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Ann Thorac Surg 2001;72:1245-1250
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Systemic adenosine A2A agonist ameliorates ischemic reperfusion injury in the rabbit spinal cord

David C. Cassada, MDa, James J. Gangemi, MDa, Jayson M. Rieger, BSb, Joel Linden, PhDc, Aditya K. Kaza, MDa, Stewart M. Long, MDa, Irving L. Kron, MDa, Curtis G. Tribble, MDa, John A. Kern, MDa

a Division of Thoracic and Cardiovascular Surgery, Department of Surgery, The University of Virginia Health System, Charlottesville, Virginia, USA
b Department of Chemistry, The University of Virginia College of Arts and Sciences, Charlottesville, Virginia, USA
c Department of Molecular Physiology, The University of Virginia Health System, Charlottesville, Virginia, USA

Address reprint requests to Dr Kern, Department of Surgery, University of Virginia Health Sciences Center, Box 181-95, Charlottesville, VA 22908
e-mail: jak3r{at}virginia.edu

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.


   Abstract
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 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The adenosine A2A agonist ATL-146e (4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester) has been shown to prevent reperfusion injury in multiple organ systems through inhibition of activated leukocyte–endothelial interaction. We hypothesized that systemic ATL-146e could reduce spinal cord reperfusion injury after aortic clamping.

Methods. Twenty-six rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group received intravenous ATL-146e for 3 hours during reperfusion. A second cohort received only vehicle and served as controls. Animals were assessed at 24 and 48 hours using the Tarlov (0 to 5) scoring system for hind limb function. To evaluate neuronal attrition, immunostaining of lumbar spinal cord sections was performed using anti-SMI 33 antibody against neurofilament.

Results. Systemic ATL-146e was tolerated without hemodynamic lability. Animals that received ATL-146e had significantly improved neurologic outcomes 24 and 48 hours after spinal cord ischemia (p < 0.001). There was preservation of neuronal architecture in the ventral horn of spinal cord sections from animals receiving ATL-146e compared with control animals.

Conclusions. Intravenous ATL-146e given during reperfusion is tolerated without hemodynamic lability, and results in substantially improved spinal cord function after ischemia by preservation of ventral horn neurons.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Spinal cord injury at the time of thoracoabdominal aneurysm repair may occur in as many as 21% of patients, and in certain high-risk populations the incidence of neurologic impairment may be as high as 38% [1–4]. Injury, with resultant paraplegia, is most likely to occur in repairs of the peridiaphragmatic aorta, from which critical spinal cord vessels often arise [4, 5]. Technical efforts to decrease the incidence of spinal cord injury are usually directed toward protection of the cord during the ischemic interval and prompt reestablishment of blood flow to the spinal cord as part of the repair [4].

Current pharmacologic research includes the use of steroids, oxygen-derived free radical scavengers, vasodilators, and drugs designed to achieve spinal cord electrical silence during ischemia/reperfusion. Laschinger and colleagues [6] have demonstrated reduced paraplegia rates in animals receiving methylprednisolone during the perioperative interval, and experimental evidence has suggested that the use of methylprednisolone may reduce neuronal apoptosis after spinal cord ischemia [7]. Vasodilators such as intrathecal papaverine [2] and localized adenosine infusion [8] have been identified as potentially therapeutic after spinal cord ischemia, but their benefit in clinical treatment remains unclear. Superoxide dismutase and related agents have produced promising results in animals [9] that may translate to clinical practice by reducing the accumulation of oxygen-derived free radicals that are directly toxic to the central nervous system.

Multiple new and old drugs have been shown in experimental models to reduce postischemic neuronal injury by inducing spinal cord electrical silence and reducing "excitotoxin" accumulation by blocking N-methyl-D-aspartate receptor-mediated glutamate activity. Among these agents are dextromethorphan, dextrophan, and MK-801. Another promising technique includes the use of naloxone in conjunction with cerebrospinal fluid drainage, reducing paraplegia from 21% to 3.4% in one patient series [10].

Systemic ATL-146e (4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester) is a novel approach to preventing spinal cord reperfusion injury by exploiting antiinflammatory adenosine A2A receptors on leukocytes and endothelium to reduce inflammation. This effect is supported by the recent observation of reduced neutrophil infiltration into rabbit spinal cords 48 hours after systemic ATL-146e treatment [11]. That study also demonstrated an incremental protective effect of increasing the treatment interval from 1 to 3 hours after aortic cross-clamp release.

The most consistently effective technical approaches to spinal cord protection have been those that cool the ischemic segment of cord through the use of partial or total cardiopulmonary bypass, injection of cold solutions into an isolated segment of aorta, or perfusion of paraspinal spaces with cold solutions [4, 5, 12–15]. Each technique is associated with significant risks and complications inherent to their clinical use, and none has been so successful as to become standard of care.

A previous report from our institution utilizing a porcine model revealed that the ischemic spinal cord could be protected using retrograde venous perfusion cooling with an adenosine-enhanced crystalloid solution [16]. From these observations, it was apparent that infusion of a systemic adenosine agonist, without spinal cord cooling, may reduce neuronal injury either by inhibiting neuronal activity through A1 receptors, or by blocking activated leukocyte–endothelial interaction during the reperfusion period of ischemic spinal cord injury through A2A receptors. Because adenosine is a nonselective agonist of all adenosine receptor subtypes (A1, A2A, A2B, and A3) it can produce cardiac slowing (A1) and hypotension (A2A and A2B). Activation of A2A receptors can produce vasodilatation, but this response appears to be less sensitive than antiinflammatory effects [16]. We hypothesized that therapy with a selective agonist of A2A adenosine receptors may prevent spinal cord reperfusion injury without the hemodynamic instability associated with systemic adenosine infusion at doses required to suppress leukocyte-mediated injury.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
All protocols were reviewed and approved by the Animal Review Committee of the University of Virginia. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 5377-3, 1996).

Animal surgical procedures
Twenty-six New Zealand rabbits (weight 3.0 to 3.5 kg) were selected and acclimatized for a minimum of 3 days within our vivarium. Each was anesthetized with an intramuscular injection of xylazine (10 mg) and ketamine (100 mg). An ear vein catheter was placed for administration of additional medications and intravenous fluids. The animals were intubated, placed supine on a heated operating table, and ventilated with a mixture of 98% oxygen and 2% halothane. Core body temperature was maintained at 36.0°C ± 0.5°C. An ear arterial catheter was placed for arterial pressure monitoring. Heparin sodium (2,000 U) was administered intravenously and allowed to circulate for 5 minutes. During this interval, the abdomen was sterilely prepared and draped. A midline laparotomy was made and the viscera reflected to the right. After opening the retroperitoneum, the abdominal aorta and vena cava were collectively clamped with Satinsky clamps just distal to the left renal artery, and again proximal to the aortoiliac bifurcation. Each animal underwent 45 minutes of warm spinal cord ischemia, with the clamps removed just before closure. Pulse oximetry assured adequate oxygenation throughout the procedure. The technique of collectively clamping the great vessels has reliably produced paraplegia in the rabbit based on the highly segmental blood supply to the abdominal aorta, and was selected based on its reproducibility [14].

Drug administration
ATL-146e was synthesized and chemically characterized within our department of chemistry [18]. This compound is a selective agonist of A2A adenosine receptors based on competition for radioligand binding to recombinant human adenosine receptor subtypes, and it inhibits the oxidative burst in activated human neutrophils [19]. Eight microliters of stock ATL-146e solution (5 µg/µL) was diluted in 4 mL normal saline carrier. Using a Harvard pump, the compound (40 µg) was infused into a marginal ear vein at a constant rate for 3 hours, beginning after 30 minutes of spinal cord ischemia. Based on the activity of serum esterases, the half-life of ATL-146e in rodents is brief, lasting minutes [18]. Although longer than the 10-second half-life of adenosine in humans, the exact serum half-life of ATL-146e in rabbits is unknown. Drug was initiated 15 minutes before cross-clamp release to establish a steady-state concentration during reperfusion, based on at least four half-lives. One group of animals (n = 13) received 0.06 µg · kg-1 · min-1 intravenous ATL-146e, infused more than 3 hours, beginning after 30 minutes of ischemic time. A second cohort (n = 13) received saline vehicle, and served as an ischemic control group.

Physiologic testing
Postoperatively, animals were supported with food and fresh water ad libitum. At 24 and 48 hours after operation, hind limb neurologic function was evaluated using the following modified Tarlov scoring system [16]: 0 = atony, 1 = slight movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal gait/hopping. The same technician performed all neurologic functional evaluations in a blinded fashion.

Histologic analysis
At postmortem examination, sections of lumbar spinal cord (n = 4 per group) were fixed in 10% formalin and paraffin embedded for sectioning. Sections 2 µm thick were affixed to glass slides, deparaffinized in xylene, and rehydrated in serial dilutions of ethanol. Antigen retrieval was performed, and the sample sections were incubated with monoclonal mouse anti-human neurofilament antibody (SMI 33, Sternberger Monoclonals Incorporated, Lutherville, MD). After washing in phosphate-buffered saline, sections were incubated with biotinylated goat anti-mouse antibody (Vector Laboratories Inc, Burlingame, CA) for 1 hour at room temperature. Immunostaining was accomplished using a horseradish peroxidase system (Vector Laboratories Inc) and diaminobenzidinechromogen (Dako Corp, Carpinteria, CA). Counterstaining was performed using filtered hematoxylin. All sections were reviewed in a blinded fashion by the same observer and evaluated quantitatively per high power field (four samples at 400x magnification) for neuronal attrition.

Statistical analysis
All results are expressed as the mean ± standard error of the mean. Data were analyzed for between-group differences using Student’s t test. Significance was defined as a p value less than 0.05, as determined using SPSS Software (SPSS Inc, Chicago, IL).


   Results
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 Abstract
 Introduction
 Material and methods
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Comment
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 References
 
Operative outcome
Thirteen experimental rabbits and 13 ischemic controls survived the procedure. There was no significant difference in body temperature between experimental (36.3°C ± 0.5°C) versus control (36.6°C ± 0.5°C). Experimental animals experienced minor transient changes in mean arterial pressure and heart rate on initiation of the ATL-146e, which returned to base line measurements during the time course of drug administration (Fig 1). Adequate urine output was maintained throughout the operative procedure. No significant differences were noted in hemodynamic measurements between experimental and control groups.



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  		Fig 1. Hemodynamic measurements of control animals and animals receiving ATL-146e during spinal cord reperfusion. ATL-146e was tolerated with no significant difference in mean pulse rate (PULSE), mean arterial pressure (MAP), nadir pulse (Nadir P), and nadir blood pressure (Nadir BP).

 
Neurologic outcome
Neurologic function improved significantly (p < 0.001) in rabbits receiving ATL-146e at 24 and 48 hours (4.1 ± 0.32, 4.1 ± 0.32) compared with ischemic control animals (0.64 ± 0.35, 0.79 ± 0.39) (Fig 2). Maintenance of urinary continence was difficult to assess accurately, and most rabbits from both groups required manual expression of the bladder to facilitate evacuation.



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  		Fig 2. Tarlov scores in ischemic control animals (0.64 ± 0.35, 0.79 ± 0.39) compared with rabbits receiving ATL-146e at 24 and 48 hours (4.1 ± 0.32, 4.1 ± 0.32). At both time intervals, we observed a significant neurologic improvement in rabbits receiving ATL-146e during reperfusion (*, p < 0.001).

 
Histologic analysis
There was markedly increased neurofilament staining in spinal cord sections from rabbits receiving ATL-146e during reperfusion compared with control animals (Fig 3). There was decreased perineuronal vacuolization in treated animals, and neuronal nuclei retained normal-appearing architecture. These differences were most pronounced within the ventral motor horn from each spinal cord section; animals receiving ATL-146e had significantly more neurons per high power field (400x) than ischemic controls (3.4 ± 0.57 versus 1.0 ± 0.36, p = 0.02).



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  		Fig 3. Representative photomicrographs demonstrating increased neurofilament staining, and preservation of histologic architecture in the ventral horn of spinal cord sections from ischemic controls (A) compared with animals receiving ATL-146e (B). Note tissue vacuolization in the ischemic control tissue compared with experimental animals. Staining was established using an antihuman neurofilament antibody and horseradish peroxidase system. (x400 before 50% reduction.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Spinal cord hypoperfusion may be an unavoidable consequence of thoracoabdominal aortic operations. Clamping of the thoracic aorta has been shown to reduce spinal blood flow in a variety of animal models, and this effect has been documented in humans as well [20]. The precise mechanisms by which low blood flow induces permanent injury are not well understood, and most current therapy is directed at reducing injury sustained during the ischemic interval. This experiment tested the effects of ATL-146e given primarily during reperfusion, after attempting to establish a steady-state blood concentration based on the short half-life observed in rodents. Our results suggest that a significant portion of neuronal injury occurs during reperfusion, as the A2A agonist ATL-146e substantially reduced injury when administered during the reperfusion period, beginning during late ischemia.

As previously stated, it has been shown in a rat model that steroids can reduce neuronal apoptosis after ischemic spinal cord injury [7]. In the referenced experiment there were no correlating differences in neurologic functional outcome, and it was unclear if the antiinflammatory effect predominated during the ischemic interval or during reperfusion. We sought to diminish reperfusion injury by continuing ATL-146e after aortic clamp removal with hopes of decreasing reperfusion inflammation in a fashion similar to that of steroid therapy.

We have shown in a prior study that retrograde venous infusion of cold adenosine in saline into the hemiazygous system during aortic cross-clamping improved neurologic outcome in a swine model for spinal cord ischemia [17]. The antiplatelet and neutrophil modulatory properties of adenosine were known, but the mechanism of the benefit from adenosine was obscure. It seemed possible that the effect of adenosine might be on the A1 receptor that is widely expressed in the brain and spinal cord [21]. We also considered the possibility that vasodilation might reduce ischemia during cross clamping, and therefore adenosine was not given during the reperfusion interval. Local drug delivery was thought to allow spinal cord protection without significant leaching into systemic circulation, avoiding profound bradycardia and hypotension associated with adenosine infusion. Because there was no significant change in hemodynamic measurements associated with ATL-146e administration, the present study indicated that ATL-146e lessens spinal cord injury by a mechanism not involving A1 receptors or vasodilatation.

As indicated by Figure 1, the A2 selectivity of ATL-146e allows it to be used in systemic doses required to produce neuroprotective effect, while avoiding the hemodynamic lability associated with systemic adenosine infusion. In a prior study, the hemodynamic effects of ATL-146e were examined by generating a dose–response curve of concentration versus neurologic outcome [11]. It was found that doses up to 0.06 µg · kg-1 · min-1 were tolerated without significant changes in the mean arterial pressure or heart rate; however, when the concentration was increased to 0.22 µg · kg-1 · min-1, there was immediate hemodynamic instability with hypotension, bradycardia, and death of the animals. The dose chosen for neurologic protection in the current study (0.06 µg · kg-1 · min-1) was well below the lethal dose, and avoided the cardiovascular collapse resultant from dosing into higher ranges where vasodilatory effects may occur.

Adenosine protects tissues from traumatic or ischemic injury by multiple receptor subtypes. The activation of A1 and A3 [22] receptors produces preconditioning to protect the heart and other tissues from subsequent ischemic injury, and A3 receptor stimulation can attenuate neutrophil activation. In contrast to preconditioning, agonists of A2A receptors can protect tissues from ischemia/reperfusion damage when added during the reperfusion period. Another A2A-selective agonist, CGS21680, was found to attenuate reperfusion injury in the dog heart [23]. This effect correlated with an inhibition of coronary endothelial adherence, neutrophil accumulation, and superoxide generation. This finding suggested that reduced inflammation might be responsible for protecting the heart during reperfusion injury.

Adenosine A2A receptors are found on leukocytes, platelets, and endothelium (Fig 4), and function to decrease neutrophil adherence and release of toxic oxidative and nonoxidative products [16, 24, 25]. Activation of A2A receptors on monocytes decreases the release of cytokines such as tumor necrosis factor-{alpha}, and interleukin-12 (IL-12), preventing subsequent endothelial activation marked by upregulation of intercellular adhesion molecule-1 [26]. Endothelial A2A receptor stimulation reduces endothelial elaboration of IL-6 and IL-8 expression and surface expression of E-selectin, vascular cell adhesion molecule-1, and P-selectin [27].



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  		Fig 4. Purinergic regulation of inflammation. ADP derived from activated platelets exerts a proaggregatory effect on platelets through cell surface receptors that is countered by ectonucleotidases that degrade ADP and produce adenosine (Ado) that activates antiaggregatory A2A receptors. Activation of A2A receptors also reduces histamine and cytokine release from mast cells and macrophages and inhibits the expression of adhesion molecules on endothelium, both through cAMP-dependent intracellular pathways. (ADP = adenosine diphosphate; AMP = adenosine monophosphate; ATP = adenosine triphosphate; cAMP = cyclic AMP; NO = nitrous oxide; TNF {alpha} = tumor necrosis factor-{alpha}.)

 
The results of this study support multiple conclusions about prevention of ischemic neurologic injury. First, ATL-146e appears to be neuroprotective if given during early reperfusion, and the protective effect is maximal within the first 24 hours after the spinal cord injury. Second, systemic administration of ATL-146e is effective, not requiring regional spinal cord perfusion, implying that treatment of blood constituents protects the cord from the localized reperfusion insult that may worsen spinal cord injury. ATL-146e has multiple known cellular and humoral immunomodulatory effects, not only decreasing neutrophil and platelet adherence at the time of injury, but also possibly decreasing initiation of tumor necrosis factor-{alpha}-induced neuronal apoptosis. Future research in adenosine A2A therapy for reperfusion injury will undoubtedly elucidate the relative importance of the multiple mechanisms of action of drugs such as ATL-146e. This class of drugs holds considerable promise for preventing multiple types of end-organ injury in which reperfusion exists as an inciting event.


   Acknowledgments
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Mr Anthony Herring, Mrs Sheila Hammond, and Ms Amy Phillips for invaluable technical assistance.

This research was supported by the Virginia Affiliate of the American Heart Association (grant VHA0060293U).


   Footnotes
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 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Doctors Kron and Linden disclose that they have a financial relationship with Adenosine Therapeutics, L.L.C., a limited liability corporation holding the intellectual patent to ATL-146e.


   References
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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