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Ann Thorac Surg 2001;71:1397-1398
© 2001 The Society of Thoracic Surgeons
a The Heart Center, Missouri Baptist Medical Center, St. Louis, Missouri, USA
Address reprint requests to Dr
Kouchoukos, The Heart Center, Missouri Baptist Medical Center, 3009 N
Ballas Rd, Suite 266-C, St. Louis, MO
63131
e-mail: ntkouch{at}aol.com
As Originally Published in 1994: by Chris K. Rokkas, MD, Loring R. Helfrich, Jr, BS, Douglas C. Lobner, PhD, Dennis W. Choi, MD, PhD, and Nicholas T. Kouchoukos, MD. Division of Cardiothoracic Surgery, Department of Surgery, and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
The release of excitatory amino
acids, particularly glutamate, into the extracellular space plays a
causal role in irreversible neuronal damage after central nervous system
ischemia. Dextrorphan, a noncompetitive
N-methyl-D-aspartate receptor antagonist, has been
shown to provide significant protection against cerebral damage after
focal ischemia. We investigated the changes in extracellular
neurotransmitter amino acid concentrations using in vivo microdialysis
in a swine model of spinal cord ischemia. After lumbar laminectomies
were performed, all animals underwent left thoracotomy and right
atrial–femoral cardiopulmonary bypass with additional aortic arch
perfusion. Microdialysis probes were then inserted stereotactically into
the lumbar spinal cord. The probes were perfused with artificial
cerebrospinal fluid and 15-minute samples were assayed using
high-performance liquid chromatography. Group 1 animals (n = 9)
underwent aortic clamping distal to the left subclavian and proximal to
the renal arteries for 60 minutes. Group 2 animals (n = 7) were treated
with dextrorphan before application of aortic clamps, and during aortic
occlusion and reperfusion. Five amino acids were studied, including two
excitatory neurotransmitters (glutamate and aspartate) and three
putative inhibitory neurotransmitters (glycine, 
-amino-butyric
acid, and serine). Somatosensory-evoked potentials and motor-evoked
potentials were monitored. Glutamate exhibited a threefold increase in
extracellular concentration during normothermic ischemia compared with
baseline values and remained elevated until 60 minutes after
reperfusion. In animals treated with dextrorphan, glutamate
concentrations decreased to one-third of baseline levels before aortic
clamping and remained unchanged during ischemia and reperfusion. There
was early loss of somato-sensory-evoked potentials and motor-evoked
potentials during ischemia in group 1 animals. Group 2 animals
demonstrated unchanged somatosensory-evoked potentials and only mild
(20%) decrease in the amplitude of motor-evoked potentials. These
results suggest that dextrorphan inhibits the release of excitatory
amino acids in the spinal cord during ischemia and, therefore, may have
a protective effect on spinal cord function during operations on the
thoracoabdominal aorta.
In the years since our initial publication, important developments have occurred in the field of neuroscience. The pathophysiologic mechanisms of neuronal ischemia and cell death have been elucidated, and multiple neurochemical pathways and cascades have been implicated. Among the recent discoveries, excitotoxicity, mediated by the neurotransmitter glutamate (an amino acid) has emerged as a predominant pathophysiologic mechanism for neuronal cell death. The release of large quantities of glutamate in the extracellular space results in overstimulation of neuronal glutamate receptors, particularly N-methyl-D-aspartate (NMDA) receptors, causing profound metabolic derangements. This concept, applied to the spinal cord, has helped to more clearly define the spinal cord ischemic injury suffered as a consequence of operations on the descending thoracic aorta.
In subsequent experiments in pigs, we confirmed the role of excitatory amino acids in the production of spinal cord ischemic injury and showed that hypothermia uniformly prevented the release of these amino acids in the extracellular space, suggesting that the protective mechanism of hypothermia is related, at least in part, to decreased release of the amino acids in the ischemic spinal cord [1]. It was later confirmed in humans that neurotransmitter excitotoxicity plays a significant role in spinal cord ischemic injury [2].
Updated in 2001: Recent experiments suggest that ischemia can induce programmed cell death (apoptosis) in some neurons. Apoptosis is characterized by a complex series of intracellular changes leading to the noninflammatory demise of the cell. The concept of necrosis and apoptosis as two distinctly different forms of neuronal cell death has had a major impact on neuroscience research. Both states can occur after an ischemic insult, but in different neurons or at different times. It has been demonstrated in vitro that glutamate can induce either early necrosis or delayed neuronal cell death in the form of apoptosis [3]. Furthermore, there is evidence that the NMDA receptor is implicated in neuronal apoptosis via a mechanism of potassium ion efflux, distinctly different from the mechanism of calcium and sodium influx that has been implicated in excitotoxicity. In a model of spinal cord ischemia in rats, we showed that both excitotoxicity and apoptosis contribute to spinal cord neuronal death [4, 5]. It was later confirmed in a rabbit model of spinal cord ischemia that motor neuron death after transient ischemia is associated with activation of apoptotic processes via a series of enzymes known as caspases and cyclins [6, 7]. Interestingly, there is no evidence for apoptotic cell death until at least 1 day following transient ischemia. Therefore, the concept that delayed paraplegia after surgery on the descending thoracic or thoracoabdominal aorta is related to delayed cell death by apoptosis is both clinically appealing and scientifically sound.
Pharmacological neuroprotection aims at attenuating the intrinsic vulnerability of neuronal tissue to ischemia by blocking biochemical cascades that cause secondary injury [8]. Several drugs that block glutamate receptors are being evaluated clinically in patients with stroke. Dextrorphan is no longer being evaluated because of an unfavorable tolerance profile in the stroke patient population [9], but the development of other glutamate inhibitors, such as lubeluzole, is actively being pursued [10]. Because of the substantial neurological side effects associated with the blocking of glutamate receptors, attention has recently shifted toward modifying the intracellular events triggered by the glutamate receptors rather than inhibiting the receptors themselves [11]. Development of caspase inhibitors, which has been targeted toward inhibition of apoptosis in neurodegenerative disorders, may result in their use to provide protection from delayed paraplegia in patients undergoing aortic surgery [12, 13].
The field of neuroprotection continues to evolve rapidly. A clearer understanding of the pathophysiology of spinal cord ischemia has helped us to achieve improved clinical results, manifested by a reduced incidence of paraplegia and paraparesis following extensive surgery on the thoracic and thoracoabdominal aorta. Although dextrorphan is no longer used clinically because of intolerable side effects, it is likely that other pharmacologic agents will be developed for use in humans that will provide protection of the spinal cord and the brain during operations on the thoracic aorta.
References
This article has been cited by other articles:
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  L. Lang-Lazdunski and J. Bachet Pharmacological spinal cord protection with magnesium during replacement of the thoracic and thoracoabdominal aorta. Ann. Thorac. Surg., December 1, 2001; 72(6): 2180 - 2181. [Full Text] [PDF]
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