HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Fabrizio M. Follis Jorge A. Wernly Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Follis, F. M. Articles by Wernly, J. A. Search for Related Content PubMed PubMed Citation Articles by Follis, F. M. Articles by Wernly, J. A.

Ann Thorac Surg 1999;67:1362-1369
© 1999 The Society of Thoracic Surgeons

---

Original Articles

Selective protection of gray and white matter during spinal cord ischemic injury¹

^a Department of Cardiothoracic Surgery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

Accepted for publication November 25, 1998.

Address reprint requests to Dr Follis, Dept of Cardiothoracic Surgery, University of New Mexico Health Sciences Center, 2211 Lomas Blvd NE, Albuquerque, NM 87131
e-mail: follis{at}unm.edu

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Ischemic injury in the gray matter is associated with excitatory amino acid neurotransmitters (EAA) release, and in the white matter is associated with intracellular sodium accumulation. We investigated the protective effect during spinal ischemia of the EAA antagonist, 2-carboxypiperazinyl-propylphosphonic acid (CPP), and the sodium channel blocker (2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX).

Methods. Sprague-Dawley rats were randomized in four groups, received intrathecally 10 µL of saline, CPP, QX, or QX/CPP, and underwent balloon occlusion of the aorta. Proximal pressure was lowered by exsanguination. In the acute protocol, 28 rats were used to calculate the length of occlusion, resulting in paraplegia in 50% of animals (P₅₀). In the chronic study, 60 rats underwent 11' occlusion. The chronic animals were scored daily for 28 days and submitted to cord histology.

Results. The P₅₀ of QX (11'22'') and QX/CPP (11'54'') were longer than saline (10'39''), suggesting a beneficial effect. Neurologic scores of all treatment groups (p = 0.0001) and histologic scores of CPP (p = 0.003) and QX/CPP (p = 0.002) were better than saline.

Conclusions. Protection of spinal cord during ischemia can be achieved with intrathecal administration of selective agents directed to the gray and white matter.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Paraplegia can result from surgical correction of diseases of the thoracic aorta, such as coarctation, aneurysm, dissection, and traumatic rupture. The spinal cord, as any part of central nervous system (CNS), is made up of white and gray matter with distinct mechanisms of ischemic injury and different vulnerability to ischemia. While in both, intracellular calcium accumulation with activation of cytoplasmic enzymes is the common pathway of injury, the events leading to the calcium paradox are dissimilar. In the gray matter, excessive stimulation of specific membrane receptors commonly known as N-methyl-D-aspartate (NMDA) receptors results in intracellular calcium migration. In the myelinated axons of the white matter, sodium accumulation occurs first and forces the sodium-calcium pump to operate in reverse, with the net result of calcium overload.

In light of the above considerations, the aim of the present study was to investigate if neurologic deficit after ischemic injury in the rat model can be prevented or decreased by the administration of pharmacological agents specifically directed to the mechanism of injury of white and gray matter. CPP [4-(3-phosphonopropyl)-2-piperazine-carboxylic acid] (Research Biochemicals Inc, Natick, MA), a competitive NMDA receptor antagonist proven to diminish neuronal injury, and QX-314 [N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide] (Research Biochemicals Inc), a compound shown to reduce ischemic injury of myelinated axons, were administered intrathecally before spinal cord ischemia.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Animal care and surgical technique
Male Sprague-Dawley rats 3–4 months old and weighing 325–400 g were kept in polycarbonate cages with free access to food and water. Animal care was delivered according to the "Principles of Laboratory Animal Care" and the "Guide for the Care and Use of Laboratory Animals" (National Academy Press, 1996). On the day of surgery, the animal was weighed, anesthetized with 2.5% halothane in a room air/oxygen mixture (1:1), and the back of the head and neck were shaved. The animal was placed in a stereotaxic head holder with the face flexed forward. Anesthesia was maintained with 1.5% halothane delivered by mask. A midline incision was made on the back of the neck. The muscle was freed at the attachment to the skull and retracted with a flat elevator, exposing the cisternal membrane. The membrane was opened and retracted with a small dural hook. The catheter (PE-10, 8.5 cm long; Becton-Dickinson, Sparks, MD) was then inserted through the cisternal opening and passed caudally 9 cm in the intrathecal space. The animal was allowed to recover for a minimum of 2–3 days before aortic occlusion. Rats showing motor weakness or sign of paresis upon recovery from anesthesia were killed.

Two or 3 days after intrathecal catheter placement, the rat was reanesthetized with 2.5% halothane in a room air/oxygen mixture (1:1). After induction, anesthesia was maintained with 1.5% halothane delivered by mask. Body temperature was monitored with a rectal probe inserted 3.5 cm into the rectum and maintained between 36.5°C and 37.5°C via an underbody heating pad. First, 10 µL of the appropriate solution (study drug or saline according to randomization protocol) was injected into the intrathecal catheter. Next, the tail artery was exposed and cannulated with a #22 angiocath for monitoring of distal (distal to the inflated balloon) blood pressure and heart rate. Likewise, the left common carotid artery was cannulated with a #22 angiocath for proximal blood pressure monitoring (proximal to the inflated balloon).

To induce spinal cord ischemia, the left common femoral artery was exposed, and a 2F Fogarty catheter was advanced in the thoracic aorta for 9.5 cm so that the tip was situated at the level of the left subclavian artery (this had been determined in a pilot study with animals of similar weight). Before occlusion, 200 units of heparin was given intraarterially and the Fogarty balloon was inflated with 0.2 cc of saline for different periods of time according to the study protocol. Satisfactory occlusion of the aorta was confirmed by a drop of the distal (tail artery) mean aortic pressure to 10 mm Hg. During occlusion, the mean proximal blood pressure was maintained at 30 mm Hg by partial exsanguination, through the left carotid artery monitoring line, into a heated closed circuit (Fig 1).

View larger version (27K): [in this window] [in a new window]   Fig 1. Balloon occlusion, proximal and distal monitoring, and partial exsanguination.

Experimental protocol
Acute study
A total of 28 animals underwent intrathecal catheter placement. Two days later, animals were reanesthetized and randomized into four groups of 7 animals each. Four groups were injected intrathecally with normal saline (NS), QX-314 (QX), CPP (CPP), or QX-314 and CPP (QX/CPP), respectively. Each group underwent balloon occlusion, with the duration of inflation determined by the "up and down" method [1]. The "up and down" method offers the main advantage of reducing the amount of experimentation. It is designed to estimate the P₅₀ or the length of ischemia that produces neurological deficit (described as a score of 10 or greater) in 50% of the rats. During preliminary experiments, we observed that the P₅₀ should lie between 10 and 11 min of aortic occlusion. Accordingly, series of test levels (occlusion times) were chosen with equal spacing (15 sec): 10', 10'15'', 10'30'', 10'45'', and 11' occlusion times. The first test was performed at 10'30''. If there was no response (no paraplegia = O), we went up by one step (10'45''), if there was a response (paraplegia = X), we went down by one step (10'15''). The procedure was repeated until all the animals of that particular group (n = 7) were finished and a sequence of X’s and O’s was obtained. The estimated P₅₀ was calculated by the formula: (final occlusion time) + [(k value obtained by looking up the sequence in Table 1) (difference between occlusion times, ie, 15'')] = P₅₀. Animals in the same group received the same drug in study (QX, CPP, NS, QX/CPP). A protective effect of the drug in study resulted in an increase of P₅₀ (increase in length of ischemia that produces neurological deficits in 50% of the rats) in comparison with normal saline group.

Chronic study
After the acute study, additional 60 animals underwent intrathecal catheter placement. Two days later, the animals were reanesthetized and randomized into five groups of 12 animals each. Four groups were injected intrathecally with: NS (11), QX (11), CPP (11), or QX/CPP (11), respectively, followed by balloon occlusion for 11 min. An occlusion period of 11 min was chosen on the basis of the P₅₀ obtained during the acute study. A fifth group underwent all the surgical manipulations except for balloon inflation (sham: 11). Because these groups were homogeneous, they were observed and scored daily for a period of 30 days and then killed. The spinal cords were studied under optical microscopy.

Evaluation of neurological status
Neurological function was appraised with a lesion score system devised to evaluate the neurologic function of hindlimbs. It included four indices of motor function, one of sensation, and one describing the character of paraplegia. Nineteen levels of deficits were defined, with a score of zero indicating normal animals, and a score of 19 indicating maximal impairment (Table 2). Scoring was performed by an operator blind as to the experimental group to which the animal belonged.

Each element was scored on a scale of 0 (negative), 1 (slight +), 2 (+), 3 (++), and 4 (+++). The total scores were then combined to yield an overall histologic score for white and gray matter from 0 to 24. The pathologist was unaware of the neurological findings when examining the slides.

Analysis of data
Estimates of P₅₀
The neurological deficits were grouped according to the lesion score (score 0–10 = no paraplegia; score 11 or above = paraplegia). In this fashion, the data were analogous to a pharmacological study where, for example, one is testing the potency of a drug by observing the fraction of groups of animals killed by a given dose. In such pharmacologic tests, the animal is either alive or dead, while in our experiment it is paraplegic (value = X) or not (value = O). The dose of drug that results in death of 50% of the animals (LD₅₀) is equivalent to the length of ischemia that produces neurological deficits in 50% of the rats (P₅₀). To calculate the P₅₀, the "up and down method for small samples" is used. The mathematical foundations of this method are well described in the paper by Dixon [1]. Therefore, P₅₀ values for paraplegia in control and drug-treated groups can be obtained. Since the groups were not homogeneous because of different occlusion times, they were not suitable for statistical evaluation.

Long term neurological evaluation
A population mean was calculated from individual lesion scores for each experimental group for each day. Differences between groups were tested with the analysis of variance for repeated measures. A p value less than 0.05 was considered statistically significant.

Histological scores
A population mean was calculated from individual histological scores for each experimental group. Differences between group means were tested with unbalanced two-way analysis of variance (ANOVA). A p value less than 0.05 was considered statistically significant.

Other experimental variables
A population mean was calculated from individual weights, hemodynamic parameters, and temperatures for each experimental group. Differences between group means were tested by nonparametric ANOVA. A p value less than 0.05 was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Estimate of p₅₀
For the saline group, the series was OOXOXXX, which, according to Table 1, resulted in a k value of 0.611. The calculation was 630 + 611 x 15 = 10'39''. For the CPP group, the series was OXXOOXX: the formula was computed based on the average of occlusion times plus a correction factor 632 + 15 x (-1.55 + 0)/7 = 10'29''. For the QX group, the series was OOXOOOO, which, according to Table 1, resulted in a k value of -0.547. The calculation was 690 + 15 x (-0.547) = 11'22''. For the QX/CPP group, the series was OOOOOOX, which, according to Table 1, resulted in a k value of -0.377. The calculation was 720 + 15 x (-0.377) = 11'54''. In comparison with the saline group, intrathecal administration of QX alone and in combination with CPP increased the duration of occlusion necessary to produce paraplegia in 50% of the animals (11'22'' and 11'54'', respectively vs 10'39''), suggesting a beneficial effect. Administration of CPP alone did not.

Long-term neurological evaluation
Neurologic scores of all treatment groups (CPP, QX, QX/CPP) were significantly (p = 0.0001) better than saline controls by ANOVA for repeated measures (Fig 2). Post hoc analysis did not reveal further protection in the combination group (QX/CPP).

View larger version (33K): [in this window] [in a new window]   Fig 2. Postoperative lesion scores of the 5 groups during the period of observation of 28 days.

Other experimental variables
Acute study
ANOVA of weights of the four groups of animals (saline, CPP, QX, QX/CPP) that underwent the "up and down" method for the calculation of P₅₀ did not reveal a significant difference (p = 0.29).

Chronic study
The following variables were analyzed: weight (WT), temperature before occlusion (T° Before), temperature after occlusion (T° After), interval between intrathecal catheter placement and aortic occlusion (IT-TO-OP), proximal and distal mean pressures before occlusion (BPP Before, BPD Before), proximal and distal mean pressures 5 min into aortic occlusion (BPP 5 Min, BPD 5 Min), and proximal and distal mean pressures after aortic occlusion (BPP After, BPD After) (Table 3). Excluding the sham group, analysis of variance of all the variables in the remaining four groups (saline, CPP, QX, QX/CPP) disclosed a statistically significant difference (p = 0.0003) only in the variable BPP 5 Min between the saline and CPP groups (mean 32.2 ± 1.7 vs 29.6 ± 1.90).

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

To our knowledge, this is the first study where the hypothesis of a distinct mechanism of ischemic injury for the white and gray matter of the spinal cord was employed to design a strategy for selectively blocking each pathway of injury with pharmacological interventions. What then are the current theories advanced for the two mechanisms of injury and what is the rationale for the use of the agents chosen in this study?

In the gray matter, glutamate and aspartate are the main excitatory amino acid neurotransmitters acting through three receptor subtypes: quisqualate, kainate and NMDA. Under anoxic or ischemic conditions, they are released in excess and activate the postsynaptic receptors, producing influx of sodium, calcium, and secondarily chloride. Neuronal swelling with cell lysis ensues. This cascade of events can be aborted by essential amino acid antagonists administered before the ischemic insult. Among them, NMDA antagonists are classified as competitive (competing with the agonist for the transmitter recognition site) and noncompetitive (impede ionic current).

While the role of the excitatory neurotransmitters has been confirmed during ischemic injury of the spinal cord [2, 3], work performed on the protective role of NMDA antagonists has been less extensive compared with cerebral ischemia. Five studies in the rabbit, two in the rat, and one in the swine have assessed noncompetitive antagonists [4–11]. Even more sparse have been the reports of competitive NMDA antagonists [12].

In the white matter, until recently, no information was available on the mechanisms of anoxic damage of central tracts. Given the different structure and function of gray and white matter regions of the mammalian CNS, it was reasonable to expect that these mechanisms might be quite different. Using the compound action potential as the best measure of functional integrity of the in vitro rat optic nerve (a central white matter tract composed exclusively of myelinated axons, oligodendrocytes, and astrocytes), Stys [13] was able to determine that Ca²⁺ influx across the axolemma plays a key role in irreversible anoxic injury in central myelinated axons. Under conditions of anoxia/ischemia, reserves of ATP are depleted rapidly, leading to failure of the Na⁺, K⁺-ATPase transporter in charge of maintaining transmembrane gradients. As a result, the Na⁺ ions entering the axoplasmic space through persistently open channels are not extruded anymore and accumulate. The rise in intraaxonal Na⁺, coupled with membrane depolarization, forces the Na⁺-Ca²⁺ exchanger to operate in reverse, importing damaging quantities of Ca²⁺ into the axon. High intracellular calcium then may cause irreversible injury through overactivation of calcium-dependent systems, such as lipases, caplains, and protein kinase [13] (Fig 3: sequence 1, 2, 3, 4). Ultrastructural examination of axons in the anoxic optic nerve reveals dissolution of the cytoskeletal elements within the axoplasm, where mitochondria become swollen with disrupted cristae, and the formation of large submyelinic vacuoles, most pronounced in the larger axons [14, 15].

View larger version (18K): [in this window] [in a new window]   Fig 3. Sequence of events leading to anoxic injury of a central myelinated axon. See text for explanation. Reprinted with permission from reference 13.

In the present investigation, although the findings support our premises and the thinking that both gray and white matter regions in ischemic spinal cord should be addressed in order to minimize the ravages of spinal cord ischemia, few discrepancies in the results, as well as the idiosyncrasies of the model and the methodologies employed, merit further discussion. Thus, the fact that QX-treated animals showed no improvement on histology does not surprise but, on the contrary, underscores the disparity between structure and clinical function and the insensitivity of histological examination of white matter regions, relegating it to a corroborative measure. Therefore, ultrastructural studies should be strongly considered in future investigations.

Despite the fact that both neurologic and histologic scores were the lowest in the QX/CPP group, combining the two drugs did not provide additional protection in comparison with each drug used separately. We can only speculate that a longer occlusion time with a more severe injury was necessary to further separate this group and show enhanced protection.

The acute study did not entirely predict the results of the chronic, because the P₅₀ of the CPP group was not longer than saline. In this regard, we believe that the "up and down" method is a convenient, yet approximate, search algorithm to test if any beneficial effect could be expected from a specific intervention in anticipation of a full chronic study, and to identify the duration of occlusion at which the effect is more likely to be shown. In this investigation, the occlusion time of the chronic portion was selected on the basis of the results of the acute data.

With regard to the various experimental variables, statistical analysis did not show differences between groups, a fact that strengthens the homogeneity and validity of this study. In particular, the weight variable has been regarded a very important one by our group as indicative of the age of the animal. We have repeatedly observed that younger animals tolerate ischemia better than older ones, and it comes without saying that this variable must be strictly controlled. The only statistically significant difference found between the saline and CPP groups in the BPP 5 Min variable (the higher the pressure, the lower the change of neurological deficit) would not have changed our conclusions, because the CPP group fared better neurologically than the saline despite a lower mean pressure during aortic occlusion.

The rat model, traditionally the preferred species by neurologists and neurosurgeons, is becoming popular in spinal cord research [18, 19] because of availability and ease of use. The spinal cord blood supply closely resembles that of the human, while the extensive neurological behavior allows detection of subtle neurological deficits. Interestingly, the metabolic rate is 3 times faster than the human, and occlusion times necessary to produce paraplegia are proportionally shorter.

The intrathecal route of administration was chosen because of the poor penetration across the blood-brain barrier of the compounds in study. In fact, the phosphono and carboxyl moieties of CPP [20] and the charged molecule of QX-314 [13] make both compounds highly hydrophilic and slow to diffuse into the CNS, when injected parenterally. On the other hand, and quite conveniently, previous work with chronic catheterization of the spinal subarachnoid space in the rat has established that a 10-µL volume extends as far as 2–3 cm from the injection site [21], around the lower thoracic and lumbar cord, the segments commonly injured by ischemia [22].

Finally, while administration of other medications in the subdural space for spinal cord protection of patients undergoing surgery of the aorta has been well documented [23], the clinical application of the compounds used awaits further studies in higher species to confirm their penetration in larger spinal cords in amounts sufficient to exert a protective effect.

In summary, from the analysis of the data presented, the following conclusions can be drawn. During spinal cord ischemia, a strategy designed to address each mechanism of injury for the white and gray matters should be considered in order to maximize postoperative neurologic function. When studying axonal degeneration and white matter damage, optical microscopy is not entirely accurate and ultrastructural methods should be included in future investigations. The use of the "up and down" method as a search algorithm is a valuable tool to enhance the accuracy and significance of a subsequent chronic study. The rationale and the interventional approach used in this investigation could be readily applied to clinical use once corroborated by additional studies in higher species.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Dr Clifford Qualls (Professor of Statistics, Emeritus, and Biostatistician, Research Office, Veteran’s Affairs Medical Center, Albuquerque, NM) for assistance in the statistical evaluation of data, and Deborah L. Heuser for technical assistance.

This work was supported by a Grant-in-Aid from the American Heart Association with funds contributed in part by the Southwest Affiliate.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
¹ This article has been selected for the open discussion forum on the STS Web site: http:/www.Sts.org/section/atsdiscussion/

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Dixon W.J. The up-and-down method for small samples. J Am Stat Assoc 1965;60:967-978.
2. Mori A., Ueda T., Nakamichi T., et al. Detrimental effects of exogenous glutamate on spinal cord neurons during brief ischemia in vivo. Ann Thorac Surg 1997;63:1057-1062.[Abstract/Free Full Text]
3. Regan R.F., Choi D.W. Glutamate neurotoxicity in spinal cord cell culture. Neuroscience 1991;43:585-591.[Medline]
4. Kochhar A., Zivin J.A., Lyden P.D., Mazzarella V. Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Arch Neurol 1988;45:148-153.[Abstract/Free Full Text]
5. Yum S.W., Faden A.I. Comparison of the neuroprotective effects of the N-methyl-D-aspartate antagonist MK-801 and the opiate-receptor antagonist nalmefene in experimental spinal cord ischemia. Arch Neurol 1990;47:277-281.[Abstract/Free Full Text]
6. Vacanti F.X., Ames A., III Mild hypothermia and Mg²⁺ protect against irreversible damage during CNS ischemia. Stroke 1984;15:695-698.[Abstract/Free Full Text]
7. Robertson C.S., Foltz R., Grossman R.G., Goodman J.C. Protection against experimental ischemic spinal cord injury. J Neurosurg 1986;64:633-642.[Medline]
8. Martinez-Arizala A., Rigamonti D.D., Long J.B., Kraimer J.M., Holaday J.W. Effects of NMDA receptor antagonists following spinal ischemia in the rabbit. Exp Neurol 1990;108:232-240.[Medline]
9. Hao J.-X., Watson B.D., Xu X.-J., Wiesenfeld-Hallin Z., Seiger Ä., Sundström E. Protective effect of the NMDA antagonist MK-801 on photochemically induced spinal lesions in the rat. Exp Neurol 1992;118:143-152.[Medline]
10. Follis F., Miller K.B., Scremin O.U., Pett S., Kessler R.M., Wernly J.A. NMDA receptor blockade and spinal cord ischemia due to aortic cross-clamping in the rat model. Can J Neurol Sci 1994;21:227-232.[Medline]
11. Rokkas C.K., Helfrich L.R., Jr, Lobner D.C., Choi D.W., Kouchoukos N.T. Dextrorphan inhibits the release of excitatory amino acids during spinal cord ischemia. Ann Thorac Surg 1994;58:312-320.[Abstract]
12. Madden K.P., Clark W.M., Zivin J.A. Delayed therapy of experimental ischemia with competitive N-methyl-D-aspartate antagonists in rabbits. Stroke 1993;24:1068-1071.[Abstract/Free Full Text]
13. Stys P.K. Anoxic and ischemic injury of myelinated axons in CNS white matter: from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab 1998;18:2-25.[Medline]
14. Stys P.K., Waxman S.G. The axon: structure, function and pathophysiology. New York: Oxford University Press, 1995:462-479.
15. Blisard K.S., Follis F., Wong R.S., Miller K.B., Wernly J.A., Scremin O.U. Degeneration of axons in the corticospinal tract secondary to spinal cord ischemia in rats. Paraplegia 1995;33:136-140.[Medline]
16. Stys P.K., Ransom B.R., Waxman S.G. Tertiary and quaternary local anesthetics protect CNS white matter from anoxic injury at concentrations that do not block excitability. J Neurophysiol 1992;67:236-240.[Abstract/Free Full Text]
17. Breckwoldt W.L., Genco C.M., Connolly R.J., Cleveland R.J., Diehl J.T. Spinal cord protection during aortic occlusion: efficacy of intrathecal tetracaine. Ann Thorac Surg 1991;51:959-963.[Abstract]
18. Kanellopoulos G.K., Kato H., Hsu C.Y., Kouchoukos N.T. Spinal cord ischemic injury: development of a new model in the rat. Stroke 1997;28:2532-2538.[Abstract/Free Full Text]
19. Marsala M. Effect of proximal arterial perfusion pressure on function, spinal cord blood flow, and histopathologic changes after increasing intervals of aortic occlusion in the rat. Stroke 1996;27:1850-1858.[Abstract/Free Full Text]
20. Chen M.-H., Bullock R., Graham D.I., Frey P., Lowe D., McCulloch J. Evaluation of a competitive NMDA antagonist (D-CPPene) in feline focal cerebral ischemia. Ann Neurol 1991;30:62-70.[Medline]
21. Yaksh T.L., Rudy T.A. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031-1036.[Medline]
22. Follis F., Scremin O.U., Blisard K.S., et al. Selective vulnerability of white matter during spinal cord ischemia. J Cereb Blood Flow Metab 1993;13:170-178.[Medline]
23. Svensson L.G., Stewart R.W., Cosgrove D.M., et al. Intrathecal papaverine for the prevention of paraplegia after operation on the thoracic or thoracoabdominal aorta. J Thorac Cardiovasc Surg 1988;96:823-829.[Abstract]
24. LeMay D.R., Neal S., Zelenock G.B., D’Alecy L.G. Paraplegia in the rat induced by aortic cross-clamping: model characterization and glucose exacerbation of neurologic deficit. J Vasc Surg 1987;6:383-390.[Medline]

This article has been cited by other articles:

				N. N. Osborne, J. P. M. Wood, A. Cupido, J. Melena, and G. Chidlow Topical Flunarizine Reduces IOP and Protects the Retina against Ischemia-Excitotoxicity Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1456 - 1464. [Abstract] [Full Text] [PDF]

				L. Lang-Lazdunski, C. Heurteaux, A. Mignon, J. Mantz, C. Widmann, J.-M. Desmonts, and M. Lazdunski Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzole Eur. J. Cardiothorac. Surg., August 1, 2000; 18(2): 174 - 181. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Fabrizio M. Follis Jorge A. Wernly Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Follis, F. M. Articles by Wernly, J. A. Search for Related Content PubMed PubMed Citation Articles by Follis, F. M. Articles by Wernly, J. A.