(Stroke. 1997;28:1451-1457.)
© 1997 American Heart Association, Inc.
Articles |
A Near-Infrared Spectroscopic Study of Cerebral Ischemia and Ischemic Tolerance in Gerbils
From the Departments of Neurology (J-Y.L., H.U., M.N., M.M., T.Y.), Physiology I (A.S.), and Internal Medicine I (M.M.), Osaka University Medical School (Japan).
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Abstract |
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Background and Purpose To explore the physiological mechanism of ischemic tolerance, we studied intracerebral oxygenation states noninvasively using near-infrared spectroscopy after bilateral common carotid artery occlusion (BCO) in gerbils with and without ischemic pretreatment.
Methods Under ether anesthesia, gerbils with sham operation (S group, n=8) and those with pretreatment consisting of BCO for 2 minutes, twice at 3 days and 2 days earlier (T group, n=8), were again subjected to BCO for 5 minutes. Changes in oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and total hemoglobin (HbT) as well as reduction in cytochrome oxidase (cyt.aa3) were calculated from the absorbance changes of the light transmitted through the brain. Seven days after the ischemic study, immunohistochemical examination was performed with an antiserum against microtubule-associated proteins.
Results In both groups, the increase of Hb and decrease of HbO2 and HbT proceeded rapidly after BCO, and the maximal deoxygenation of hemoglobin occurred within 2.5 minutes. Reduction of cyt.aa3 also ensued rapidly and reached the maximal reduction within 3 minutes in both groups. In the T group, however, both deoxygenation of hemoglobin and reduction of cyt.aa3 progressed more slowly than in the S group. The time (seconds) necessary for a maximal change for cyt.aa3 was significantly longer in the T group (203.8±34.0 [mean±SD]; P<.01) than in the S group (68.0±14.7). The time necessary for a half-maximal change was also significantly longer in the T group than in the S group for both Hb (22.0±7.5 and 13.5±4.0, respectively; P<.05) and cyt.aa3 (23.9±5.7 and 11.6±4.3; P<.01). After recirculation for 7 days, all gerbils in the S group were found to have neuronal death in the hippocampus, while those in the T group did not.
Conclusions The present study indicated that mild ischemic stress can induce improvement in oxygen metabolism during subsequent ischemia, which might be causally related to the phenomenon known as "ischemic tolerance," in which a protective effect toward ischemic/postischemic injury is induced by earlier mild ischemic pretreatment.
Key Words: hemoglobin • immunohistochemistry • near-infrared spectroscopy • neuroprotection • oxygen • gerbils
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Introduction |
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Previous immunohistochemical studies in which antibodies against cytoskeletal proteins such as MAPs were used have shown that brain is very sensitive to ischemia and that ischemic and postischemic neuronal damage developed within 5 minutes after the onset of ischemia.1 2 3 While extensive neuronal cell death evolved during reperfusion for more than 24 hours in various locations including the CA1 region of the hippocampus, the frequency and distribution of such postischemic damage depended on the duration and the severity of ischemic stress.3 4
In 1990, Kitagawa and coworkers5 reported protection of gerbil brains by pretreatment with sublethal ischemia and termed this phenomenon ischemic tolerance. Although various studies have been undertaken to elucidate the mechanism of this phenomenon,6 7 8 most focused their efforts on analyses of specific gene expression and protein synthesis during the early phase of reperfusion, and it has not been determined whether any difference exists in hemodynamic and/or metabolic derangement during ischemia with or without pretreatment. One reason for delay in the investigation in this field was lack of a method for continuous monitoring of cerebral blood flow and metabolism.
NIRS is a noninvasive technique that allows measurement of changes in the cerebral oxygenation state and hemodynamics.9 10 11 12 Light in the near-infrared region (700 to 900 nm) can transmit through living tissues relatively well. Changes in absorbance in this region can be attributed to those in the HbT and the oxygenation-deoxygenation state of hemoglobin, which serves as a carrier of oxygen in the circulating blood, and in the reduction-oxidation (redox) state of cytochrome oxidase (or cytochrome aa3; cyt.aa3), which serves as an oxygen acceptor in the tissue.9 10 12 Thus, we are able to follow changes in the tissue oxygenation as changes in HbO2 or Hb, the cerebral blood volume as changes in HbT, and the tissue viability as changes in the redox state of cyt.aa3.
In the present study we sought to assess changes in the cerebral oxygenation state by using NIRS after BCO in gerbils and tried to determine whether pretreatment for induction of ischemic tolerance made any difference during subsequent ischemia. The results indicated that improvement of oxygen metabolism did occur during ischemia and appeared to be closely associated with the development of ischemic tolerance. Part of the present work has been reported in abstract form.13
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Materials and Methods |
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Animals
Adult male Mongolian gerbils weighing 70 to 80 g were used in the present study. The present protocol was approved by the Animal Care and Use Committee of the Osaka University Medical School. Gerbils were allowed free access to food and water and were kept in an air-conditioned room at constant temperature (25°C) until the experiment. Gerbils were divided into two groups: the ischemia-tolerant group (T group, n=8) and the ischemia-sensitive group (S group, n=8). Under ether anesthesia, gerbils in the T group were pretreated with BCO for 2 minutes with miniature aneurysmal clips through a midline incision in the neck, twice at 3 days and 2 days before the NIRS experiment.5 For gerbils in the S group, CCAs were exposed bilaterally at the same time point as for gerbils in the T group but without arterial occlusion. At the time of the NIRS experiment, each gerbil was placed under an NIRS apparatus, and absorbance changes of the transmitted light through the brain were monitored before and during BCO for 5 minutes under ether anesthesia as described below. The body temperature was maintained at 37.0°C to 38.0°C with a homeothermic blanket control unit during the experiment. The MABP was monitored by means of a pressure transducer (AD-601G, Nihon Koden Co) inserted into the left femoral artery. After measurement during ischemia for 5 minutes, clips were removed and each gerbil was allowed to recover in a separate cage.
NIRS
Under ether anesthesia, each gerbil was placed in
the supine position with the head immobilized with a
homemade stereotaxic device capable of accommodating the
NIRS instrument. The investigators engaged in NIRS experiments were
unaware of the preconditioning status of each animal. Hair was removed
around the light path to avoid excess scattering. The emitting optode
from laser diodes was attached to the lower jaw, and the optode
receiving the transmitted light through the brain was placed close to
the scalp around the bregma. The distance (L) between two optodes was
kept constant at 2.0 cm in all experiments. We collected the NIRS data
with a four-wavelength (690, 780, 805, and 830 nm) spectrophotometer
(OM-100A, Shimadzu Co). Changes in concentrations of
oxygenated hemoglobin (
[HbO2]),
deoxygenated hemoglobin ([Hb]), total hemoglobin
([HbT]), and oxidized cyt.aa3
([cyt.aa3(OX)]) were calculated as
follows14 15 16 :
 | (1) |
 | (2) |
 | (3) |
 | (4) |
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From continuous tracings calculated as described above, the time points at which the maximal changes (tmax) and the half-maximal changes (t1/2) were obtained and the degree of changes in each component were determined at every 30 seconds after induction of ischemia with the use of an image- analyzing software (NIH image 1.60).
Immunohistochemical Procedure
After reperfusion for 7 days after the NIRS study, each gerbil
was decapitated under ether anesthesia, and the brain was
quickly removed, divided into coronal sections, fixed in 5% acetic
acid/ethanol, and embedded in paraffin.1 4 The
immunohistochemical reaction for MAPs (MAP I and II) was performed with
4-µm tissue sections encompassing the portion of the hippocampus in
the vicinity of the light path with the use of an
avidin-biotin-peroxidase complex method. The antiserum for MAPs from
gerbil brains has been described before.2 Harris
hematoxylin was used for counterstaining to visualize cell nuclei.
Statistical Analysis
All values were expressed as mean±SD. The statistical
significance of the difference between the T and S groups was
analyzed by one-way ANOVA followed by the Bonferroni test, and
the significance of tmax and
t1/2 was
analyzed by unpaired t test with the computer
software StatView 4.1 (Abacus Concepts Inc).
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Results |
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Fig 1
shows representative tracings
of [Hb], [HbO2], [HbT], and
[cyt.aa3(OX)] and changes after BCO in the S
and T groups. Rapid increase of [Hb] and concomitant decrease of
[HbO2], as a result of deoxygenation of
intracerebral hemoglobin, were observed in both groups.
These changes reached the respective maximal levels within 2.5 minutes
and remained constant during ischemia for 5 minutes. Decrease
of [HbT] reflecting cerebral blood volume was also observed, but the
change occurred more quickly than that of [Hb] or
[HbO2] in both groups. The profile of changes in
[cyt.aa3(OX)] was similar to that of
[HbO2] in both groups.
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For quantitative assessment of these ischemia-related changes
and statistical analyses of the differences between the T and S
groups, we determined (1) the extent of changes from the
preischemic level at every 30 seconds after induction of
ischemia and (2) tmax and
t1/2 of [Hb],
[HbO2], [HbT], and
[cyt.aa3(OX)] from the original tracing of
each gerbil (see Fig 1
) by using an image analyzer.
As shown in Fig 2A, the extent of
deoxygenation of hemoglobin was almost the same at all
ischemic periods in both groups. At 30 seconds and 1 minute
after the onset of ischemia, the changes in both [Hb] and
[HbO2] were smaller in the T group than the S group,
although the difference was statistically insignificant. The
tmax values for [Hb] and [HbO2] in the T
group (124.7±38.1 and 131.1±39.6) were also smaller than those in the
S group (91.0±41.2 and 89.0±34.7), but the difference was not
significant (Fig 2B). However, there were longer
t1/2 values in both
[Hb] and [HbO2] in the T group (Fig 2C), although
the difference was significant only in [Hb] (13.5±4.0 seconds in
the S group and 22.0±7.5 in the T group; P<.05),
suggesting a slower rate of deoxygenation. The maximal
change for [Hb] was 47.5±18.5 in the S group and 49.5±17.0
µmol/L·DPF in the T group after 5 minutes of ischemia,
while the maximal change for [HbO2] was 64.0±20.5 in the
S group and 65.0±19.5 µmol/L·DPF in the T group at 5
minutes, respectively, which was without statistical significance.
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) and T (
) groups. B and C, Duration of
the ischemic period necessary for the maximal (B) and
half-maximal (C) changes of 
) and T (
) groups. *P<.05 vs S
group.
HbT also decreased rapidly in both groups, and the lowest level
(19.0±2.9 µmol/L·DPF in the S group and 18.5±2.3 in the T
group) was obtained 30 seconds after the onset of ischemia
(Figs 1 and 2A). There was no significant difference between the two
groups. The tmax and
t1/2 values for
[HbT] were not determined because of rapid changes in both
groups.
The profile of [cyt.aa3(OX)] is shown in
Fig 3A. The change at the end of ischemia (5
minutes) was 5.3±0.8 µmol/L·DPF for the S group and
5.4±1.0 for the T group. There was no significant difference between
the two groups. Reduction of [cyt.aa3(OX)]
in the S group was rapid and reached the maximal level at 1 minute
after ischemia. Reduction of
[cyt.aa3(OX)] in the T group also proceeded
(although more gradually) and did not reach the complete reduction
level until 3 minutes. The difference in
[cyt.aa3(OX)] was significant between the
two groups at 30 seconds (4.37±0.54 µmol/L·DPF in the S
group and 3.19±0.75 in the T group; P<.01) and 1 minute
(5.32±0.76 µmol/L·DPF in the S group and 4.18±0.90 in the
T group; P<.05) of ischemia. The slower reduction
of [cyt.aa3(OX)] in the T group was also
reflected in the significantly longer tmax value of
[cyt.aa3(OX)] (68.0±14.7 seconds in the S
group and 208.1±39.3 in the T group; P<.001; Fig 3B) and
t1/2 value (11.6±4.3 in the S group and 23.8±5.7
in the T group; P<.001; Fig 3C).
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The Table shows changes in MABP before and during
ischemia. There was no difference in the
preischemic MABPs. After BCO, an increase in MABP was
observed in both groups, as shown by Nadasy et al,18 and
no significant difference was observed between the two groups.
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Fig 4 shows the immunohistochemical reaction for MAPs in
the S and T groups after the NIRS study for 5 minutes and reperfusion
for 7 days. All gerbils in the S group showed complete loss of the
immunohistochemical reaction in the pyramidal cell layer of
the CA1 region in the hippocampus, while all gerbils in the T group
showed survival of most neurons in the same region. These
immunohistochemical results were consistent with the previous
reports.5 7
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NIRS is a noninvasive technique to detect changes in the tissue oxygenation state and hemodynamics in the brain.9 10 11 12 14 19 20 21 To quantify changes in the concentrations of Hb, HbO2, HbT, and cyt.aa3(OX), it is desirable to estimate the actual optical path length in the gerbil brain. However, it is technically difficult to assess the actual optical path length from individual animals at the present time. Therefore, we established a constant interoptode distance of 2.0 cm for all NIRS measurements with transmitted light, since the optical path length can be considered equal to an interoptode distance multiplied by a DPF.12 17 19 Furthermore, we assumed that the DPF (and therefore the optical path length) is constant during our experiments. We therefore could assess prompt deoxygenation of intracerebral hemoglobin, decrease of HbT reflecting cerebral blood volume, and prompt reduction of cyt.aa3 soon after BCO in the gerbil.
As shown in Figs 1 through 3, decrease of HbT completed soon after
occlusion and both deoxygenation of hemoglobin and
reduction of cyt.aa3 followed. These results
were comparable to those in previous reports with experimental cerebral
ischemia21 and reflected changes caused by the
shutdown of blood supply to the brain and subsequent depletion of
tissue oxygen. Since the profiles of [Hb] and
[HbO2] were not identical (Fig 2), some vascular
reactions might also have been involved.22 Furthermore,
deoxygenation of hemoglobin and reduction of
cyt.aa3 also seem to have reached the respective
complete levels, judging from the calculated values of approximately
250 µmol/L for hemoglobin and approximately 20 µmol/L for
cyt.aa3, if we assume that DPF was 4 (optical
path length=4 L),17 which are similar to the reported
values in the brain23 (Figs 2 and 3). This finding is also
supported by the fact that the maximal level of
deoxygenation of hemoglobin and that of reduction in
cyt.aa3 corresponded with the respective
complete levels obtained from the analysis of gerbils killed by
intraperitoneal injection of an excess amount of
ketamine hydrochloride after ischemia (data not shown).
Thus, our NIRS results indicated that complete ischemia was
attained in the gerbil forebrain after BCO. Marked decline of cerebral
blood flow has been reported diffusely in the gerbil forebrain after
BCO24 because of a lack of Willis's ring.25
Complete reduction of cyt.aa3 also seemed
compatible with previous reports showing severe and diffuse decrease of
ATP in this stroke model,26 27 as in the case of brain
hypoxia.11 19 Therefore, our NIRS results obtained
from the light transmitted through the brain around the bregma should
have reflected cerebrovascular and metabolic changes
occurring in the forebrain diffusely.
The main finding of the present study was that gerbils pretreated
with repeated sublethal ischemia (2 minutes) developed a delay
in the time necessary for reduction of cyt.aa3
during subsequent 5-minute ischemia, suggesting the delay in
depletion of intracerebral oxygen compared with gerbils
without ischemic pretreatment. Since all gerbils with the delay
showed protection from severe immunohistochemical damage and those
without the delay showed no protection (Fig 4), the improvement in
oxygen metabolism should have played a major role in such a
protective effect.
The immunohistochemical damages observed in the group without
pretreatment were located in the CA1 and adjacent areas of the
hippocampus (Fig 4). This area is known to be the most vulnerable, and
damages outside the hippocampus were rarely observed after
recirculation after BCO for 5 minutes.1 2 3 4 Although the
immunohistochemical manifestation was apparently focal, severe
ischemic stress was diffusely induced in the forebrain in this
ischemia model, and it was the same in the ischemic
tolerance model shown here.6 Thus, focal
immunohistochemical damages in the hippocampus in the present study
are to be considered a reflection of the selective vulnerability in the
hippocampus, and we expect to see immunohistochemical damages in the
cerebral cortex, caudoputamen, and thalamus if
ischemic tolerance can be achieved after preconditioning and
ischemia for longer than 5 minutes.
The mechanism for the delay in reduction of
cyt.aa3 in the T group is not entirely clear.
Judging from complete reduction of cyt.aa3
achieved at the end of ischemia in both groups, however, the
increase of oxygen supply or the decrease of oxygen consumption rate
(or oxygen demand) can be considered possibilities. Since oxygen supply
is unlikely to increase in ischemia28 (Fig 2A), we
believe the latter possibility of metabolic suppression to
be more plausible. This possibility is also supported by the report of
decreased oxygen demand 5 to 20 hours after an episode of cerebral
ischemia.29 The induction of tolerance to hypoxic
brain damage might also be attributable to decrease of oxygen
demand.30
Although no significant change was observed in the temporal profiles of
Hb, HbO2, and HbT or blood pressure (Table) during
ischemia, we cannot exclude the possibility that some changes
in vasoreactivity improved oxygen supply as a result of local
redistribution of blood (Fig 3A).
Recent reports suggested that the gene expression of heat shock proteins,6 7 8 oxygen radical scavengers,31 32 and nerve growth factors33 might be involved in the development of ischemic tolerance. It is quite possible that multiple factors are involved in the development of ischemic tolerance and improvement of oxygen metabolism during ischemia shown in the present study, and the expressions of the aforementioned factors34 are not mutually exclusive.
In summary, our results indicate that improvement in oxygen metabolism during the early phase of ischemia seems closely related to the development of ischemic tolerance in the gerbil model of cerebral ischemia. Analysis of the relationship between vasoreactivity and oxygen metabolism may delineate the protective mechanism further.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture of Japan and a Japan Heart Foundation research grant. We thank Dr Hideo Eda of the Shimadzu Co for discussion of the algorithm.
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Footnotes |
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Reprint requests to Dr Takehiko Yanagihara, Department of Neurology, Osaka University Medical School, 2-2 Yamada-Oka, Suita, Osaka 565, Japan.
Received January 14, 1997; revision received March 26, 1997; accepted March 28, 1997.
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