(Stroke. 1998;29:1967-1971.)
© 1998 American Heart Association, Inc.
Behavioral Testing Does Not Exacerbate Ischemic CA1 Damage in Gerbils
Frederick Colbourne, PhD;
Roland N. Auer, MD, PhD;
Garnette R. Sutherland, MD
From the Departments of Pathology (F.C., R.N.A.) and Clinical
Neurosciences (Division of Neurosurgery) (G.R.S.), Faculty of Medicine,
University of Calgary, Calgary, Alberta, Canada.
Correspondence to Frederick Colbourne, PhD, Department of Pathology, Faculty of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1. E-mail colbourn{at}acs.ucalgary.ca
 |
Abstract
|
|---|
Background and Purpose—Previous
research studying ablative lesions has suggested that functional use
may exacerbate brain injury. If true, this would have considerable
ramifications not only for the mechanistic understanding of neuronal
injury but also for the clinical use of physiotherapy. In this report
the hypothesis that behavioral use of brain tissue exacerbates
ischemic hippocampal injury was tested.
Methods—Gerbils were subjected to sham operation or 5 minutes of
normothermic ischemia. To produce borderline
hippocampal CA1 injury and enhance susceptibility to exacerbation, 2 of
3 ischemic groups were cooled (>48 hours) beginning at 6 hours
after ischemia. Increased use of the hippocampus was produced
by a battery of tests involving 3 novel small mazes, a T maze, and an
open field. One hypothermic group was not tested and served as a
control.
Results—Behavioral testing failed to worsen ischemic
damage since neuronal loss in the behaviorally tested and untested
hypothermic groups was 12% and 8%, respectively, while that in the
untreated ischemic group was 81% at a 1-month survival.
Accordingly, protected CA1 cells tolerated the neuronal activity
associated with behavioral testing. Concomitant with marked CA1
neuroprotection, a significant reduction in behavioral deficits with
the hypothermic treatment was observed. Importantly, behavioral testing
was found to transiently elevate brain temperature.
Conclusions—CA1 neuronal survival was unaffected by behavioral
testing or the associated mild fever. Hypothermia delayed for 6 hours
provided sustainable CA1 neuroprotection.
Key Words: cerebral ischemia • fever, stress-induced • hippocampus • hypothermia • gerbils
|
Introduction
|
|---|
Arecent study by Kozlowski et
al1 suggested that the behavioral use of neurons
aggravated cortical injury. These investigators used an electrolytic
sensorimotor cortex lesion in rat immediately followed by prolonged
casting of the normal ipsilateral limb and subsequently increased use
of the affected limb contralateral to the lesion. They found that the
increased use of the affected limb resulted in a significantly greater
degree of cortical damage. The authors concluded that use of
compromised neurons worsened injury.
These provocative results, if true, have profound
implications for functional activity (eg, physiotherapy, speech
therapy) after stroke. Global cerebral ischemia in rodents,
which models human cardiac arrest encephalopathy, is a clinically
relevant model ideally suited to study the effects of delayed
behavioral testing. Notably, brief global ischemia produces a
2- to 3-day delayed loss of hippocampal CA1
neurons.2 3 4 Indeed, there is some evidence that
the typical loss of CA1 cells is, in part, mediated by functional
activity since CA1 neurons can be irreversibly depolarized and killed
by low-frequency afferent stimulation during the initial few days after
ischemia, and this is related to abnormal
[Ca2+]i
regulation.5 6 7 8 Accordingly, the activation of
"place cells"9 10 in spatial environments
(ie, exploration tests) and the induction of long-term potentiation or
similar mechanisms during learning and memory11
may intolerably strain damaged CA1 neurons, since memory formation depends on
glutamate release and calcium entry in these
cells.12
Untreated global ischemia in rodent models, such as the
gerbil, produces near-total CA1 loss before the fourth
day,2 3 13 which has a typical all-or-none
pattern of injury.14 Thus, it is difficult to
assess the effects of delayed behavioral testing on untreated global
ischemia. Since prolonged postischemic hypothermia
partially protects CA1 neurons,14 15 16 17 these
incompletely protected CA1 neurons can be used to assess the effects of
delayed functional testing. Moreover, some hypothermia-treated CA1
neurons persistently show signs of nonlethal injury (ie, dilated
endoplasmic reticulum and mitochondria, intranuclear vacuoles,
mitochondrial autolysosomes),13 and this
vulnerability may result in enhanced susceptibility to the normal
physiological stimulation that occurs during
hippocampal-dependent learning and memory tasks. Accordingly, we
hypothesized that testing of spatial learning and working memory may
have a detrimental effect on hypothermic neuroprotection.
|
Materials and Methods
|
|---|
Subjects
Female Mongolian gerbils were obtained from High Oak Ranch
(Baden, Ontario, Canada) at 
11 to 12 weeks of age and were used
after an acclimation period of 4 to 6 weeks (weight, 54 g). There
were 4 groups: SHAM (n=14) (sham operation), ISCH (n=12)
(normothermic ischemia), ISCH+HYPO (n=20)
(ischemia plus hypothermia), and ISCH+HYPO-NT (n=20)
(ischemia plus hyperthermia, not tested) (see below for
complete description of groups). All groups except ISCH+HYPO-NT were
given behavioral tests of learning and memory. During the experiment,
animals had free access to food and water and were housed individually
under diurnal light conditions (lights on at 8 AM and off
at 8 PM). This experiment conformed to the guidelines of
the Canadian Council on Animal Care as well as the standards of the
Animal Care Committee of the University of Calgary.
Ischemia and Temperature Control
Gerbils were implanted (65 mg/kg IP sodium pentobarbitol
[Somnotol]) with a guide cannula as described
previously.18 19 After 2 days, telemetry brain
temperature probes (model XM-FH, Mini-Mitter Co) were inserted
under brief halothane anesthesia. Animals recovered in
individual cages (23 cm widex14 cm highx31 cm long) that rested on
RLA-1020 receivers interfaced to a computer running DataQuest IV
(DataSciences, Int). Baseline temperature (2-second average from
anterior dorsal striatum) and general motor activity (30-second sum)
were recorded every 30 seconds and averaged every 5 minutes.
Ischemia or sham occlusion surgery was done between 8
AM and 1 PM 4 days after cannula implantation.
Briefly, gerbils were anesthetized with halothane (2.0%
induction, 1.5% maintenance, 0.5% during ischemia)
followed by a midline neck incision, isolation of both carotid
arteries, and subsequent occlusion (except for SHAM) with
microaneurysm clips for 5 minutes followed by verification of
reflow. Core temperature was kept near 37°C by a heating blanket, and
brain temperature was regulated to 36.4°C by an overhead infrared
lamp.19
After sham operation, the gerbils were returned to their cages
for monitoring. After ischemia, animals were shaved to
facilitate subsequent temperature regulation for 2 to 3 days in their
cages. One group of ischemic animals (ISCH) had their
temperature regulated at a mild hyperthermic
pattern14 15 for 24 hours and were then kept from
falling below 35.5°C for an additional 24 hours. This was to minimize
variability. The ISCH+HYPO and ISCH+HYPO-NT groups were subjected to a
similar pattern for the first 6 hours. At that time they were slowly
cooled (1.0°C/30 min) to 32°C and kept at that temperature for 24
hours. Gerbils were then rewarmed (1.0°C/30 min) to 34°C and kept
at that temperature for 24 hours. After this, animals were rewarmed to
35°C and kept between 35°C and 36°C for 12 hours. All groups were
monitored for 6.5 days, at which time they were briefly
anesthetized and their brain probes were removed.
Temperature regulation after surgery was achieved in the awake,
freely-moving animal by a precise (±0.2°C) servo-controlled system
that used infrared lamps (175 W), fans, and fine water
misters.19 Gerbils had free access to food (rat
chow) and water throughout this experiment. After surgery, for the
first 4 days only, gerbils were given 7 g of mixed hamster food
(Staple VME Diet, Hagen) daily. This seed mixture is preferred over
their regular diet and has the advantage of not getting soaked by the
water misters.
Behavioral Testing
Gerbils in the SHAM, ISCH, and ISCH+HYPO groups were repeatedly
tested, while gerbils in the ISCH+HYPO-NT group were not. Since tests
of spatial learning (small mazes, open field) and working memory (T
maze) require the use of the hippocampus, the ISCH+HYPO and
ISCH+HYPO-NT group comparison examined the hypothesis that behavioral
testing may diminish hypothermic CA1 neuroprotection. Behavioral data
are presented elsewhere.19A
The SHAM, ISCH, and ISCH+HYPO groups were exposed to 3 (A, B, and
C) initially novel and distinct mazes (22 cm widex32 cm longx15 cm
high) on days 4 to 6 after ischemia/sham occlusion surgery.
Gerbils were placed in each maze for 15 minutes once per day (ie, 3
mazes per day) over 3 consecutive days. The 3 maze sessions per day,
which took place between 1 and 4 PM, were separated by 1
hour (start to start). Each maze had a unique internal design thought
to be distinguishable by the gerbils. Accordingly, 3 (versus 1 or 2)
mazes were used to stimulate greater use of the hippocampus.
On the morning of day 8 after ischemia/sham operation,
gerbils (SHAM, ISCH, and ISCH+HYPO) were placed in an open field
(1x1-m box; 60 cm high) for three 10-minute sessions (1-hour intertest
interval). Ischemic hippocampal damage causes increased and
persistent locomotion in this test, which is dependent on
novelty.15 20 21
On the morning of days 9 and 10, SHAM, ISCH, and ISCH+HYPO gerbils were
familiarized to a T maze (60 cm stem length, 30 cm arm lengths, 10 cm
wide, 12 cm high) for three 5-minute sessions per day. During the next
6 days, gerbils were given 10 pairs of trials per day in which they
received sunflower seeds (not food deprived) as reward. This T-maze
procedure, which measures spatial working memory, was previously used
in the gerbil and found to reflect hippocampal
integrity.15 22
Histology
Gerbils were killed at 30 to 31 days after
ischemia by an overdose of Somnotol and
transcardiac perfusion with 30 mL of heparinized saline and
120 mL of 4.0% buffered formaldehyde. Brains were left in situ
overnight in fixative before removal. They were then processed,
embedded in paraffin, and coronally sectioned at 6 µm. Sections
were stained with hematoxylin and eosin. Viable (not eosinophilic) CA1
neurons were counted in medial (next to subiculum), middle, and lateral
(adjacent to CA2) grids (each 0.2 mm long) at -1.7 and -2.2
mm to bregma,23 as described
previously.15 The number of viable neurons was
compared between groups by a 1-factor ANOVA (for each CA1 region) with
specific group contrasts.14 15
Sections of the heart, liver, lung, kidney, and adrenal gland were also
collected, grossly examined, processed, and stained with hematoxylin
and eosin.
|
Results
|
|---|
Baseline brain temperature collected the day before
ischemia/sham occlusion surgery was similar between
groups, with a range of 36.4°C to 36.7°C, which is similar to
previous work.14 15 16 19 Brain temperature during
and after ischemia (Figure 1
) was
regulated as desired (see Materials and Methods). There were no
significant differences between the ISCH (35.9±0.6°C) (±SD),
ISCH+HYPO (35.9±0.4°C), and ISCH+HYPO-NT (36.0±0.3°C) groups
during occlusion. The temperature of these groups was also similar
(<0.25°C difference) for the first 6 hours after ischemia,
at which time cooling was induced in the hypothermia groups, as
intended.
View larger version (23K):
[in this window]
[in a new window]
|
Figure 1. Brain temperature during (0 hours) and after
ischemia/sham occlusions presented as 5-minute
averages. Postischemic temperature was regulated to the
desired levels in the ISCH, ISCH+HYPO, and ISCH+HYPO-NT groups (see
Materials and Methods) by the combined use of an overhead lamp, fan,
and water misting system. The increases in temperature in the SHAM,
ISCH, and ISCH+HYPO groups at 102, 126, and 150 hours were due to
placing the gerbils in the small mazes (see Figure 2 ).
|
|
One SHAM gerbil was excluded because its dental cap and probe became
loose and fell off by day 4 after ischemia. In total, 4
hypothermic gerbils died. One ISCH+HYPO gerbil died unexpectedly at 19
days of unknown cause. This gerbil had completed behavioral testing and
had an intact CA1 zone (only signs of autolysis and not necrosis) that
was similar to others in its group. The histology data were not
included because of the shorter survival time. Three ISCH+HYPO-NT
gerbils died during or soon after hypothermia of unknown cause.
Histopathological examination of sections from the heart, lung, liver,
kidney, and adrenal gland of the first 26 gerbils entered into the
study did not reveal any group differences or deleterious effects of
cerebral ischemia or cooling. The only deleterious effect of
hypothermia was a transient loss of weight (4 g by day 7), which has
been repeatedly found.14 15 16 19 It is possible
that the animals that died prematurely (ISCH+HYPO-NT) did not have
sufficient energy reserves to tolerate this lengthy hypothermic
treatment.
The behavioral data are presented elsewhere.19A
Briefly, untreated ischemia resulted in impairments on all
tests, and these deficits were attenuated by hypothermic treatment.
Notable, however, was the finding that exposure to the small mazes
caused a rise in brain temperature that began with or immediately after
placement in the small mazes and continued for a brief time after maze
exposure. These temperature elevations, seen at 102, 126, and 150
hours after ischemia (Figure 1), were due to placing the
gerbils in the novel mazes. While hyperthermia was similar in SHAM and
ISCH groups, it was initially (day 4 after ischemia) blunted in
the ISCH+HYPO group (Figure 2).
Temperature during these maze sessions did not correlate with CA1
damage (r=0.03).
View larger version (22K):
[in this window]
[in a new window]
|
Figure 2. Brain temperature (°C) averaged every 5 minutes
from 15 minutes before the small-maze sessions to 30 minutes after the
end of each session. The time on the x axis is relative
to start of each maze session, which is also denoted by a bar. Data are
averaged over the 3 sessions on each test day. The SHAM and ISCH groups
displayed a similar febrile response to the small mazes, while the
ISCH+HYPO group initially had an attenuated fever that recovered to the
level of the other groups on day 6 after ischemia. The greatest
temperature rise occurred near the end of each maze session and
dissipated thereafter. See Materials and Methods for description of
groups.
|
|
Extensive (overall counts averaged 19% of normal) CA1 damage
(Figure 3) occurred in the ISCH group
(P<0.0001). Hypothermia significantly
(P<0.0001) and almost completely attenuated CA1 injury in
all sectors and levels at a 30-day survival. There were no significant
(F1,56 <1) CA1 differences between ISCH+HYPO and
ISCH+HYPO-NT groups, and therefore behavioral testing did not lessen
CA1 neuroprotection.
View larger version (29K):
[in this window]
[in a new window]
|
Figure 3. CA1 cell counts (percentage of SHAM ±SD) at
1.7 and 2.2 mm posterior to bregma. Normal-looking neurons were
counted in medial, middle, and lateral sectors, each being 0.2-mm
lengths of the CA1 pyramidal layer. Six-hour delayed
hypothermia significantly blunted injury (vs ISCH,
P<0.0001) in all sectors at both levels, with no
significant differences between the ISCH+HYPO and ISCH+HYPO-NT groups.
Only the medial -1.7 mm sector of the ISCH+HYPO group had counts
significantly lower than SHAM. See Materials and Methods for
description of groups.
|
|
|
Discussion
|
|---|
The hypothesis that hippocampal-dependent tasks might
promote CA1 neurodegeneration after ischemia and hypothermic
intervention was not supported because behavioral testing did not
affect neuroprotection. Earlier or more prolonged testing than that
presently used might reveal a detrimental effect. Clearly, any such
effect would be difficult to discern from behaviorally induced
increases in brain temperature. Delayed hyperthermia is known to
increase brain injury after global24 25 26 and
focal ischemia27 28 and traumatic brain
injury.29 In this study, the brief elevations in
temperature associated with behavioral testing were not usually
>38°C, and they occurred 
4 days after ischemia and
therefore were unlikely to influence outcome.
Exposure to the small mazes on days 4, 5, and 6 elevated brain
temperature. Others have also noted that stressful situations, such as
a novel open field, can increase
temperature,30 31 32 and this is thought to be a
fever.30 33 34 Our data suggest that the CA1 zone
is unimportant in this type of febrile response since SHAM and ISCH
groups had very similar fevers during and after the maze sessions over
the 3 test days. Notably, Morrow and colleagues35
have argued that the hippocampus is the site of glucocorticoid negative
feedback that acts to dampen stress-induced fever. Our data appear to
contradict this since extensive CA1 damage, which eliminates most of
the hippocampal output, should eliminate glucocorticoid feedback. If
so, fevers would have been more pronounced or prolonged over the course
of the 3 sessions on each day (3-hour span), and this was not the case.
Finally, the initial blunting of stress-induced fever in the ISCH+HYPO
groups is a novel and surprising finding. Further experiments will be
needed to determine the mechanism.
Hyperthermia may have confounded the results of Kozlowski et
al,1 since immediate postinjury casting of the
normal limb, which increased use of the affected limb on a continuous
basis, may have persistently elevated brain temperature (by stress
and/or increased movement activity), and this confounding
parameter, unmeasured in their experiment, may be
responsible for the greater lesion size. Clearly, the detrimental
effects of hyperthermia must be carefully considered not only with
early rehabilitation efforts but also in mechanistic studies of
neuronal injury. Notably, several other factors may explain the
different conclusions of this study and that of Kozlowski et
al.1 First, these studies used different models
of brain injury. Second, behavioral testing was initiated immediately
after injury in the cortical lesion study,1
whereas it was begun 4 days after ischemia in the present
study and behavioral manipulations/testing were much briefer in the
present study. Thus, quicker and longer behavioral testing
paradigms may have a greater detrimental effect. Further experiments
are needed to determine this.
This study also shows that 6-hour delayed hypothermia can significantly
and persistently (30 days) reduce CA1 neuronal injury after forebrain
ischemia in the gerbil. This is a substantial improvement over
previous work15 in which we found very limited
CA1 protection with a 4-hour delayed hypothermic intervention (24
hours' duration) after ischemia. The superior efficacy in the
present study was likely due to the use of a longer duration of
hypothermia (>48 hours).
In summary, the data show that behavioral testing and the associated
transient fever did not lessen the neuroprotective effects of prolonged
postischemic hypothermia. It remains possible that
behavioral pressure may have greater detrimental effects following the
use of less efficacious neuroprotectants or after other types of stroke
(eg, focal ischemia). Such studies must necessarily control
brain temperature if mechanistic conclusions are to be made regarding
the effect of neuronal use on brain injury.
|
Acknowledgments
|
|---|
Research support was provided by the Heart and Stroke Foundation
of Canada. Dr Colbourne gratefully acknowledges postdoctoral fellowship
support from the Heart and Stroke Foundation of Canada. The authors
acknowledge the technical support of Bonnie Colbourne and Drs Fangwei
Yang and Dubravka Raki
.
Received March 20, 1998;
revision received May 18, 1998;
accepted June 5, 1998.
|
References
|
|---|
1.
Kozlowski DA, James DG, Schallert T. Use-dependent
exaggeration of neuronal injury after unilateral sensorimotor cortex
lesions. J Neurosci. 1996;16:4776–4786.[Abstract/Free Full Text]
2.
Kirino T. Delayed neuronal death in the gerbil
hippocampus following ischemia. Brain Res. 1982;239:57–69.[Medline]
[Order article via Infotrieve]
3.
Pulsinelli WA, Brierley JB, Plum F. Temporal
profile of neuronal damage in a model of transient forebrain
ischemia. Ann Neurol. 1982;11:491–498.[Medline]
[Order article via Infotrieve]
4.
Petito CK, Feldmann E, Pulsinelli WA, Plum F. Delayed
hippocampal damage in humans following cardiorespiratory arrest.
Neurology. 1987;37:1281–1286.[Abstract/Free Full Text]
5.
Andiné P, Jacobson I, Hagberg H. Calcium uptake
evoked by electrical stimulation is enhanced
postischemically and precedes delayed neuronal death in CA1
of rat hippocampus: involvement of NMDA receptors. J Cereb
Blood Flow Metab. 1988;8:799–807.[Medline]
[Order article via Infotrieve]
6.
Andiné P, Jacobson I, Hagberg H. Enhanced
calcium uptake by CA1 pyramidal cell dendrites in the
postischemic phase despite subnormal evoked field
potentials: excitatory amino acid receptor dependency and relationship
to neuronal damage. J Cereb Blood Flow Metab. 1992;12:773–783.[Medline]
[Order article via Infotrieve]
7.
Tsubokawa H, Oguro K, Robinson HPC, Masuzawa T, Kirino
T, Kawai N. Abnormal Ca2+ homeostasis before cell
death revealed by whole cell recording of ischemic CA1
hippocampal neurons. Neuroscience. 1992;49:807–817.[Medline]
[Order article via Infotrieve]
8.
Silver IA, Erecinska M. Ion homeostasis in rat
brain in vivo: intra- and extracellular [Ca2+]
and [H+] in the hippocampus during recovery
from short-term, transient ischemia. J Cereb Blood
Flow Metab. 1992;12:759–772.[Medline]
[Order article via Infotrieve]
9.
O'Keefe J, Dostrovsky J. The hippocampus as a spatial
map: preliminary evidence from unit activity in the freely-moving rat.
Brain Res. 1971;31:171–175.
10.
O'Keefe J. Place units in the hippocampus of the
freely moving rat. Exp Neurol. 1976;51:78–109.[Medline]
[Order article via Infotrieve]
11.
Barnes CA. Involvement of LTP in memory: are we
"searching under the street light"? Neuron. 1995;15:751–754.[Medline]
[Order article via Infotrieve]
12.
Alkon DL, Rasmussen H. A spatial-temporal model of cell
activation. Science. 1988;239:998–1005.[Abstract/Free Full Text]
13.
Colbourne F, Sutherland GR, Auer RN. New features of
delayed neuronal death in gerbils treated with prolonged
postischemic hypothermia. Soc Neurosci Abst. 1997;23:1917. Abstract.
14.
Colbourne F, Corbett D. Delayed and prolonged
post-ischemic hypothermia is neuroprotective in the gerbil.
Brain Res. 1994;654:265–272.[Medline]
[Order article via Infotrieve]
15.
Colbourne F, Corbett D. Delayed
postischemic hypothermia: a six month survival study using
behavioral and histologic assessments of neuroprotection. J
Neurosci. 1995;15:7250–7260.[Abstract]
16.
Corbett D, Nurse S, Colbourne F. Hypothermic
neuroprotection: a global ischemia study using 18–20 month old
gerbils. Stroke. 1997;28:2238–2243.[Abstract/Free Full Text]
17.
Colbourne F, Sutherland G, Corbett D.
Postischemic hypothermia: a critical appraisal with
implications for clinical treatment. Mol Neurobiol. 1997;14:171–201.[Medline]
[Order article via Infotrieve]
18.
Colbourne F, Nurse SM, Corbett D. Temperature changes
associated with forebrain ischemia in the gerbil. Brain
Res. 1993;602:264–267.[Medline]
[Order article via Infotrieve]
19.
Colbourne F, Sutherland GR, Auer RN. An automated
system for regulating brain temperature in awake and freely moving
rodents. J Neurosci Meth. 1996;67:185–190.[Medline]
[Order article via Infotrieve]
19A.
Colbourne F, Auer RN,
Sutherland GR. Characterization of postischemic behavioral deficits in
gerbils with and without hypothermic neuroprotection. Brain
Res. In press.
20.
Wang D, Corbett D. Cerebral ischemia, locomotor
activity and spatial mapping. Brain Res. 1990;533:78–82.[Medline]
[Order article via Infotrieve]
21.
Babcock AM, Baker DA, Lovec R. Locomotor activity in
the ischemic gerbil. Brain Res. 1993;625:351–354.[Medline]
[Order article via Infotrieve]
22.
Babcock AM, Graham-Goodwin H. Importance of
preoperative training and maze difficulty in task performance
following hippocampal damage in the gerbil. Brain Res Bull. 1997;42:415–419.[Medline]
[Order article via Infotrieve]
23.
Loskoto WJ, Lomax P, Verity MA. A
Stereotaxic Atlas of the Mongolian Gerbil Brain (Meriones
unguiculatus). Ann Arbor, Mich: Ann Arbor Science Publishers;
1975.
24.
Coimbra C, Drake M, Boris-Möller F, Wieloch T.
Long-lasting neuroprotective effect of postischemic
hypothermia and treatment with an anti-inflammatory/antipyretic drug:
evidence for chronic encephalopathic processes following
ischemia. Stroke. 1996;27:1578–1585.[Abstract/Free Full Text]
25.
Coimbra C, Boris-Möller F, Drake M, Wieloch T.
Diminished neuronal damage in the rat brain by late treatment with the
antipyretic drug dipyrone or cooling following cerebral
ischemia. Acta Neuropathol (Berl). 1996;92:447–453.[Medline]
[Order article via Infotrieve]
26.
Baena RC, Busto R, Dietrich WD, Globus MY-T, Ginsberg
MD. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat
hippocampus following global ischemia. Neurology. 1997;48:768–773.[Abstract/Free Full Text]
27.
Chen H, Chopp M, Welch KM. Effect of mild hyperthermia
on the ischemic infarct volume after middle cerebral artery
occlusion in the rat. Neurology. 1991;41:1133–1135.[Abstract/Free Full Text]
28.
Kim Y, Busto R, Dietrich WD, Kraydieh S, Ginsberg MD.
Delayed postischemic hyperthermia in awake rats worsens the
histopathological outcome of transient focal cerebral ischemia.
Stroke. 1996;27:2274–2281.[Abstract/Free Full Text]
29.
Dietrich WD, Alonso O, Halley M, Busto R. Delayed
posttraumatic brain hyperthermia worsens outcome after fluid percussion
brain injury: a light and electron microscopic study in rats.
Neurosurgy. 1996;38:533–541.[Medline]
[Order article via Infotrieve]
30.
Kluger MJ, O'Reilly B, Shope TR, Vander AJ. Further
evidence that stress hyperthermia is a fever. Physiol Behav. 1987;39:763–766.[Medline]
[Order article via Infotrieve]
31.
Moser E, Mathiesen I, Andersen P. Association between
brain temperature and dentate field potentials in exploring and
swimming rats. Science. 1993;259:1324–1326.[Abstract/Free Full Text]
32.
Erickson CA, Jung MW, McNaughton BL, Barnes CA.
Contribution of single-unit spike waveform changes to
temperature-induced alterations in hippocampal population spikes.
Exp Brain Res. 1996;107:348–360.[Medline]
[Order article via Infotrieve]
33.
Long NC, Vander AJ, Kluger MJ. Stress-induced rise of
body temperature in rats is the same in warm and cold environments.
Physiol Behav. 1987;47:773–775.
34.
Briese E, Cabanac M. Stress hyperthermia:
physiological arguments that it is a fever.
Physiol Behav. 1991;49:1153–1157.[Medline]
[Order article via Infotrieve]
35.
Morrow LE, McClellan JL, Klir JJ, Kluger MJ. The CNS
site of glucocorticoid negative feedback during LPS- and psychological
stress-induced fevers. Am J Physiol. 1996;271:R732–R737.[Abstract/Free Full Text]
Editorial Comment
W. Dalton Dietrich, PhD, Guest Editor
Departments
of Neurological Surgery and Neurology,
University of Miami School of Medicine,
Miami, Florida
|
Introduction
|
|---|
This study tested the hypothesis that behavioral testing after
transient global ischemia in gerbils exacerbates CA1
hippocampal damage. This interesting question is the result of previous
data from other laboratories showing that "excessive
rehabilitation" procedures initiated immediately after focal brain
injury aggravate outcome.1 2 In the present study,
behavioral tests requiring the use of the hippocampus failed to worsen
CA1 hippocampal damage, while postischemic hypothermia
improved histopathological and behavioral outcome.
The question of whether repeated episodes of behavioral testing
adversely influence ischemic outcome is of obvious clinical
interest in terms of rehabilitation strategies to promote functional
recovery after central nervous system injury. Using the present
study protocol, the authors could not demonstrate that cognitive
testing worsened outcome. Significant differences between the study
design and previous investigations,1 2 in which the
extensive use of a forelimb led to more cortical damage, most likely
explain the negative findings. First, unlike previous studies,
behavioral testing in this study was initiated days after the
ischemic insult. Second, the overuse of 1 limb in previous
studies was continuous for an extended period, while the present
behavioral testing procedures were not considered extensive. Thus, the
degree and temporal profile of the induced behavioral stress as well as
the type of brain injury (ie, global versus focal) may be important
variables in determining whether use-dependent exaggeration of
neuronal injury can be demonstrated.
It is known that elevations in core and brain temperature occur in
rodents during periods of increased motor activity. Thus, the
present observation that behavioral testing transiently increased
brain temperature in sham and ischemic gerbils is not
surprising. Whether activity-induced mild hyperthermia is involved in
the detrimental consequences of previous casting studies is, however,
extremely interesting. We know from previous work that the postinjured
brain is extremely sensitive to delayed temperature
elevations.3 Also, recent clinical data indicate that
elevations in brain temperature occur after traumatic or
ischemic injury.4 5 Thus, it is possible that
activity-induced increases in local brain temperature could conceivably
lead to aggravation of tissue injury in brain regions surrounding a
focal lesion.
A variety of abnormal conditions, including the uncoupling of cerebral
blood flow and metabolism, the generation of
ischemic depolarizations as well as elevations in extracellular
levels of neurotransmitters, and abnormal gene expression, have been
proposed to contribute to the vulnerability of the ischemic
penumbra.6 On the basis of the present discussion,
future investigations are required to determine whether elevations in
local brain temperature contribute to penumbral vulnerability after
ischemic stroke and/or whether temperature elevations
participate in the use-dependent exaggeration of neuronal injury. If,
for example, regional brain hyperthermia is shown to occur as a
consequence of flow-metabolism uncoupling, selective brain
hypothermia could be used to inhibit this hyperthermic response to
injury.
Received March 20, 1998;
revision received May 18, 1998;
accepted June 5, 1998.
|
References
|
|---|
1.
Kozlowski DA, James DG, Schallert T.
Use-dependent exaggeration of neuronal injury after unilateral
sensorimotor lesions. J Neurosci.. 1996;16:4776–4786.
2.
Kozlowski DA, von Stuck SI, Lee SM, Hovda DA, Becker DP.
Behaviorally-induced contusions following traumatic brain
injury: use-dependent secondary insults. Soc Neurosci
Abstr.. 1996;22:1905. Abstract.
3.
Dietrich WD, Alonso O, Halley M, Busto R. Delayed
posttraumatic brain hyperthermia worsens outcome after fluid-percussion
brain injury: a light and electron microscopic study in rats.
Neurosurgery.. 1996;38:533–541.
4.
Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W.
Brain temperature monitoring and modulation in patients with
severe MCA infarction. Neurology.. 1997;48:762–767.[Abstract/Free Full Text]
5.
Henker RA, Brown SD, Marion DW. Comparison of
brain temperature with bladder and rectal temperatures in adults with
severe head injury. Neurosurgery.. 1998;42:1071–1075.[Medline]
[Order article via Infotrieve]
6.
Ginsberg MD, Belayev L, Zhao W. Recruitment of
the ischemic penumbra into the necrotic core.
Cerebrovasc Dis. 1997;7(suppl 5):14–18.
Top
Abstract
Introduction
