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Ann Thorac Surg 1999;68:874-880
© 1999 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Ischemic preconditioning reduces neurologic injury in a rat model of spinal cord ischemia

^a Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Address reprint requests to Dr Zvara, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27127-1009
e-mail: dzvara{at}wfubmc.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Background. Ischemic preconditioning (IPC) is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia render a tissue more resistant to a subsequent, more prolonged ischemic insult. We hypothesized that IPC of the spinal cord would reduce neurologic injury after experimental aortic occlusion in rats and that this improved neurologic benefit could be induced acutely after a short reperfusion interval separating the IPC and the ischemic insult.

Methods. Forty male Sprague-Dawley rats under general anesthesia were randomly assigned to one of two groups. The IPC group (n = 20) had 3 minutes of aortic occlusion to induce spinal cord ischemia 30 minutes of reperfusion, and 12 minutes of ischemia, whereas the controls (n = 20) had only 12 minutes of ischemia. Neurologic function was evaluated 24 and 48 hours later. Some animals from these groups were perfusion-fixed for hematoxylin and eosin staining of the spinal cord for histologic evaluation.

Results. Survival was significantly better at 48 hours in the IPC group. Sensory and motor neurologic function were significantly different between groups at 24 and 48 hours. Histologic evaluation at 48 hours showed severe neurologic damage in rats with poor neurologic test scores.

Conclusions. Ischemic preconditioning reduces neurologic injury and improves survival in a rat model of spinal cord ischemia. The protective benefit of IPC is acutely invoked after a 30-minute reperfusion interval between the preconditioning and the ischemic event.

	Introduction

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Paraplegia remains a devastating complication after operations on the descending and thoracoabdominal aorta. Svensson and associates [1] reported a 16% incidence of neurologic injury in patients having thoracoabdominal aortic operations. The incidence of paraplegia depends on multiple factors, including the type and extent of reconstruction, the duration of aortic cross-clamping, the presence of dissection, patient age, and the urgency of operation [1, 2]. Several techniques have been evaluated for efficacy in reducing paraplegia after aortic cross-clamping: cerebral spinal fluid drainage [3–5], distal aortic perfusion [5, 6], and regional hypothermia of the spinal cord [7, 8]. Here we report the results of experiments involving ischemic preconditioning (IPC) of the spinal cord as a novel strategy for spinal cord protection.

Ischemic preconditioning is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia with reperfusion render a tissue more resistant to a subsequent, more prolonged ischemic insult. Murry and coworkers [9] first described the phenomenon in dogs by demonstrating that a series of short, sublethal coronary artery occlusions followed by reperfusion protected the heart from subsequent lethal ischemia and reperfusion. Two recent reports document the protective benefit of IPC in the spinal cord. Munyao and colleagues [10] studied rabbits that had 30 minutes of aortic clamping either with or without a preceding (12 or 48 hours earlier) 12.5-minute period of IPC. Rabbits with IPC 12 hours before the insult had significantly better motor function than controls, whereas rabbits that had IPC 48 hours earlier showed variable neurologic recovery. Histologic evaluation correlated well with clinical observations of hind limb function. Matsuyama and coauthors [11] studied IPC of the spinal cord using a model of aortic cross-clamping in the dog. The IPC group had aortic cross-clamping for 20 minutes, and controls had no cross-clamping. After 48 hours, the aorta was cross-clamped for 60 minutes in both groups. After a 24-hour recovery, 3 of 6 control dogs were paraplegic, whereas none in the IPC group were paraplegic. There was evidence of elevated heat shock protein levels at 48 hours in dogs without paraplegia in both groups.

In both of these studies, the reperfusion interval between the IPC and the subsequent ischemic event was several hours or days. Although much research in the brain demonstrates neuroprotection with IPC involving long reperfusion intervals ranging from 1 day to 5 days [12–15], recent evidence suggests that shorter reperfusion intervals of 10 minutes to 6 hours also provide neuroprotection [16–18]. Such a wide time window of interval reperfusion suggests that more than one mechanism is present in IPC protection of the brain. To date, we know of no published studies of the effect of a short reperfusion interval in a model of spinal cord ischemia. We hypothesized that IPC of the rat spinal cord by aortic occlusion would reduce neurologic deficit and that the mechanisms of IPC protection can be acutely invoked by a 30-minute reperfusion interval between the IPC and the sustained ischemic event.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
The institutional Animal Care and Use Committee of Wake Forest University School of Medicine, Winston-Salem, NC, approved all animal surgical and testing procedures. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Male Sprague-Dawley rats weighing 425 ± 27 g in the study group and 421 ± 26 g in the control group were used in this experiment (p = 0.86). The rats were allowed access to standard rat chow and water ad libitum. All rats were neurologically intact prior to anesthesia and instrumentation.

Surgical procedure
The rats were anesthetized with 1.5% halothane in a 45% oxygen and air mixture. They were allowed to breathe spontaneously with a nonsealing face-mask device. Arterial blood gas sampling was performed prior to any aortic occlusion (baseline) and at the end of the procedure just prior to emergence from general anesthesia. A probe was inserted 8.0 cm into the rectum, and body temperature was measured and maintained between 36.5° and 37.5°C with a circulating warm water (37.5°C) underbody-heating pad. The tail artery was cannulated with a PE-50 polyethylene catheter to obtain arterial blood samples and to monitor mean distal aortic blood pressure (MDAP). The left femoral artery was isolated, and a Fogarty 2F balloon-tipped catheter (Baxter, Santa Ana, CA) was introduced for later advancement into the descending thoracic aorta. The left internal carotid artery was cannulated with a 20-gauge catheter for measurement of mean proximal aortic pressure (MPAP). The carotid artery cannula was connected to a heated blood-collection circuit (37.5°C) that included an 88-cm vertical column of heparinized normal saline solution (1 U/mL). When the aorta was occluded, proximal aortic blood was allowed to bleed into the heparinized column, maintaining MPAP at 65 ± 3 mm Hg. Mean proximal aortic pressure, MDAP, and temperature were recorded at 1-minute intervals by a PC–based data acquisition system (Micro-Med, Louisville, KY).

To induce spinal cord ischemia, the Fogarty 2F catheter in the left femoral artery was inserted retrograde into the descending thoracic aorta 10.5 cm from the femoral arteriotomy so that the tip of the catheter balloon lay just caudal to the left subclavian artery. This distance was confirmed at postmortem examination of 3 rats sacrificed for catheter placement measurements. After instrumentation, all rats were given 200 units of heparin sodium. During the experimental protocol, the catheter was inflated with 0.05 mL of saline solution, and aortic occlusion was confirmed by reduction in MDAP. At the end of the IPC occlusion period, the vented blood from the carotid artery cannula was reinfused over 60 seconds, and the Fogarty catheter was retracted into the femoral artery. At the end of the 12-minute ischemic period, blood from the heat exchanger was again returned over 60 seconds, 4 mg of protamine sulfate was administered, catheters were removed, surgical wounds were closed, and the rats were returned to their cages for recovery.

Experimental protocol
After instrumentation, the rats were randomized into two groups: IPC group and control group. Rats in the IPC group had 3 minutes of ischemia, 30 minutes of reperfusion, and then 12 minutes of ischemia. The 30-minute reperfusion interval and the 12-minute ischemic insult are based on results of preliminary experimentation evaluating various reperfusion intervals and insult times (Appendix 1). Rats in the control group had a similar time of anesthesia but only the 12-minute period of ischemia. At 24 and 48 hours after recovery from general anesthesia, all rats were subjected to neurologic testing. Five neurologic tests were performed: four evaluated motor deficit, and one evaluated sensory deficit. These tests and their relative scores are shown in Appendix 2. One member of the research team who was blinded to the study groups conducted the neurologic testing. After neurologic testing, the rats were euthanized in accordance with guidelines of the Institutional Animal Care and Use Committee.

Histology
Rats selected for histologic analysis were killed with an intraperitoneal injection of sodium pentobarbital (150 mg/kg). After a direct left ventricular bolus of 0.5 mL of heparin, rats were perfused with 100 mL of 0.9% normal saline solution (37°C) followed by 10% buffered formalin, 100 mL/g of body weight. The entire perfused rat was post-fixed in the same fixative for 24 hours at 4°C. Afterward, whole spinal cords were dissected free, blocked into rostral and caudal sections, and postfixed for another 24 hours. The spinal cords were further cut into two blocks corresponding to the third to fourth cervical segment (normal control) and the fourth to sixth lumbar segment (experimental region of ischemia). Spinal cord tissue was embedded in paraffin, and serial transverse sections (9 µm) were obtained from both cervical and lumbar blocks. The slides were stained by the hematoxylin and eosin method and evaluated for evidence of cellular degeneration and necrosis.

Statistical analysis
Neurologic testing data were examined for normality prior to analysis. Tarlov, inclined plane, and total motor deficit scores were compared between groups using Mann-Whitney rank sum tests. Statistical analysis of placing, righting, and sensory neurologic data were performed using Fisher’s exact tests. Heart rate, MPAP, MDAP, and temperature were analyzed using mixed-models repeated-measures analysis of variance. For all statistical analysis a p value of less than 0.05 was considered significant. Data are expressed as the mean ± the standard error of the mean unless otherwise indicated.

	Results

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Forty rats were used in the experiment, 20 in the IPC group and 20 in the control group. One rat in the IPC group died prior to the 24-hour testing, and 7 rats in the control group died (3 prior to the 24-hour testing and 4 prior to the 48-hour testing) (p = 0.04).

Data for MPAP, MDAP, and heart rate are shown in Figure 1. Immediately after the first balloon inflation in the IPC group, MDAP dropped to 10.9 ± 0.8 mm Hg. During the 12-minute ischemic interval, it fell to 6.9 ± 0.7 mm Hg in the IPC group and 9.3 ± 0.5 mm Hg in the control group (p = not significant). During all ischemic periods, MPAP was controlled at 65 ± 3 mm Hg. Blood pressures in the IPC group were significantly depressed during the 30-minute reperfusion after the 3-minute IPC compared with the control group. After the 12-minute ischemic insult, both groups had significant differences in MPAP. Heart rate dropped significantly during balloon occlusion in both groups. After the 3-minute IPC and the 12-minute ischemic insult, heart rate in the IPC group remained depressed compared with the control group. Arterial blood gases at baseline and at the end of the second reperfusion interval were similar in the two groups. Rectal temperature was 37.3° ± 0.05°C in the control group and 37.2° ± 0.08°C in the IPC group (p = 0.35).

View larger version (32K): [in this window] [in a new window]   Fig 1. Heart rate, mean proximal aortic pressure, and mean distal aortic pressure during experimental protocol for control group (CTRL) and ischemic preconditioning group (IPC). (BL = baseline; IPC = 3-minute period of aortic occlusion, or ischemic preconditioning; ISC = 12-minute prolonged ischemic insult; REP-1 = 30-minute reperfusion interval; REP-2 = period of reperfusion after ISC [closure of surgical wounds and recovery of animal]; — = interval of significant difference between groups.)

View larger version (17K): [in this window] [in a new window]   Fig 2. Data from the four motor neurologic tests (Tarlov scale, righting, placing, and inclined plane) were combined for a composite neurologic score and are presented as a box plot. The scores are shown in Table 1 and are summated for each animal. A score of 10 indicates complete motor neurologic deficit, whereas a 0 indicates a normal animal. Mann-Whitney rank sum test demonstrated significant difference between groups at both time points. (CTRL = control group; IPC = ischemic preconditioning group; boxed area = 25th to 75th percentile; — = 10th and 90th percentiles; = individual animals above or below 10th and 90th percentiles; broken line = median value for group.).

View larger version (153K): [in this window] [in a new window]   Fig 3. Photomicrograph of ventral horn of lumbar spinal cord (L5) from rat in ischemic preconditioning group with motor deficit score of 0 48 hours after injury. The gray matter architecture is clearly conserved and shows healthy surviving motor neurons (hatched arrowheads) and relatively low numbers of infiltrates (black arrowheads) in response to the limited damage. The few atrophied and darkly stained neurons (white arrowheads) are an artifact of formalin fixation. Laminae 6 through 10 are numbered and outlined according to Rexed’s criteria [21]. (Hematoxylin and eosin; x10 before % reduction.)

View larger version (160K): [in this window] [in a new window]   Fig 4. Photomicrograph of ventral horn of lumbar spinal cord (L5) from control rat with motor deficit score of 10 48 hours after aortic occlusion. The process of necrosis is evidenced by the shrunken, anuclear, darkly stained acidophilic motor neurons (hatched arrowheads) and the neuronal phagia (lesions characterized by a remnant empty space left by phagocytized neurons) (black arrowhead). Also typical of necrosis is the marked increase in basophilic infiltrates, which densely surround the microvasculature and diffusely occur around necrotic tissue (white arrowheads). Laminae 6 through 10 are numbered and outlined according to Rexed’s criteria [21]. (Hematoxylin and eosin; x10 before % reduction.)

	Comment

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

This study documents an acute benefit of IPC in an in vivo model of spinal cord injury. This finding differs markedly from the work of both Matsuyama and co-workers [11] and Munyao and colleagues [10]. These groups demonstrated the benefit of IPC in a model of spinal cord injury; however, their reperfusion times were very long. Matsuyama and associates measured heat shock protein synthesis and found a positive correlation between heat shock proteins and neurologic protection. Munyao and coauthors did not investigate a possible mechanism of protection; however, they speculated that heat shock proteins are involved, as their production occurs 4 hours after injury, falling within the time frame of the experimental model [19]. Our data clearly show that IPC spinal cord neuroprotection is found after a very short reperfusion interval, suggesting that additional mechanisms other than heat shock proteins may be important in this in vivo model of spinal cord protection.

The histology of the rat spinal cords at 48 hours confirms the clinical observations. All cervical sections examined from both groups were normal. However, rats with severe motor deficit (motor score = 10) exhibited clear pathologic processes within the lumbar regions: eosinophilic neuronal degeneration, inflammatory cell infiltration, and frank necrosis. Rats with little motor deficit or no deficit (motor score = 0) did not. The rat with an intermediate deficit (motor score = 4) showed corresponding histopathologic findings, ie, moderate necrosis surrounded by normal tissue. This histology is qualitative in nature and does not help delineate possible mechanisms of IPC protection. However, such limited data do provide anatomic correlation with physiologic function.

An unexpected observation was that the two groups had differing hemodynamic profiles after the 3-minute IPC aortic occlusion. In the IPC group, there was a significant reduction in MPAP, MDAP, and heart rate after IPC occlusion. The cause of these differing profiles is unknown. Every attempt was made to ensure that the groups were comparable in all respects. Indeed, on the basis of work by Taira and Marsala [20], MPAP was controlled at 65 ± 3 mm Hg during balloon inflation to ensure equal spinal cord ischemic conditions in both groups. It is impossible to know if these differing profiles had any effect on the observed protection. One can speculate that some agent may have been released as a result of the IPC event. For example, systemically released adenosine may reduce heart rate and blood pressure and may also be involved in the protective response observed in this experiment. In this initial experiment, we did not test the hypothesis that adenosine, or any other particular agent, can mediate protection. The cause and the importance of these hemodynamic observations require further investigation.

One limitation in this study is the use of a noxious stimulus to provoke hind limb withdrawal for sensory motor testing in animals with potential motor deficit. Indeed, if the animal is unable to withdraw its paw secondary to complete motor paralysis, then such a test for sensation remains suspect. Although not reported, we noted no evidence of pain with the paw pinch in animals with complete motor neurologic deficit (ie, vocalization and other body withdrawal).

In summary, IPC reduces neurologic injury and improves survival in a rat model of spinal cord ischemia. The protective benefits of IPC are invoked acutely after a 30-minute interval of reperfusion between the preconditioning and the ischemic event. The results of histologic evaluation at 48 hours are consistent with those of neurologic testing. The mechanisms responsible for this acute protective effect are unknown.

	Acknowledgments

 
We thank Dr Martin Marsala at the University of California, San Diego, for his technical assistance in preparing this model.

This study was partially funded by a grant from the American Heart Association—NC Affiliate program.

	Appendix 1

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Results of preliminary experimentation

Determination of Ischemic Interval Time of aortic occlusion (min) 8 10 11 12 14 16 No. tested 3 2 1 2 1 1 Result N N N A A A

Determination of Reperfusion Interval Between Ischemic Preconditioning and Ischemic Insult Interval (min) 5 15 30 60 240 Combined motor deficit score at 48 hoursa 0, 10 1, 10, 10 0, 0, 1 0, 10 ... No. dead at 48 hours 2 1 0 0 1 No. tested 4 4 3 2 1

^a See Appendix 2 for explanation of test scoring.

IPC = ischemic preconditioning group.

^a Combined motor deficit score is sum of four neurologic tests described in Appendix 2; 0 = normal animal, 10 = complete hind-limb paralysis.

A = neurologically injured animal at 48 hours after ischemia (abnormal); N = neurologically intact animal at 48 hours after ischemia (normal).

	Appendix 2

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Neurologic tests

Motor Deficit Tests Tarlov Scale Score Description 0 Walks normally 1 Walks with mild deficit 2 Supports weight on hind limb; may take one or two steps 3 No weight bearing, but frequent or vigorous movement of hind limb 4 No weight bearing, barely perceptible movement of hind limb 5 No weight bearing, no movement of hind limb Righting Score Description 0 Rat placed on back; immediately turns over (righting) 1 Weak or no righting

Placing Score Description 0 Rat grasps ledge with hind limb when suspended in air (placing) 1 Weak or no placing Inclined Plane Score Description 0 Animal grips platform with hind limbs at 45 degree angle 1 Animal grips platform with hind limbs at a maximum angle of 40 degrees 2 Animal grips platform with hind limbs at a maximum angle of 35 degrees 3 Animal fails to grip platform with hind limbs at 35 degree angle

^a See Appendix 2 for explanation of test scoring.

IPC = ischemic preconditioning group.

^a Combined motor deficit score is sum of four neurologic tests described in Appendix 2; 0 = normal animal, 10 = complete hind-limb paralysis.

A = neurologically injured animal at 48 hours after ischemia (abnormal); N = neurologically intact animal at 48 hours after ischemia (normal).

	References

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 

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