chemistry could alter the response to neuroprotective treatments.
Therefore, we evaluated the efficacy of hypothermia in an older
population (aged 18 to 20 months) of gerbils. Methods Three groups of gerbils were exposed to a 5-minute episode of global ischemia or sham occlusion. One group was cooled during ischemia (mean brain temperature of 32°C). A second group was maintained at normothermia (36.4°C) during occlusion and the first hour of reperfusion. Beginning 1.0 hour after occlusion, these gerbils were gradually cooled to 32°C and maintained at this level before gradual rewarming to 37°C at 25 hours after ischemia. The third ischemic group was kept at normothermia during surgery and the first hour of reperfusion. After surgery, all animals were tested for acute (ie, within 30 hours of ischemia) changes in locomotor activity as well as for chronic (ie, 5, 10, and 30 days after ischemia) habituation deficits in an open field test.
Results Both intraischemic and postischemic hypothermia provided robust protection (P<.0001) of hippocampal CA1 neurons when assessed 30 days after ischemia. However, intraischemic hypothermia was more effective than postischemic hypothermia in providing behavioral protection.
Conclusions This study demonstrates that both intraischemic and prolonged postischemic hypothermia provide robust and lasting (30-day survival) histological protection against a severe ischemic insult. The extent of behavioral protection with postischemic hypothermia was less than that previously observed in younger animals. This suggests that neuroprotective treatments in young animals may lose efficacy as a result of aging.
Key Words: aging • cerebral ischemia • hypothermia • neuroprotection • gerbils
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Introduction |
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Almost 75.0% of all strokes affect people aged 65 years or older.1 2 Despite these statistics, it is standard practice to use young animals in models of cerebral ischemia.2 3 This may be problematic for several reasons. First, elderly individuals may simply not tolerate aggressive stroke interventions. Second, the aging brain undergoes numerous biochemical,4 5 6 morphological,7 8 9 10 and electrophysiological11 12 changes that could alter the pattern of vulnerability to cerebral ischemia. Third, in older animals there is evidence for depletion of ATP, increased accumulation of intracellular calcium, poorer recovery of ion homeostasis, mitochondrial impairment, and increased formation of free radicals.5 6 13 14 All of these events might be expected to worsen ischemic outcome in the older animal. However, in other respects the aged brain may be less vulnerable to ischemia since NMDA receptor populations and NMDA responsivity are decreased.9 15
In the few studies that compared susceptibility to ischemia between young and old animals it was found that older animals are generally more vulnerable, but there is some controversy.16 In one global ischemia study, 18- to 22-month-old rats exhibited greater CA1 and striatal neuronal injury than 5- to 6-month-old animals.17 However, a more recent study reported region specific changes in sensitivity to forebrain ischemia, with the striatum and cortex being more vulnerable but CA1 less vulnerable in older rats.16 In focal ischemia, infarct volumes appear larger in older animals.16 18 Given the above results, it is possible that treatments found effective in young animals would not necessarily be as effective in older animals. Since clinical trials are largely based on demonstrated efficacy in animal models, it is important to know whether results derived from young animals can be extrapolated to an older population. Thus, we examined the neuroprotective efficacy of intraischemic and postischemic hypothermia in a gerbil model of global ischemia that used 18- to 20-month-old animals. Hypothermia was selected because it has repeatedly been shown to convey lasting functional and histological protection19 20 21 22 23 24 in young animals to a degree unsurpassed by current pharmacological treatments.24 Neuroprotection was assessed with a combined histological and behavioral approach that has been described previously.20 22 25 26
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Materials and Methods |
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Subjects
Thirty female Mongolian gerbils were used in this study after approval by the Memorial University Animal Care Committee in accordance with guidelines established by the Canadian Council of Animal Care. Gerbils were obtained from High Oak Ranch (Baden, Ontario, Canada) at approximately 12 weeks of age. Animals were housed in groups of up to 4 per cage until approximately 18 months of age, when they were used in the present experiment and subsequently housed individually. All gerbils had free access to food and water throughout this experiment.
One group of gerbils was subjected to 5 minutes of normothermic ischemia (36.4°C) without any treatment (I; n=5). Other groups were sham operated (S; n=8); subjected to ischemia under mild (32°C) brain hypothermia (IH; n=8); and subjected to normothermic ischemia followed 1 hour later by 24 hours of mild (32°C) postischemic hypothermia (PH; n=9).
Temperature Measurement and Control
All gerbils were implanted with a 5.0-mm guide cannula as
described previously.19 Implant surgery was performed
under 1.5% to 2.0% halothane (70% N2O/30%
O2) followed by a 35 mg/kg IP postoperative dose of
sodium pentobarbital.
Two days after cannula implantation, gerbils were briefly anesthetized with halothane while the telemetry brain probes (model XM-FH, Mini-Mitter Co, Inc) were inserted. The probe sampled the temperature of the anterior dorsal striatum, and the data were recorded three times per minute. Baseline temperature was collected over a 3-hour period (early afternoon) in freely moving animals followed by probe removal.
Two days after baseline temperature measurement, gerbils were
anesthetized with 1.5% to 2.0% halothane (70%
N2O/30% O2). Animals were then wrapped in a
homeothermic body blanket (Harvard Apparatus), and a water
blanket (Mul-T-Pads, model TP-3E, Gaymar Industries Inc) was wrapped
around the dorsal and lateral surfaces of the head. The brain
temperature probe was reinserted, and a rectal probe was inserted to
sample core temperature. After a midline neck incision, the common
carotid arteries were carefully isolated. Once brain temperature
stabilized at normothermic levels (ie, 36.4°C), bilateral
carotid artery occlusion (5-minute duration) was induced in I, IH, and
PH groups. Sham-operated gerbils were treated similarly but did not
undergo occlusion. In the IH group, brain temperature was selectively
lowered to 30°C (achieving a mean brain occlusion temperature of
32°C) by perfusing cold water through the water blanket surrounding
the head immediately after placement of the microaneurysm
clips. Rewarming began just after clip removal. In all animals
subjected to ischemia, the carotid arteries were visually
inspected after clip removal to verify reflow. The wound was sutured,
and each animal was returned to its cage for further temperature
measurement/control. A 100-W lamp was used to maintain brain
temperature if it fell below 37.0°C during the first hour after
surgery. This usually was not necessary since bilateral carotid
occlusion in gerbils produces a slight (0.7°C) rise in
postischemic brain temperature.27 28
Beginning 1 hour after ischemia, animals in the PH group were slowly cooled at a rate of 1.0°C/10 min to 32°C. They were then maintained at 32°C (±0.2°C) for 24 hours until gradually rewarmed to 37°C at 25 hours after ischemia. This 24-hour whole-body cooling period was manually produced in the awake, freely moving animal by a combination of an overhead fan, water spray, and a 100-W lamp, as described elsewhere.19 20 Such extended hypothermic periods have been repeatedly found to be safe in the unanesthetized rodent.19 20 24 29
At approximately 30 hours after ischemia, all gerbils were briefly anesthetized with 2.0% halothane while the brain probes were removed. Animals were then returned to the vivarium where they were housed except for days on which behavioral testing occurred.
Behavioral Testing
Since the Mini-Mitter brain probes also provide a measure of
gross activity levels, which are useful in predicting the severity of
an ischemic insult,30 this acute measure of
activity was recorded simultaneously with brain
temperature for a 30-hour period after ischemia/sham surgery.
To test for chronic habituation impairments, gerbils were placed in an
open field on days 5, 10, and 30 after surgery, as previously
described.19 20 26 Each test session lasted 10 minutes,
during which the activity scores were collected by an automated image
analysis system. This test has been previously shown to
accurately predict the degree of ischemia-induced hippocampal
damage.20 22 26 31 Elevated open field scores reflect
impaired habituation as opposed to simple motor
hyperactivity,26 which normally subsides by 2 days after
ischemia.30
Histology
Gerbils were killed 30 days after ischemia with an
overdose of sodium pentobarbital. They were then transcardially
perfused with 15 mL of heparinized saline followed by 50 mL of 10%
formalin. The brains were left in fixative for 1 day before removal
from the skulls. After further fixation, paraffin-embedded brains were
then sectioned at 6 µm and stained with hematoxylin and eosin.
As previously reported,20 32 the number of viable CA1
neurons in medial, middle, and lateral sectors (sector length=0.2
mm) was determined at -1.7 (level A) and -2.2 (level B) mm to
bregma and in a single sector (medial CA1) at -2.8 (level C)
mm.33 The summated number of
histologically viable neurons from levels A, B, and C
was analyzed by ANOVA, as previously
described.19 20
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Baseline temperature data were similar in all groups with an overall average of 36.7°C, which is similar to previous results in younger animals.19 20 22 29 32 There were no significant group differences (F3,26 <1). Brain temperature during and for the first hour after surgery (Fig 1
, Table) was
manipulated close to the desired values outlined in "Materials and
Methods." Note that the PH group had a slight (0.2°C) but not
significantly (t12=1.24, P=.24) higher
temperature during ischemia compared with the I group. In
addition, during the first postischemic hour the average
temperature of the IH group was 0.3°C to 0.4°C below that of the
I and PH groups. This difference was due to the extra time required to
rewarm the IH group to normothermic levels after
ischemia. Although the average temperature of the PH group was
significantly above the IH group average temperature during the first
postischemic hour (F1,26=5.33,
P=.03), it is unlikely that these negligible differences
(ie, 0.41°C) account for any of our experimental findings.
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Acute activity levels increased dramatically in the I group 2 hours
after occlusion and remained high for nearly the entire 30-hour
monitoring period (Fig 1
). Both intraischemic and
postischemic hypothermia blunted the magnitude and duration
of this acute ischemia-induced behavioral activation.
Open field testing (Fig 2) revealed
significant group differences (F3,26=3.62,
P=.026) (main effect). Specific contrasts showed that the I
group was significantly impaired (higher activity scores) compared with
the S group (F1,26=7.39, P=.012).
Intraischemic hypothermia significantly reduced this
habituation impairment (F1,26=7.86, P=.009).
Postischemic hypothermia did attenuate this impairment, but
this was not significant (F1,26=1.70, P=.204).
Repeated exposure to the open field resulted in reduced activity scores
(F2,52=49.67, P<.001) compared with the first
test session 5 days after ischemia/surgery (Fig 2). There was,
however, a significant group by day interaction
(F6,52=2.52, P=.032). Notably, the IH group had
a different trend over days than the I (F2,52=5.34,
P=.008) and PH (F2,52=3.92, P=.026)
groups. This was due to the activity levels of the IH group dropping
dramatically on day 10 to the level of S animals (Fig 2).
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Normothermic ischemia in these aged gerbils
consistently resulted in extensive CA1 necrosis at all three
levels assessed (Fig 3). This is similar
to previous findings in young animals,19 20 22 except that
injury was slightly greater in the most posterior level (level C,
86% necrosis in old animals versus 71% necrosis in young animals).
However, this difference was not significant (t17=1.94,
P=.069). Intraischemic hypothermia markedly reduced
CA1 injury (versus the I group) at all levels of the hippocampus
(P<.001). In fact, cell counts were not statistically
different from S animals (P>.13). Similarly, 24 hours of
postischemic, mild hypothermia provided robust and
significant neuroprotection at all CA1 levels (P<.001).
Cell counts in the PH group were statistically different from the S
group at 1.7 (level A) mm posterior to bregma
(t15=2.65, P<.018). The degree of
neuroprotection was quite similar in both the IH and PH groups with no
significant differences at any anterior-posterior level of CA1
(P>.16).
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It was noted that all animals gradually lost weight over the course of the experiment (30-day survival), partly as a result of being segregated into individual cages. However, in the PH group animals lost an additional 5 g by the first postischemic day, as previously noted,20 with young gerbils subjected to extended postischemic cooling. As before, the weight of the PH gerbils recovered to that of the other animals in the study by the fifth postischemic day. Other than this transient effect, no deleterious effects of prolonged postischemic hypothermia were observed.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The highly significant histological protection of CA1 neurons across three anterior-posterior levels of the hippocampus (86.8%, 89.9%, and 98.9% of age-matched S controls) 30 days after intraischemic hypothermia in these older gerbils is similar to the degree of protection we observed in young animals.22 Postischemic hypothermia also provided substantial protection of CA1 neurons. However, protection across all three hippocampal levels was on average
12% less effective (77.6%,
82.6%, and 87.6%, respectively, for levels A, B, and C) than our
previous results with postischemic hypothermia in young
gerbils.19 None of these differences were significant
(t15=P>.05). The posterior CA1 region of the
hippocampus is considerably more resistant to ischemia
than anterior CA1.34 Thus, it is notable that the extent
of CA1 necrosis (86%) observed at the posterior boundary of the
hippocampus in old gerbils (group I), although less than more anterior
regions, was somewhat, although not significantly, greater than that
(71%) observed in our previous studies utilizing young
gerbils.20 22 This observation, coupled with the modest
reduction in efficacy seen with postischemic hypothermia,
suggests that CA1 neurons may be more vulnerable in older gerbils, but
this speculation awaits confirmation by directly comparing larger
groups of young and old animals in a single study. Although systematic
cell counts were not performed in brain regions other than CA1, there
was no indication of enhanced neuronal loss in the caudate and cortex.
With the occlusion durations used in the present study, these brain
regions are rarely affected in 3- to 5-month-old gerbils. Our histological results are consistent with those described initially by Yao et al,17 who noted increased damage to CA1 neurons after 20 minutes of forebrain ischemia in 18- to 22-month-old female rats. A recent study16 reporting reduced CA1 injury in aged male rats is difficult to reconcile with our results. The discrepancy could be due to many factors, including postischemic survival time (ie, 7 versus 30 days), methods of histological analysis, and sex differences in vulnerability to ischemic damage.35 Obviously more studies are required to identify the factors that most markedly affect ischemic outcome in aged animals.
The dramatic and protracted increase in nonspecific motor activity that begins 2 to 3 hours after ischemia36 37 38 was almost completely negated by intraischemic hypothermia and to a lesser extent by postischemic hypothermia. Prolonged cooling produces some sedation in normal animals; however, activity levels return to normal within 1 day after reestablishment of normothermia (F.C., unpublished data, 1996). As we have previously noted in young gerbils,30 acute activity patterns on the first day after ischemia can be used to gauge the efficacy of ischemic treatments.
Intraischemic hypothermia also prevented chronic habituation deficits in the open field, confirming our findings in young animals,22 as well as similar functional protection reported by others.21 31 In contrast to our previous findings in young gerbils,20 postischemic hypothermia did not provide significant behavioral protection in the open field test in aged gerbils, although there was a trend toward better performance. This may reflect a real difference between young and old animals. It is possible that CA1 neurons are more vulnerable to ischemia in older animals and that additional or more potent therapies will be required to protect cells from damage. For example, increasing the duration of postischemic hypothermia from 12 to 24 hours has been shown to greatly enhance long-term survival of CA1 neurons.19 20 24 Perhaps increasing the duration of postischemic hypothermia in the present study from 24 to 36 or even 48 hours would have increased the degree of CA1 protection.
It should be noted that the sample size in the present study was small (n=5 to 9 per group), and the variability in open field behavior among older animals is substantially greater than that observed in young animals. Thus, larger group sizes and the use of additional, more complex behavioral tests (eg, T maze) that have greater selectivity for hippocampal function might have revealed greater functional savings after postischemic hypothermia. In addition, it is possible that the behavioral deficits arose from a combined loss of several neuronal groups in addition to CA1. For example, somatostatin-positive hilar neurons and CA2 neurons are as sensitive, if not more sensitive, to ischemic injury than CA1 neurons.39 40 In older animals these neurons may have been protected by intraischemic hypothermia but might have been irreversibly injured before effective postischemic hypothermic levels (ie, 32°C) were achieved. Finally, it is conceivable that ischemia induces subtle but functionally important forms of neuronal injury (eg, loss of dendritic spines) not revealed by Nissl stains, and postischemic hypothermia may not have prevented this injury. If so, such possibilities underscore the need to employ behavioral and electrophysiological end points when assessing neuroprotection.22 41
Intraischemic hypothermia has been termed the "gold standard" of neuroprotection,42 and the present data extend this claim to include older animals. Postischemic hypothermia, although less effective than intraischemic hypothermia, is nonetheless a very effective treatment. The present results suggest that treatments found effective in young animals may not convey the same degree of protection in an older population because of a variety of age-related changes that could alter sensitivity to ischemia. Therefore, it would be wise to confirm the efficacy of a particular therapy in young and old animals, preferably in several models, before it is advanced to clinical trials.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Heart and Stroke Foundation of Newfoundland and Labrador awarded to Dr Corbett. Drs Colbourne and Nurse were recipients of PhD studentships from the Medical Research Council of Canada and from Memorial University, respectively. The authors are grateful to Suzanne Evans and Paul Dooley for assistance with temperature regulation and for helpful comments on this manuscript.
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Footnotes |
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Reprint requests to Dr Dale Corbett, Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's, NF, Canada A1B 3V6.
Received May 5, 1997; revision received June 27, 1997; accepted July 10, 1997.
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C. M. Maier, K. vB. Ahern, M. L. Cheng, J. E. Lee, M. A. Yenari, G. K. Steinberg, and J. R. Kirsch Optimal Depth and Duration of Mild Hypothermia in a Focal Model of Transient Cerebral Ischemia : Effects on Neurologic Outcome, Infarct Size, Apoptosis, and Inflammation • Editorial Comment: Effects on Neurologic Outcome, Infarct Size, Apoptosis, and Inflammation Stroke, October 1, 1998; 29(10): 2171 - 2180. [Abstract] [Full Text] [PDF]
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F. Colbourne, R. N. Auer, G. R. Sutherland, and W. D. Dietrich Behavioral Testing Does Not Exacerbate Ischemic CA1 Damage in Gerbils • Editorial Comment Stroke, September 1, 1998; 29(9): 1967 - 1971. [Abstract] [Full Text] [PDF]
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