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(Stroke. 1995;26:1047-1052.)
© 1995 American Heart Association, Inc.

Articles

Transient Forebrain Ischemia Protects Against Subsequent Focal Cerebral Ischemia Without Changing Cerebral Perfusion

Kazushi Matsushima, MD Antoine M. Hakim, MD, PhD

From the Neuroscience Research Institute, University of Ottawa, Ontario, Canada.

	Abstract

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Background and Purpose The possibility that the brain may be preconditioned to be more tolerant of ischemia is an important concept with important clinical implications. Exploring the concept offers the possibility of advancing our understanding of protective molecular responses in the brain. This article compares two preconditioning methods and explores the role that changes in regional cerebral blood flow (rCBF) may play in conferring ischemic protection.

Methods Temporary occlusion of the middle cerebral artery (MCA) using the thread model was preceded 4 days earlier by short-lasting focal or global ischemia or by sham surgery. rCBF was measured in the frontoparietal region of the ischemic hemisphere during all focal ischemia episodes. Four days after the second ischemic exposure, animals were killed, and the size of infarction was determined.

Results rCBF was significantly higher in the frontoparietal region during MCA occlusion when it was preceded by prior focal ischemia (36.8±7.6 mL · 100 g^-1 · min^-1 at 30 minutes) compared with controls (24.7±4.0 mL · 100 g^-1 · min^-1, P=.0008). Despite this, there was no significant difference in the resulting infarct volume. In contrast, when MCA occlusion was preceded by global ischemia, infarct volume was significantly reduced (68.1±30.9 mm³ in the controls versus 22.9±22.1 mm³ in the preconditioned group, P=.002) without significant change in rCBF.

Conclusions Protection from ischemic injury requires specific conditions of prior exposure to ischemia. Improved perfusion would not seem to be a sufficient or necessary accompaniment to providing neuroprotection.

Key Words: cerebral ischemia • neuroprotection • perfusion

	Introduction

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A large body of literature agrees that in both gerbils and rats short-lived global ischemia that falls short of killing cells provides a protective effect against delayed neuronal death in the hippocampal CA1 neurons during subsequent "lethal" global ischemia.^{1 2 3 4 5 6} This phenomenon has been referred to as ischemic tolerance. One mechanism contributing to this phenomenon may be the synthesis of stress proteins, including heat-shock proteins.^{5 6 7} The suggestion has been made that the earlier "nonlethal" global ischemia may facilitate the recovery of protein synthesis more rapidly in the vulnerable structures and lead to the replacement of denatured proteins with newly synthesized ones.^{8 9} Nonetheless, a number of issues remain unexplored in this phenomenon. It is not known whether the protective effect involves any change in perfusion through the synthesis or recruitment of new collateral vessels after the first ischemic episode, yet this may be suspected as a potentially important mechanism leading to ischemic tolerance. It also is not clear if the first ischemic episode has to coincide anatomically with the second one and be of a particular severity. This article explores some of these issues because of the potential importance of ischemic tolerance in cerebrovascular disease. Every transient ischemic attack is potentially a "nonlethal first ischemic episode," and the possibility of improving cerebral resistance to ischemic injury by nonpharmacological means is intriguing. Accordingly, we compared short-lasting global and focal ischemic insults in their ability to attenuate ischemic damage from subsequent focal ischemia in the rat and measured the changes in regional cerebral blood flow (rCBF) that may accompany this process.

	Materials and Methods

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The procedures followed during the experiments represented in this article were in accordance with institutional guidelines.

Experimental Design
In experiment 1 the effect of prior short-lasting middle cerebral artery (MCA) occlusion on rCBF and histological outcome after a second period of MCA occlusion was studied. Two groups were prepared: one (n=9) had MCA occlusion of 180-minute duration 4 days after an earlier episode of MCA occlusion lasting 30 minutes, and the other group (n=8) was subjected to MCA occlusion of 180 minutes after sham operation. Histological outcome was measured 4 days after the second ischemic episode. In experiment 2, the effect of prior global ischemia on rCBF during, and histological outcome following, a subsequent episode of MCA occlusion was studied. Again, two groups were prepared: one (n=10) had MCA occlusion of 120 minutes 4 days after a 5-minute episode of forebrain ischemia induced by four-vessel occlusion, and the other group (n=9) had MCA occlusion of 120-minute duration 4 days after sham operation. The sham-operated animals in experiment 2 (sham 2) had occluded vertebral arteries while the sham-operated animals in experiment 1 (sham 1) did not.

Surgical Procedures
Male Wistar rats weighing 230 to 250 g were used in all experiments and were allowed free access to food and water before and after all procedures.

Experiment 1
On day 1, rats were anesthetized with 2% halothane in a mixture of 30% oxygen/70% nitrous oxide. A platinum electrode (0.1 mm in diameter) was implanted in the left frontoparietal cortex (bregma, -1.5 mm; lateral, 4.0 mm; depth, 3.0 mm) and fixed with dental cement for subsequent measurement of rCBF. On day 2, rats were again anesthetized as above, the tail artery was cannulated with a PE-50 polyethylene catheter for physiological monitoring, and focal cerebral ischemia was induced by the method of Koizumi et al^{10 11} with minor modifications. Briefly, the left common, external, and internal carotid arteries were carefully exposed after a ventral midline incision was made in the neck. The distal portions of the left external and ipsilateral common carotid arteries were ligated with 4-0 silk suture. Immediately after, a 4-0 nylon monofilament thread thickened at its distal 5-mm tip with nail polish was introduced through the ipsilateral common carotid artery into the internal carotid artery. After introducing this occluder thread, the common carotid artery just distal to the point of insertion was ligated to prevent bleeding, and the tip of the occluder thread was progressed until the point of resistance. The occlusion of the MCA by the occluder was confirmed by measuring rCBF with the hydrogen clearance method. Thirty minutes after induction of ischemia, the thread was withdrawn, the suture over the common carotid was released, and reperfusion was again confirmed by measuring rCBF. Anesthesia was discontinued, and the rat was allowed free access to food and water until the next procedure. In the control group (sham 1), only the left external and common carotid arteries were ligated, and the occluder thread was introduced into the internal carotid momentarily and then removed. Four days later, with the animals under the same anesthetic conditions, the right femoral artery was cannulated for physiological measurements, and the MCA was occluded for 3 hours. Tail mean arterial blood pressures were checked every 10 minutes after MCA occlusion. rCBF was measured every 30 minutes during ischemia and after release of the MCA occlusion. The rats were again allowed free access to food and water. Four days after the second MCA occlusion, the rats were decapitated under the same anesthetic conditions, and the brains were removed and frozen in methylbutane cooled by liquid nitrogen and processed for histological assessment.

Experiment 2
Forebrain ischemia was induced by four-vessel occlusion as described by Pulsinelli and Brierley.¹² Briefly, on day 1 rats were anesthetized as described above, and vertebral arteries were electrocauterized. A platinum electrode (0.1 mm in diameter) was also implanted and fixed as described above. The following day, rats were again anesthetized, and both common carotid arteries were exposed. The control (sham 2) group underwent all these procedures including bilateral vertebral occlusions, but at this point the animals were returned to their cages. The anesthesia was discontinued. In the other rats, at the first sign of recovery from anesthesia, the common carotid arteries were occluded with aneurysm clips for 5 minutes, and then the clips were released. Rats that did not become unresponsive during this procedure were excluded from the study. The others were returned to their cages and allowed free access to food and water. Four days later under the same anesthetic conditions, the tail artery was cannulated for physiological monitoring, and the MCA was occluded for 120 minutes by the thread method as described above. rCBF was monitored by the hydrogen clearance method before MCA occlusion every 30 minutes during ischemia and after release of MCA occlusion. Again, rats were allowed free access to food and water. Four days later, the rats were decapitated, and the brains removed as above.

In experiments 1 and 2, rectal and temporal muscle temperatures and values of mean arterial blood pressure (MABP), arterial blood gases, plasma pH, and hematocrit were monitored as physiological parameters.

Measurement of Infarct Volume
Brain sections (20 µm in thickness) were stained with cresyl violet and with hematoxylin and eosin. Infarct area in 15 brain sections was measured by a microcomputer-based image display system (MCID, Imaging Research Inc) using the method described by Swanson et al.¹³ These sections were equally spaced along the anterior-posterior axis of the brain. Infarct volume was calculated as the integral of the infarct areas and their locations.¹³ White matter fascicles passing through the basal ganglia were not counted in the measurement of subcortical infarct volume.

Statistical Analysis
All data are expressed as mean±SD. Infarct area in each section and total infarct volume were compared by one-way ANOVA and independent t test. The changes of rCBF and physiological parameters at each time point were compared by one-way ANOVA. Mean rCBF changes for the entire study were compared by two-way ANOVA with repeated measurements.

	Results

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Experiment 1
Physiological Variables
During the first episode of MCA occlusion, MABP values of the group undergoing preconditioning ischemia were statistically higher than the sham group, but there was no difference during the second episode. Rectal and temporalis muscle temperatures and blood gas values were not statistically different between the two groups and are given in Table 1.

View this table: [in this window] [in a new window]   Table 1. Physiological Variables During Experiment 1

rCBF Determinations
In the first episode, the group undergoing preconditioning ischemia had rCBFs of 26.4±6.2 and 22.0±5.1 mL · 100 g^-1 · min^-1 immediately and 30 minutes after MCA occlusion, respectively (Fig 1a). During the second episode, rCBF in sham 1 and the preconditioned groups were 24.7±4.0 and 36.8±7.6 mL · 100 g^-1 · min^-1 at 30 minutes (F_(1,15)=17.73, P=.0008), 29.5±3.4 and 36.7±6.7 mL · 100 g^-1 · min^-1 at 60 minutes (F_(1,15)=8.07, P=.012), and 32.0±6.0 and 40.0±6.3 mL · 100 g^-1 · min^-1 at 180 minutes after MCA occlusion (F_(1,15)=7.15, P=.017), respectively. Thus, rCBF at several time points during the second ischemic period was significantly higher in the preconditioned group compared with its control counterpart. Average rCBF values during the entire second period of MCA occlusion were 31.2±3.5 and 36.1±5.3 mL · 100 g^-1 · min^-1, respectively, in the group without and with the preconditioning focal ischemia, the difference being significant (F_(1,15)=5.10, P=.039). Immediately after release of MCA occlusion and in the days following the second ischemic period, average rCBF values during the reperfusion phase were not statistically different between the two groups.

View larger version (26K): [in this window] [in a new window]   Figure 1. Graphs show time course of regional cerebral blood flow changes (rCBF). a, Experiment 1: rCBF changes in the group with sham operation plus 180 minutes of middle cerebral artery occlusion (MCAO) () and in the group with 30-minute MCAO plus 180-minute MCAO (). b, Experiment 2: rCBF changes in the group with sham operation plus 120-minute MCAO () and in the group with 5-minute four-vessel occlusion plus 120-minute MCAO (). ECAO+CCAO indicates occlusion of the external and ipsilateral common carotid arteries. Values are mean±SD. *P<.05, **P<.01.

Histological Outcome
Infarction was noted in the neocortex and subcortical structures in both groups (Table 2). Cortical infarct volumes were 15.5±12.7 and 21.0±21.5 mm³ in the groups without and with the preconditioning focal ischemia, respectively, but this difference was not statistically significant. Subcortical infarct volumes were also not significantly different. Thus, despite the higher blood flow during the longer period of focal ischemia associated with prior focal ischemic preconditioning, no change in infarct volume could be detected.

View this table: [in this window] [in a new window]   Table 2. Infarct Volumes in Experiments 1 and 2

Experiment 2
Physiological Variables
There were no significant differences in the measured MABP, rectal and temporalis muscle temperature, or blood gas values between the preconditioned and control groups, and these values were not different from those in experiment 1. They are therefore not reported.

rCBF Determinations
When the external and common carotid arteries were ligated, before MCA occlusion, rCBF was 98.0±15.1 and 81.5±10.9 mL · 100 g^-1 · min^-1 in the group without and with preconditioning ischemia, respectively (F_(1,17)=7.29, P<.05) (Fig 1b). rCBF at all other time points showed no significant difference between the groups. Mean rCBF during MCA occlusion was 19.7±1.6 and 21.3±3.3 mL · 100 g^-1 · min^-1 in the groups without and with the preconditioning ischemia, respectively, but these values were not statistically different. Moreover, there was no significant difference in rCBF between both groups during the reperfusion period.

Histological Outcome
Fig 2 shows the histogram of mean cortical infarct areas by section. It can be seen that most sections showed a significantly smaller cortical infarct area in the preconditioned animals compared with controls. Total cortical infarct volumes were 68.1±30.9 and 22.9±22.1 mm³ in the groups without and with the preconditioning ischemia, respectively (F_(1,17)=13.18, P=.002), indicating that preconditioning significantly reduced total cortical infarct volume (Table 2). Total subcortical infarct volume was not significantly different in the groups without and with preconditioning ischemia. Thus, preconditioning with global ischemia improves the histological outcome of subsequent focal ischemia without any effect on rCBF during the MCA occlusion phase.

View larger version (30K): [in this window] [in a new window]   Figure 2. Histograms of cortical infarct areas in experiment 2. The numbers refer to spaced sections along the anterior-posterior axis of the brain. Shaded bars indicate the group with sham operation plus 120 minutes of middle cerebral artery occlusion (MCAO); open bars, group with 5-minute four-vessel occlusion plus 120-minute MCAO. Values are mean±SD. *P<.05, **P<.01.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The possibility that the brain may be preconditioned to become more tolerant of ischemia is an important concept with potential therapeutic implications. Despite a number of studies that have reported the phenomenon,^{1 2 3 4 5 6} questions remain as to the optimum preconditioning strategy and whether the improved outcome is simply due to improved collateral flow. This study shows that preconditioning with short-lasting focal ischemia could not protect from subsequent, more prolonged focal ischemia despite the increment in rCBF to the area surrounding the ischemic core, whereas preconditioning with global ischemia was effective in reducing cortical infarct volume despite the absence of change in rCBF. Thus, our data suggest that the attenuation of ischemic damage resulting from preconditioning is probably not related to improvement in the perfusion of the ischemic area. rCBF is indeed higher in the preconditioned brain, but that does not appear to be a sufficient condition for histological protection.

More work is now needed to confirm and amplify this conclusion. Specific durations of ischemia were used during the preconditioning and subsequent phases, and only one interischemic interval was used. We imposed a longer period of focal ischemia (180 minutes versus 120 minutes) when the preconditioning episode was focal (experiment 1) as opposed to global (experiment 2) because the latter preconditioning maneuver required permanent occlusion of the vertebral arteries. Thus, we suspected that the second ischemic episode would be more severe in experiment 2, which was borne out by the lower rCBF values in the focal-ischemia phase of experiment 2 compared with experiment 1. As well, the sham 2 animals, which also underwent bilateral occlusions of the vertebral arteries and only 120 minutes of subsequent focal ischemia, suffered the largest volumes of focal infarction. Thus, we believe that a shorter episode of focal ischemia in experiment 2 was justified. In general, both the preconditioning and the second ischemic duration were defined from preliminary data obtained in the laboratory and from a review of the literature, but different intervals and ischemic durations may alter the conclusions. In addition, rCBF was measured in only one location judged to be a watershed zone that may survive moderate but not severe decreases in perfusion, but autoradiographic measurements with [¹⁴C]iodoantipyrine would describe regional rCBF more fully, perhaps identifying different rCBF trends from the ones reported. Finally, the thread model used here for MCA occlusion was selected because it allows repeated ischemic exposure with minimal cranial surgery, but the histological outcome in this model is variable, and using other models of MCA occlusion may alter the conclusion. Despite these limitations, this work points to specific characteristics of the preconditioning phase that are necessary for subsequent protection from ischemia.

Almost all prior reports on ischemic preconditioning have used global ischemia to provide protection to the hippocampal CA1 neurons during subsequent more prolonged global ischemia in gerbils and rats.^{1 2 3 4 5 6} Although this phenomenon has been largely confined to delayed neuronal death in the hippocampal CA1 region, Kitagawa et al³ showed that ischemic tolerance is notable in various brain regions including the cerebral cortex, caudate putamen, and the thalamus. Simon et al¹⁴ showed that two brief periods (6 minutes) of global cerebral ischemia attenuated ischemic damage from subsequent permanent focal cerebral ischemia, and a recent report showed that focal ischemia in the MCA territory can provide protection during subsequent global ischemia.¹⁵

We can only speculate on the physiological mechanisms leading to neuroprotection. A number of investigators have suggested that the development of ischemic tolerance is associated with synthesis of stress proteins including heat-shock proteins,^{3 16 17} but other molecular responses to ischemia such as the production of neurotrophic factors¹⁸ and specific growth factors¹⁹ may play a role in conferring neuroprotection to the ischemically preconditioned brain. Activation of the voltage-sensitive calcium channels is an important mediator of the molecular responses to ischemia,^{20 21} and the in vivo responses of this channel to focal permanent,^{22 23} focal reversible,²⁴ and forebrain ischemia,²⁵ as well as to spreading depression,²⁶ have been described. Activation of this channel is known to induce immediate early gene mRNA,^{20 21} but the translation of the message into proteins is an energy-requiring process that may not be possible in brain areas with severe reduction in flow.^{27 28 29} Thus, conditioning of the brain to be more tolerant of subsequent ischemia is likely to be the outcome of a complex process that requires the first episode to be sufficiently severe to induce voltage-sensitive calcium channels but not be damaging, the interval between the two episodes to be of the appropriate duration needed for induction of protective genes, and that sufficient energy remain after preconditioning to permit protein synthesis to occur. It is also possible, as this work shows, that the first episode can more easily induce these responses if it were not accompanied by a blood flow gradient but rather consisted of a severe reduction in rCBF occurring globally for a short time.

The possibility that ischemia may increase tolerance of the brain to subsequent ischemic events raises the prospect that a transient ischemic attack may not only be a harbinger for stroke but may also be an alerting signal to the brain to induce protective processes.³⁰ Thus, the equivalent clinical question to the one we address here is whether a stroke that occurs in a particular cerebral territory would be smaller if the same region had suffered a prior short ischemic episode. This is a clinically testable hypothesis, but the present study suggests that the requirements for such a phenomenon would be very specific regarding the nature of the preconditioning event, its duration, and its severity, and whether the rCBF drop during the event is uniform or consisting of a gradient. Finally, bringing cerebral preconditioning to the clinical realm is still a long way off, but already it is clear that many of our present notions will have to change. For example, some drugs now in clinical trials, such as N-methyl-D-aspartate and voltage-sensitive calcium channel blockers,^{31 32} have been shown to reduce the production of growth factors,^{18 33} agents the brain may need to protect itself from ischemic damage; such findings increase the need to understand more fully the effects of our current approaches to stroke therapy.

	Acknowledgments

 
The authors would like to thank Georgette Roy for her technical assistance and Robin Millbank for her clerical help. This work was supported by a grant from the Heart and Stroke Foundation of Ontario and the Medical Research Council of Canada.

	Footnotes

 
Reprint requests to Dr Antoine M. Hakim, Neuroscience Research Institute, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario, K1H 8M5, Canada.

Received August 29, 1994; revision received December 9, 1994; accepted March 3, 1995.

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