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Anesth Analg 2001;92:418-423
© 2001 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Time Course of Acquisition of Ischemic Tolerance and Induction of Heat Shock Protein 70 after a Brief Period of Ischemia in the Spinal Cord in Rabbits

Mishiya Matsumoto, MD, Kazunobu Ohtake, MD, Hiroya Wakamatsu, MD, Satoe Oka, MD, Takashi Kiyoshima, MD, Kazuhiko Nakakimura, MD, and Takefumi Sakabe, MD

Department of Anesthesiology-Resuscitology, Yamaguchi University School of Medicine, Ube, Japan

Address correspondence and reprint requests to Mishiya Matsumoto, MD, Department of Anesthesiology-Resuscitology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We examined the time course of development of ischemic tolerance in the spinal cord and sought its mechanism exploring the expression of heat shock protein 70 (HSP70). Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta. In Experiment 1, neurologic and histopathologic outcome was evaluated 48 h after prolonged ischemia (20 min) that was given 2 days, 4 days, or 7 days after a short period of ischemia (ischemic pretreatment) sufficient to abolish postsynaptic component of spinal cord evoked potentials. Control animals were given prolonged ischemia 4 days after sham operation. In Experiment 2, HSP70 expression in motor neurons after pretreatment without exposure to prolonged ischemia was examined by immunohistochemical staining. Ischemic pretreatment 4 days (but not 2 days or 7 days) before 20 min ischemia exhibited protective effects against spinal cord injury. In the cytoplasm, HSP70 immunoreactivity was mildly increased after 2, 4, and 7 days of ischemic pretreatment. However, the incidence of nuclear HSP70 immunoreactivity 2 days, 4 days, and 7 days after ischemic pretreatment was 2 of 6 animals, 4 of 6 animals, and 1 of 6 animals, respectively (none in the control group). These results suggest that ischemic tolerance is apparent 4 days after ischemic pretreatment and that HSP70 immunoreactivity in the nucleus may provide some insight into the mechanisms of ischemic tolerance in the spinal cord.

Implications: Ischemic tolerance in the spinal cord is induced in 4 days, not yet induced in 2 days but gone by 7 days, after ischemic pretreatment. The amount of heat shock protein 70 (HSP70) in the cytoplasm does not explain this temporal profile, but HSP70 in the nucleus might play a role in the acquisition of ischemic tolerance.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Arecent advance in brain and spinal cord ischmia research is the discovery of ischemic tolerance (1,2). After being subjected to a mild ischemic insult (preconditioning stimulus), neurons acquire tolerance to a subsequent period of prolonged ischemia (1). Although the molecular mechanism of ischemic tolerance is unknown, heat shock protein 70 (HSP70)has been reported to play a role (2).

Matsuyama et al. (3) and Sakurai et al. (4) demonstrated ischemic tolerance in the spinal cord by the evaluation of neurologic and histopathologic outcome. Matsuyama et al. (3) observed HSP70 immunoreactivity in motor neurons in three of four animals 48 h after the pretreatment. Sakurai et al. (4) reported that HSP70 immunoreactivity in the motor neurons was strong at 8 h after pretreatment, mild at 1 or 2 days after pretreatment, and not observed at 7 days after pretreatment. However, the evaluation of tolerance was performed with only a single interval (2 days) between the pretreatment and subsequent ischemic insult in these studies (3,4). Furthermore, though HSP70 may be involved in the mechanism of ischemic tolerance as they suggested (3,4), it has not been determined whether acquisition of ischemic tolerance is related to the amount of HSP70.

We sought to determine the time course of the effects of ischemic pretreatment on spinal cord damage after a subsequent prolonged ischemic insult. Animals were subjected to prolonged ischemia with variable intervals, namely, 2 days, 4 days, or 7 days after ischemic pretreatment. In addition, we investigated the immunoreactivity of HSP70 2 days, 4 days, and 7 days after ischemic pretreatment to see whether acquisition of ischemic tolerance may be related to the magnitude of HSP70 expression.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This experiment was approved by our institutional ethics committee. Fifty-four New Zealand white rabbits weighing 2.9 ± 0.2 (mean ± SD) kg were used in this study. The methods for producing spinal cord ischemia have been previously reported (5,6).

Experiment 1
Animals were randomly assigned to one of the following groups: 2-day interval between ischemic pretreatment and subsequent prolonged ischemia (two day group, n = 8), 4-day interval (four day group, n = 8), 7-day interval (seven day group, n = 8), or 4-day interval between sham operation and prolonged isch-emia (a control group, n = 8).

The rabbits were anesthetized in a plastic box with 5% sevoflurane in oxygen. An ear vein catheter was inserted for administration of fluid and drugs. A small dose of pentobarbital (20–30 mg) was administered for facilitation of intubation. After intubation of the trachea with a 3-mm cuffed endotracheal tube (Mallinckrodt, St. Louis, MO), the lungs were mechanically ventilated with 2% isoflurane in 40% oxygen/60% nitrogen, and PaCO2 was maintained at 35–42 mm Hg. End-tidal concentrations of isoflurane and CO2 were continuously measured by an infrared anesthetic analyzer (Nippon Colin, Komaki, Japan). IV infusion of lactated Ringer’s solution was started at a rate of 3–4 mL · kg-1 · h-1. Core temperature was monitored with an esophageal thermistor (Model MGA-III, Type 219; Nihon Kohden, Tokyo, Japan). To estimate spinal cord temperature, paravertebral muscle temperature at the level of L4 to L5 was monitored by a needle-type thermistor (Model PTC-201; Unique Medical, Tokyo, Japan). Paravertebral temperature was controlled to 38.0°C with a heating lamp and warming pad throughout the study.

In the right lateral position, a skin incision was made at the twelfth costal level. The retroperitoneal abdominal aorta at the level of left renal artery was exposed. A PE-60 catheter was placed around the aorta immediately distal to the left renal artery. Then an occluder tube was tunneled to the skin for later occlusion of the aorta to produce spinal cord ischemia.

To monitor segmental spinal cord evoked potential (SSCEP), the left sciatic nerve was exposed and bipolar electrodes were placed around the nerve. The stimuli used were square-wave pulses of 0.1 ms duration and 0.6 mA intensity delivered at 3 Hz. Two silver needle electrodes were inserted into the midline interspinous ligament so that they were in contact with the lamina at the L4-5 and L5-6 levels. The SSCEPs were recorded in a bipolar fashion from the needle electrodes using Neuropack Four Mini (Model MEB-5304; Nihon Kohden). Fifty repetitions were averaged. SSCEPs were recorded before ischemia and every 1 min during ischemia. The typical recording of SSCEP from L4-5 and L5-6 demonstrates two positive waves and four negative waves. The first two negative waves (N1 and N2) are presynaptic components and the last two waves (N3 and N4) are postsynaptic (7).

After completion of surgery, end-tidal isoflurane concentration was maintained at 2%. Heparin 400 U was administered IV immediately before aortic occlusion. Spinal cord ischemia was produced by pulling the PE catheter and clamping an occluder tube. The duration of initial mild ischemia was determined by the time when N3 wave in SSCEP disappeared. In the control group, only surgical manipulation without aortic occlusion was performed.

The PE catheter was then removed and all incisions were sutured. Isoflurane was discontinued and the lungs were ventilated with 100% oxygen. Extubation of the trachea was performed when vigorous spontaneous ventilation and movement occurred. The animals were allowed to recover in a warmed plastic box that contained supplemental oxygen for 6 h. IV fluid was provided until the animals began to drink. An antibiotic (cefazolin 30 mg · kg-1, IM) was administered once daily.

After the predetermined interval, animals were again anesthetized in the same manner as in the ischemic pretreatment. After skin infiltration with 0.25% bupivacaine, PE-60 catheters were inserted into both femoral arteries to measure blood pressure above and below the aortic occlusion. The right femoral catheter was advanced 3 cm into the abdominal aorta and the other was advanced 17 cm. Before catheter insertion, heparin 400 U was administered IV. In the right decubitus position, a PE-60 catheter was placed around the aorta in the same manner as in the first ischemia. SSCEP was not monitored to negate the possibility that repeated surgery and stimulation of left sciatic nerve affected neurologic assessment.

After completion of surgery, end-tidal isoflurane concentration was maintained at 2%. Heparin 400 U was administered IV immediately before aortic occlusion. Spinal cord ischemia was produced by pulling the PE catheter and clamping an occluder tube for 20 min.

The PE catheters were then removed and all incisions were sutured. Isoflurane was discontinued and the lungs were ventilated with 100% oxygen. Extubation of the trachea and postischemic care were the same as for ischemia pretreatment. Bladder contents were expressed manually as required.

At 6, 12, 24, and 48 h after recirculation, the rabbits were neurologically assessed by an observer unaware of the treatment group using the five-point grading scale described by Drummond et al. (8): 4 = normal motor function; 3 = ability to draw legs under body and hop, but not normally; 2 = some lower extremity function with good antigravity strength but inability to draw legs under body; 1 = poor lower extremity motor function, weak antigravity movement only; and 0 = paraplegic with no lower extremity function.

After completion of neurologic function scoring at 48 h, the animals were reanesthetized with 2% isoflurane in oxygen. Transcardiac perfusion and fixation were performed with 1000 mL heparinized saline followed by 500 mL 10% phosphate-buffered formalin. The lumber spinal cord was removed and refrigerated in 10% phosphate-buffered formalin for 48 h, dehydrated in graded concentrations of ethanol and butanol, and embedded in paraffin. Coronal sections (at L5) were cut at a thickness of 8 µm and stained with hematoxylin and eosin.

Neuronal injury was evaluated at a magnification of 400x by an observer unaware of group assignment. Ischemic neurons were identified by cytoplasmic eosinophilia with loss of Nissl substance and by the presence of pyknotic homogenous nuclei. In each slice, normal neurons in the anterior spinal cord (anterior to a line drawn through the central canal perpendicular to the vertical axis) were counted.

Experiment 2
Animals were anesthetized and surgery was performed in the same manner as described above for ischemic pretreatment. Animals were randomly assigned to one of the following groups: 2 days interval between the pretreatment and perfusion-fixation of the spinal cord (two day group, n = 6), 4-day interval (four day group, n = 6), 7-day interval (seven day group, n = 6), and 4-day interval between the sham operation and perfusion-fixation (control group, n = 4). Because previous studies consistently suggested that HSP70 immunoreactivity in the neurons was not observed in sham pretreatment animals (3,4), we chose four animals for the control group. In this series of experiments, animals were not exposed to the second ischemia. After the predetermined interval, perfusion and fixation were performed in the same manner as Experiment 1. The lumbar spinal cord was removed and refrigerated in 10% phosphate-buffered formalin for 1 wk.

After dehydration in graded concentrations of ethanol and butanol, the spinal cords were embedded in paraffin. Coronal sections (at L5) were cut at a thickness of 8 µm. The sections were deparaffinized using xylene and ethanol. Endogenous peroxidase was inactivated using 3% hydrogen peroxide in methanol. After rinsing in phosphate-buffered saline (pH 7.2, 0.1 mol/L), nonspecific protein binding was blocked with 10% normal goat serum. The sections were incubated for 12 h with a mouse monoclonal antibody against HSP70 (SPA-810; Stressgen, Victoria, BC, Canada) diluted 1: 200 at 4°C. This was followed by incubation with antimouse second antibody (Histofine simple stain PO[M]: amino acid polymers combining with peroxidase and goat antimouse Ig, Nichirei, Japan) at room temperature for 30 min and visualized with diaminobenzidine hydrochloride. These sections were then counterstained with hematoxylin. The degree of staining was rated as nil (-), partial/weak (±), mild (+), or strong (++). A positive control slide (perfusion and fixation at 8 h interval after 10 min pretreatment (4), rated as strong) and reagent control slide (stained without the primary antibody, rated as nil) were stained in the same manner as the unknown specimen slide to interpret staining results.

Physiologic variables were analyzed by a repeated-measures analysis of variance. The time required for N3 to disappear, hindlimb motor function, number of normal neurons in the anterior spinal cord, and the degree of HSP70 staining were analyzed using Kruskal-Wallis test followed by the Mann-Whitney U-test with Bonferroni corrections. P < 0.05 was considered statistically significant. Parametric data are presented as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All animals were neurologically normal after ischemic pretreatment. The times for N3 wave in SSCEP to disappear were 7.3 ± 1.4 min, 7.4 ± 1.6 min, or 6.6 ± 1.9 min, in the two day group, four day group, or seven day group, respectively. There were no differences among the groups. Physiologic variables for prolonged ischemia in Experiment 1 are shown in Table 1. The results of neurologic assessments are shown in Figure 1. The final neurologic status (48 h) in the four day group was better than that in the control group (P = 0.0021). There was no significant difference in neurologic status among the four groups at 6, 12, 24 h after 20 min ischemia. The number of normal neurons in the anterior spinal cord in the four day group was more than in the control group (P = 0.0038) ( Fig. 2). Some animals in the two day or seven day groups were neurologically normal, but neither the final neurologic status nor the number of normal neurons in the anterior spinal cord of the two day group or the seven day group was different from that in the control group.


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  		Table 1. Physiologic Variables
 


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  		Figure 1. Individual neurologic function score change from 6 to 48 h after reperfusion of subsequent prolonged (20 min) ischemia. Each symbol represents data for one animal. Neurologic function score: 4 = normal motor function; 3 = ability to draw legs under body and hop, but not normally; 2 = some lower extremity function with good antigravity strength but inability to draw legs under body; 1 = poor lower-extremity motor function, weak antigravity movement only; 0 = paraplegic with no lower-extremity function. *Significant difference from the control group at 48 h.

 


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  		Figure 2. The number of normal motor neurons in the anterior spinal cord (L5 level) 48 h after reperfusion of subsequent prolonged (20 min) ischemia. Each symbol represents data for one animal. *Significant difference from the control group.

 
Immunohistochemical staining revealed induction of HSP70 in the ischemic pretreatment groups, but not in the control group ( Fig. 3 A–D). The degrees of immunoreactivity for HSP70 in the cytoplasm were mild (+) in all animals in the two day, four day, or seven day groups, i.e., there was no apparent difference among the three pretreatment groups. HSP70 immunoreactivity in the nucleus of the motor neuron was observed in two of six animals in the two day group, four of six animals in the four day group and one of six animals in the seven day group, although there was no difference in the incidence of nuclear HSP70 immunoreactivity among the three groups.



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  		Figure 3. Immunohistochemical staining against heat shock protein 70 (HSP70) in the ventral horn of the spinal cord. A, at four days after sham operation (control); B, at two days after ischemic pretreatment; C, at four days after ischemic pretreatment; D, at seven days after ischemic pretreatment. HSP70 immunoreactivity in the cytoplasm of the motor neurons was similar two, four, and seven days after ischemic pretreatment. However, HSP70 immunoreactivity in the nucleus of motor neurons was present at four days, but not seven days after ischemic pretreatment. Immunoreactivity at 2 days was intermediate. In control group, there was no HSP70 immunoreactivity in either the cytoplasm or the nucleus. Original magnification 100x.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The principal findings of the present study are that a short period of spinal cord ischemia (ischemic pretreatment) determined by the time for N3 wave in SSCEP to disappear reduces neuronal damage after twenty minutes of spinal cord ischemia given at a four day interval, but not a two or seven day interval, and that HSP70 is induced in the cytoplasm of motor neuron similarly two days, four days, or seven days after ischemic pretreatment, but HSP70 immunoreactivity in the nucleus appeared to be greatest in the four day group.

Ischemic tolerance phenomenon was first found in the brain by Kitagawa et al. (1). Subsequent work by Kato et al. (9) demonstrated that ischemic tolerance was induced by two minutes (but not one minute) of bilateral carotid artery occlusion in gerbils. In contrast, three minutes of ischemia alone resulted in severe damage. It was speculated that one minute of ischemia is not sufficient to perturb cellular metabolism, leading to no acquisition of tolerance. In contrast, three minutes of ischemia is so severe that neurons die. Determination of proper duration of ischemia is thought to be a key factor for acquisition of ischemic tolerance. Although occlusion of the abdominal aorta of the rabbit produces reproducible spinal cord ischemia, residual blood flow in the spinal cord during aortic occlusion may vary from animal to animal. Therefore, we chose the time for N3 wave in SSCEP to disappear as the optimal ischemic duration for preconditioning in each animal. N3 and N4 waves are postsynaptic components; N4 wave disappears first and then the N3 wave disappears as ischemia continues (7). The time for the N3 wave to disappear was an appropriate interval to induce ischemic tolerance in this study.

In a canine spinal cord ischemia model, Matsuyama et al. (3) demonstrated that cross-clamping of the thoracic aorta for 20 minutes 48 hours before a second ischemic insult of 60 minutes improved neurologic score 24 hours after the second insult. In rabbits, Sakurai et al. (10) demonstrated that occlusion of the abdominal aorta with an intraaortic balloon for 10 minutes, 48 hours before a secondary ischemic insult of 15 minutes, improved neurologic and histopathologic outcome. Munyao et al. (11) also reported that occlusion of the abdominal aorta of rabbits for 12.5 minutes given 12 hours, but not 48 hours, before a second ischemic insult (30 minutes) improved neurologic and histopathologic status. However, the design of that study may not have been appropriate for statistical analysis because the animals were not randomized to treatment groups (11). Furthermore, the final evaluation that was performed 24 hours after reperfusion (11) may have been too early. Therefore, in these previous studies of spinal cord ischemia, the temporal profile of effects of ischemic pretreatment on the neuronal injury after secondary ischemic insult remained unclear. In the present study, we have elucidated the temporal profile of ischemic tolerance in the spinal cord in this model. The protective effect is present four days after pretreatment.

To explore the mechanism for the protective effect of pretreatment observed only in the four day group, but not in the two day or seven day group, we examined HSP70 expression using immunohistochemical staining technique. HSP70 assists protein folding. Functions include the initial folding of newly synthesized proteins to refolding of proteins damaged by environmental stress (12). In the present study, animals that had no ischemic pretreatment did not show HSP70 immunoreactivity in motor neurons. In contrast, animals that received ischemic pretreatment showed HSP70 immunoreactivity. The magnitude of HSP70 in the cytoplasm of motor neurons was similar at two days, four days, or seven days after the pretreatment. Therefore, the amount of HSP70 in the cytoplasm per se after ischemic pretreatment does not explain the temporal profile of ischemic tolerance. Our results are not consistent with Sakurai et al. (10) in terms of the time course of the magnitude of HSP70 immunoreactivity in the motor neurons. In our study, HSP70 immunoreactivity in the cytoplasm was observed until seven days after ischemic pretreatment, whereas it was observed from eight hours to two days, but not seven days, after the pretreatment by Sakurai et al. (10). It is not clear whether this is a result of the difference of the method to produce spinal cord isch-emia (aorta clamping vs balloon occlusion) or of the duration of pretreatment (the time for the N3 wave [SSCEP] to disappear versus ten minutes).

Regarding HSP70 distribution in motor neurons, there have been no other studies that examined HSP70 immunoreactivity in the nucleus in relation to the acquisition of ischemic tolerance. In the present study, HSP70 immunoreactivity in the nucleus of motor neurons exhibited a trend for a difference among the three groups. The physiological significance of HSP70 immunoreactivity in the nucleus a few days after pretreatment is unknown. Recently, HSP70 has been reported to act as RNA-binding entities to guide the appropriate folding of RNA substrates for subsequent regulatory processes such as messenger RNA degradation and/or translation (12). Molecules other than proteins might interact with HSP70 in the nucleus in ischemic tolerance. Although HSP70 may not be solely responsible for ischemic tolerance (13), HSP70 immunoreactivity in the nucleus may provide some insight into the mechanisms of ischemic tolerance in the spinal cord.

In summary, we have elucidated the temporal profile of efficacy of ischemic pretreatment in the spinal cord in this model. The protective effect was apparent four days after the pretreatment. The amount of HSP70 in the cytoplasm does not explain the temporal profile of ischemic tolerance. Although it should be further explored, HSP70 in the nucleus might play a role in the acquisition of ischemic tolerance.


   Acknowledgments
 
Supported, in part, by the Ministry of Education, Science, Sports, and Culture Grant #09671567.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Kitagawa K, Matsumoto M, Tagaya M, et al. Ischemic tolerance phenomenon found in the brain. Brain Res 1990; 528: 21–4.[ISI][Medline]
  2. Kirino T, Tsujita Y, Tamura A. Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab 1991; 11: 299–307.[ISI][Medline]
  3. Matsuyama K, Chiba Y, Ihaya A, et al. Effect of spinal cord preconditioning on paraplegia during cross-clamping of the thoracic aorta. Ann Thorac Surg 1997; 63: 1315–20.[Abstract/Free Full Text]
  4. Sakurai M, Hayashi T, Abe K, et al. Enhancement of heat shock protein expression after transient ischemia in the preconditioned spinal cord of rabbits. J Vasc Surg 1998; 27: 720–5.[ISI][Medline]
  5. Matsumoto M, Iida Y, Sakabe T, et al. Mild and moderate hypothermia provide better protection than a burst-suppression dose of thiopental against ischemic spinal cord injury in rabbits. Anesthesiology 1997; 86: 1120–7.[ISI][Medline]
  6. Wakamatsu H, Matsumoto M, Nakakimura K, et al. The effects of moderate hypothermia and intrathecal tetracaine on glutamate concentrations of intrathecal dialysate and neurologic and histopathologic outcome in transient spinal cord ischemia in rabbits. Anesth Analg 1999; 88: 56–62.[Abstract/Free Full Text]
  7. Cheng M-K, Robertson C, Grossman RG, et al. Neurological outcome correlated with spinal evoked potentials in a spinal cord ischemia model. J Neurosurg 1984; 60: 786–95.[ISI][Medline]
  8. Drummond JC, Moore SS. The influence of dextrose administration on neurologic outcome after temporary spinal cord ischemia in the rabbit. Anesthesiology 1989; 70: 64–70.[ISI][Medline]
  9. Kato H, Liu Y, Araki T, et al. Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Res 1991; 553: 238–42.[ISI][Medline]
  10. Sakurai M, Aoki M, Abe K, et al. Selective motor neuron death and heat shock protein induction after spinal cord ischemia in rabbits. J Thorac Cardiovasc Surg 1997; 113: 159–64.[Abstract/Free Full Text]
  11. Munyao N, Kaste M, Lindsberg PJ. Tolerization against loss of neuronal function after ischemia-reperfusion injury. Neuroreport 1998; 9: 321–5.[Medline]
  12. Henics T, Nagy E, Oh HJ, et al. Mammalian Hsp70 and Hsp110 proteins bind to RNA motifs involved in mRNA stability. J Biol Chem 1999; 274: 17318–24.[Abstract/Free Full Text]
  13. Kitagawa K, Matsumoto M, Mabuchi T, et al. Ischemic tolerance in hippocampal CA1 neurons studied using contralateral controls. Neuroscience 1997; 81: 989–98.[ISI][Medline]
Accepted for publication October 23, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press