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Ann Thorac Surg 1995;59:1316-1320
© 1995 The Society of Thoracic Surgeons

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Symposium: Conference on Cardiopulmonary Bypass

Glutamate, Calcium, and Free Radicals as Mediators of Ischemic Brain Damage

Laboratory for Experimental Brain Research, University of Lund, University Hospital, Lund, Sweden

Abstract

Calcium is considered a mediator of ischemic brain damage whether this is due to global or forebrain ischemia or to focal ischemia. Supporting evidence is the translocation of extracellular calcium into cells during ischemia, the precipitous rise in the free cytosolic calcium concentration, and the role of calcium in activating lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabolic cascades. In vitro and in vivo experiments suggest that the main route of entry is through channels gated by glutamate receptors. These experiments led to the excitotoxic hypothesis of cell death. The in vitro experiments further support the role of calcium as a mediator of cell death. Both cell calcium overload and acidosis enhance the production of partially reduced oxygen species, thus predisposing to free radical–related damage. In transient global or forebrain ischemia, free radicals formed during reperfusion may contribute to a perturbed membrane function, leading to a sustained alteration of cell calcium metabolism with ultimate mitochondrial calcium overload. In focal ischemia (stroke), free radicals may be important mediators of the infarction process. Infarction can be regarded as a form of secondary damage, which is probably caused by microvascular dysfunction. Very likely, such dysfunction is triggered by upregulation of adhesion molecules such as ICAM-1, microvascular ``plugging,'' and an inflammatory response at the blood–endothelial cell interface. The involvement of free radicals in this type of secondary damage is supported by results showing that nitrones that act as free radical spin-traps ameliorate focal ischemic damage with a therapeutic window of many hours.

The objective of this article is to discuss mechanisms of primary and secondary brain damage after global and focal ischemia. More detailed accounts of the topics discussed have been given in recent articles, which should be referred to for further information and additional references [1–4].

In this context, primary brain damage is defined as neuronal necrosis, or pannecrosis (``infarction''), that is the direct result of ischemia or trauma. For example, if an artery is permanently occluded, the area supplied by the artery sustains primary damage, particularly if it is nourished by end-arterial branches of the occluded artery. Simply, neither reperfusion nor continued supply from collateral vessels can maintain viability. We define secondary damage as neuronal necrosis or infarction that occurs after a delay of hours or days. In many cases, the damage reflects the maturation of cell injury incurred at the time of the primary insult; nonetheless, cells may resume function in the free interval between primary insult and final cell death. A special form of secondary cell death is transsynaptic neuronal necrosis, affecting neurons that may not even have been involved in the primary ischemia. The mechanisms, whose principles were outlined by Saji and Reis [5], probably involve loss of trophic influences or loss of inhibitory tone as a result of damage to network neurons whose cell bodies are in ischemic areas.

Secondary brain damage typically occurs after trauma and subarachnoid hemorrhage and is then often due to ischemia caused by bleeding, edema, or vascular spasm. However, particularly if transient and of brief duration, ischemia per se can give rise to damage that is delayed by hours or days. The now classic case is the conspicuously delayed necrosis of CA1 pyramidal cells in the hippocampus after brief periods of forebrain ischemia in Mongolian gerbils and rats [6–8]. It is becoming increasingly evident, though, that secondary brain damage also occurs in focal ischemia, affecting cells outside the densely ischemic core, thus representing the territory of distribution of the occluded artery. Further, transsynaptic neuronal damage has been described also in focal ischemia and in that case can affect neurons outside the ischemic areas [9].

Types of Ischemia

A discussion of the pathophysiology of ischemic brain damage is greatly facilitated if ischemia is divided into two major types: global or forebrain ischemia and focal ischemia. In fact, a distinction between the two is imperative for an understanding of the effects of antiischemic drugs [1–3, 10].

Global or Forebrain Ischemia
A typical feature of this type of ischemia is that the ischemia is of brief or intermediate duration, thus allowing recirculation and long-term recovery. The damage is often conspicuously delayed. Global ischemia, as occurs in cardiac arrest, can be sustained only for periods of up to 12 minutes; exacting resuscitative measures are then required. For these reasons, a majority of researchers now use forebrain ischemia caused by carotid artery clamping in gerbils and rats, either alone (gerbils) or combined with vertebral artery occlusion or hypotension (rats) [7, 11]. In these models, brain stem structures receive a sufficient blood supply to allow uncompromised cardiovascular and respiratory functions during recovery. As a result, recirculation is prompt, usually giving rise to an initial period of reactive hyperemia.

Focal Ischemia
In focal ischemia, for example that caused by occlusion of a middle cerebral artery, the ischemia is usually less severe and is longer lasting, if not permanent. One can distinguish between a core of tissue (the focus) with relatively dense ischemia and perifocal tissues (penumbra), which are less densely ischemic because they receive a collateral blood supply from leptomeningeal branches of other major arteries. It is a widely held view that cells in the focus are so poorly supplied with oxygen that they are doomed unless reperfusion can be quickly reinstituted, whereas those in the penumbra are at risk. This division into the focus and the penumbra is relatively arbitrary, but the important thing is that an extension of the infarct into the penumbra zone can be prevented by drugs.

It should be emphasized that focal ischemia as described can also be induced by occlusion of smaller arteries than the middle cerebral artery. The important feature is that the distribution territory of the occluded artery is surrounded by tissues that are both partly compromised by a reduction in blood flow rates and exposed to chemical mediators of secondary ischemic damage that are released from the densely ischemic tissue.

Pathophysiology

Global or Forebrain Ischemia
When ischemia is of brief duration and followed by prompt and adequate reperfusion, one can discern three consecutive stages: the initial events, the free interval, and the phase of secondary cell death [4].

The initial events are characterized by rapidly developing energy failure involving depletion of adenosine triphosphate stores and by loss of ion homeostasis. The latter encompasses massive efflux of K⁺ from cells and cellular uptake of Ca²⁺, Na⁺, and Cl^-, the last two being accompanied by osmotically obligated water [12, 13]. One result of this is an increase in the free cytosolic calcium concentration (Ca²⁺_i) to values of 10 to 60 µmol [14]. Depletion of high-energy phosphates leads to arrest of macromolecular synthesis, leaving unmatched their degradation in spontaneous or enzyme-catalyzed reactions; in addition, the rise in Ca²⁺ activates enzymes that degrade phospholipids, proteins, and deoxyribonucleic acid [15–17]. Activation of phospholipases, with hydrolysis of phospholipids, leads to accumulation of free fatty acids, including arachidonic acid. Protein synthesis and gene expression are, for natural reasons, arrested.

In summary, the initial series of reactions triggered by ischemia encompass energy failure, downhill fluxes of ions across depolarized membranes, and degradation of macromolecules including glycogen and phospholipids as well as proteins and deoxyribonucleic acid. Some of the metabolites formed are biologically active and others, constituting putative mediators of secondary cell damage, are formed when recirculation restores the oxygen supply.

In the free interval, production of adenosine triphosphate is resumed, membranes are repolarized, and synaptic activity returns; interestingly, neuronal function can also be resumed in cells destined to die, such as the CA1 cells of the hippocampus. However, both metabolic rate and blood flow can be depressed over hours and days [18, 19], and recovery of protein synthesis is slow even in areas that are resistant to ischemic damage and may never be resumed in cell populations destined to die [20–22].

Recirculation triggers a spurt of reactions of putatively large pathophysiologic importance. Major components of this cascade of reactions are the metabolic conversion of the accumulated arachidonic acid to platelet-activating factor, products of cyclooxygenase and lipoxygenase, oxygen free radicals, and nitric oxide (for literature see [2, 3]. As will be discussed, the result can be oxidation or nitrosylation of proteins, formation of chemoattractants and activators of adhesion molecules for polymorphonuclear leukocytes, and free radical damage to key cellular structures. The time course of the reactions involved is unknown, but as the rate of maturation of damage varies between different cell populations, either the rates or the nature of the reactions must differ between cells.

The phase of delayed cell death is characterized by secondary depletion of energy stores, a finding suggesting mitochondrial failure [23]. Because cell death seems to be preceded by mitochondrial accumulation of calcium, the hypothesis has been advanced that the initial insult leads to a sustained change in membrane function and to a slow, gradual rise in Ca²⁺_i, with ultimate mitochondrial failure [2, 4, 24]. As cell damage is ameliorated by pretreatment with dimethylthiourea, a free radical scavenger [25], the postulated perturbation of membrane function, with an increased cycling of calcium, may be the result of protein oxidation caused by the formation of free radicals [26].

Focal Ischemia
Discussion of the pathophysiology of focal ischemic damage usually centers around events in the penumbra zone. It was postulated a few years ago that cells at risk in perifocal areas are threatened by two main pathophysiologic events: regularly occurring depolarization waves, accompanied by K⁺ efflux and Ca²⁺ influx, and a gradual compromise of microcirculation, causing extension of the infarct into the penumbra zone [2, 3]. The depolarization waves [27] or the accompanying Ca²⁺ transients [28] were originally believed to cause damage by straining cell energy metabolism or by triggering untoward Ca²⁺-mediated reactions. This hypothesis has recently been revived by those who postulate that glutamate antagonists ameliorate focal ischemic damage by suppressing or blocking the depolarization events in perifocal tissues [29].

The role of microvascular dysfunction was suggested by results showing that the infarct size could be somewhat reduced by enzymatic scavengers of •O₂^- and H₂O₂, which are not supposed to cross the blood-brain barrier [30]. However, even more persuasive data were reported in reperfusion experiments. For example, del Zoppo and colleagues [31] found that primates subjected to 3 hours of middle cerebral artery occlusion and 1 hour of reperfusion showed relatively extensive ``plugging'' of capillaries and postcapillary venules by polymorphonuclear leukocytes. These and other experiments suggest that microvascular failure is the cause of the gradually developing infarct in perifocal areas.

Mediators of Ischemic Brain Damage

In this context, interest should be focused on mediators that lead to secondary damage in global or forebrain ischemia and focal ischemia. Mechanisms of primary damage (autolysis) are of less interest, particularly from a therapeutic point of view.

Global or Forebrain Ischemia
As discussed, dense global or forebrain ischemia leads to calcium influx and to a rise in Ca²⁺_i of potentially detrimental consequences. In this sequence of events, release of excitatory amino acids from presynaptic endings and activation of postsynaptic glutamate receptors play an important role [2–4, 15, 32]. This is because activation of the amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA) type of glutamate receptor allows influx of Na⁺ by way of receptor-gated channels, thereby leading to depolarization, and because activation of the N-methyl-D-aspartate (NMDA) type of glutamate receptor opens a channel permeable to Ca²⁺. This receptor-gated channel is normally blocked by Mg²⁺ in physiologic concentrations, but the block is relieved by depolarization. Thus, depolarization is the trigger of calcium influx, not only through the NMDA receptor–gated channel but also through a series of voltage-sensitive calcium channels.

Although the excitotoxic hypothesis has received much attention and although NMDA antagonists reduce both the rate of influx of Ca²⁺ and the rate of rise in Ca²⁺_i during ischemia [33], they fail to ameliorate the subsequent neuronal necrosis (for discussion see [26]). The damage is ameliorated by AMPA receptor antagonists and by some drugs reducing presynaptic transmitter release. Most importantly, these drugs are efficacious even when given many hours after the primary ischemic insult, a finding suggesting that they act by reducing postischemic glutamate release, Na⁺ influx, or both, which, by causing depolarization, leads to influx of calcium by multiple pathways. Conceivably, the major cause of the delayed damage is an upregulation of glutamate release or of Na⁺ and Ca²⁺ influx, thus explaining the slow, gradual calcium accumulation. Neither microvascular failure nor rapidly developing mitochondrial failure is believed to be involved.

In this scenario, the main role of free radicals may be to enhance oxidation or modification by other means of membrane proteins of key importance to influx and extrusion of calcium or its sequestration in intracellular organelles. However, we need to know more about the possibility of ongoing production of free radicals, which is of putative importance for the ultimate fate of the metabolically perturbed cells.

Focal Ischemia
Results obtained during the last few years do not support the view that repeated depolarization waves can alone explain the recruitment of the penumbra zone in the infarction process. Thus, attempts to induce neuronal necrosis by repeated K⁺-induced depolarizations in animals in which neocortical energy metabolism was compromised by bilateral carotid artery ligation have failed [34]. Further, one cannot dismiss the possibility that the K⁺ and Ca²⁺ transients reflect a critical degree of depolarization and that drugs ameliorating the damage do so by affecting the purported, critical depolarization rather than by blocking the K⁺ and Ca²⁺ waves triggered by the depolarization. Finally, as evidence of early microvascular dysfunction is at hand, the possibility must be considered that the primary damage in the focus triggers secondary damage in better perfused areas. Although it cannot at present be excluded that long periods of ischemia give rise to failure of mitochondrial function, it appears likely that the target of these putative mediators is the microvasculature.

Recent results support the contention that the infarction process represents secondary damage and hint that this damage affects mainly the vascular compartment. First, it has been demonstrated that the spin-trapping agent -phenyl-N-tert-butyl nitrone (PBN) reduces infarct size in rats when given up to 12 hours after permanent middle cerebral artery occlusion [35] or up to 3 hours after the initiation of recirculation after 2 hours of middle cerebral artery occlusion [36]. The dramatic effect of posttreatment suggests that the primary ischemia triggers events that give rise to secondary damage after a delay of a few hours. Second, additional data have accumulated demonstrating that ischemia triggers the expression or upregulation of adhesion molecules on endothelial cells and on polymorphonuclear leukocytes and that obstruction of capillaries and postcapillary venules is an early event in focal ischemia [31, 37]. Third, focal ischemic damage can be ameliorated by blocking adhesion molecules on endothelial cells and polymorphonuclear leukocytes by administration of antibodies to ICAM-1 and CD 11b/CD18 [38–40].

Because PBN is a spin-trapping agent, it probably acts by scavenging free radicals. In the gerbil, the nitrone reduces signs of protein oxidation, improves function, and reduces brain damage after transient forebrain ischemia [41–43]. In the rat, PBN lacks effect in transient forebrain ischemia (K. Pahlmark, B. K. Siesjö; unpublished data), although it reduces infarct size in focal ischemia. This suggests that focal ischemic damage, notably infarction, is due to other mechanisms than those operating in forebrain or global ischemia of brief duration. Tentatively, the difference is that in focal ischemia of long duration, mitochondrial function suffers or microvascular patency and function are compromised. Two factors can be identified that may cause microvascular dysfunction. First, the initial period of ischemia triggers a cascade of reactions resulting in enhanced expression of adhesion molecules on the endothelial cells. Second, the reduction in perfusion rate favors adhesion of polymorphonuclear leukocytes (and platelets) and, possibly, an oxidative burst that causes an inflammatory response at the blood–endothelial cell interface [44].

It appears likely that the initial depolarization and calcium influx during ischemia represents a triggering event for reactions that last for many hours and that cause gradual compromise of the microcirculation in tissues at risk. Once triggered, these reactions may be self-sustained. This would explain why glutamate antagonists have a very narrow therapeutic window (less than 1 hour). Because nitrones of the PBN class have a window of many hours, they presumably act on the reactions leading to gradual secondary damage. It can be speculated that the wide therapeutic window observed reflects the time taken for expression of messenger ribonucleic acids for adhesion molecules such as ICAM-1 and for their synthesis. If this is so, the nitrones must be assumed to act on the inflammatory cascade causing microvascular failure.

Acknowledgments

This study was supported by the Swedish Medical Research Council (B94-14X-00263-30A), the US Public Health Service through grant 5R01 NS07838-24 from the National Institutes of Health, and the Medical Faculty at Lund University.

Footnotes

Presented at the Conference on CNS Dysfunction After Cardiac Surgery: Defining the Problem, Fort Lauderdale, FL, Dec 10–11, 1994.

Address reprint requests to Dr Bo Siesjö, Laboratory for Experimental Brain Research, University Hospital, S-221 85 Lund, Sweden.

References

1. Folbergrová J, Zhao Q, Katsura K, Siesjö B. -Phenyl-N-tert-butyl nitrone improves recovery of brain energy state in the rats following transient focal ischemia. Proc Natl Acad Sci USA (in press).
2. Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia. I. Pathophysiology. J Neurosurg 1992;77:169–84.[Medline]
3. Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia. II. Mechanisms of damage and treatment. J Neurosurg 1992;77:337–54.[Medline]
4. Siesjö BK. Basic mechanisms of traumatic brain damage. Ann Emerg Med 1993;22:959–69.[Medline]
5. Saji M, Reis D. Delayed transneuronal death of substantia nigra neurons prevented by -aminobutyric acid agonist. Science 1987;235:66–9.[Abstract/Free Full Text]
6. Kirino T. Delayed neuronal death in the gerbil hippocampus following transient ischemia. Brain Res 1982;239:57–69.[Medline]
7. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982;11:491–8.[Medline]
8. Smith M-L, Kalimo H, Warner DS, Siesjö BK. Morphological lesions in the brain preceding the development of postischemic seizures. Acta Neuropathol (Berl) 1988;76:253–64.[Medline]
9. Tamura A, Kirino T, Sano K, et al. Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat. Brain Res 1990;510:154–7.[Medline]
10. Siesjö BK, Katsura K, Pahlmark K, Smith M-L. The multiple causes of ischemic brain damage: a speculative synthesis. In: Krieglstein J, Oberpilcher H, eds. Pharmacology of cerebral ischemia. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 1992:511–25.
11. Smith M-L, Bendek G, Dahlgren N, et al. Models for studying long-term recovery following forebrain ischemia in the rat. II. A 2-vessel occlusion model. Acta Neurol Scand 1984;69:385–401.[Medline]
12. Erecinska M, Silver I. Ions and energy in mammalian brain. Prog Neurobiol 1994;43:37–71.[Medline]
13. Hansen AJ. Effects of anoxia on ion distribution in the brain. Physiol Rev 1985;65:101–48.[Free Full Text]
14. Silver I, Erecinska M. Intracellular and extracellular changes of [Ca²⁺] in hypoxia and ischemia in rat brain in vivo. J Gen Physiol 1990;95:837–66.[Abstract/Free Full Text]
15. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1:623–34.[Medline]
16. Siesjö B. The role of calcium in cell death. In: Price D, Aguayo A, Thoenen H, eds. Neurodegenerative disorders: mechanisms and prospects for therapy. Chichester: John Wiley, 1991:35–59.
17. Siesjö BK. Historical overview. Calcium, ischemia, and death of brain cells. Ann NY Acad Sci 1988;522:638–61.[Medline]
18. Kozuka M, Smith M-L, Siesjö B. Preischemic hyperglycemia enhances postischemic depression of cerebral metabolic rate. J Cereb Blood Flow Metab 1989;9:478–90.[Medline]
19. Pulsinelli W, Levy D, Duffy T. Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann Neurol 1982;11:499–509.[Medline]
20. Hossmann K-A. Disturbances of cerebral protein synthesis and ischemic cell death. In: Kogure K, Hossmann K-A, Siesjö BK, eds. Neurobiology of ischemic brain damage. Amsterdam: Elsevier, 1993:161–77.
21. Thilmann R, Xie Y, Kleihues P, Kiessling M. Persistent inhibition of protein synthesis precedes delayed neuronal death in post-ischemic gerbil hippocampus. Acta Neuropathol 1989;71:88–93.
22. Wieloch T, Bergstedt K, Hu BR. Protein phosphorylation and the regulation of mRNA translation following cerebral ischemia. In: Kogure K, Hossmann K-A, Siesjö BK, eds. Neurobiology of ischemic brain damage. Amsterdam: Elsevier, 1993:179–91.
23. Pulsinelli WA, Duffy TE. Regional energy balance in rat brain after transient forebrain ischemia. J Neurochem 1983;40:1500–3.[Medline]
24. Deshpande JK, Siesjö BK, Wieloch T. Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia. J Cereb Blood Flow Metab 1987;7:89–95.[Medline]
25. Pahlmark K, Folbergrová J, Smith M-L, Siesjö BK. Effects of dimethylthiourea on selective neuronal vulnerability in forebrain ischemia in rats. Stroke 1993;24:731–7.[Abstract/Free Full Text]
26. Siesjö B, Kristián T, Katsura K. The role of calcium in delayed postischemic brain damage in cerebrovascular diseases. In: Moskowitz M, eds. Nineteenth Princeton Conference. Boston: Butterworth-Heinemann, 1994.
27. Nedergaard M. Mechanisms of brain damage in focal cerebral ischemia. Acta Neurol Scand 1988;77:1–23.[Medline]
28. Siesjö BK, Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metabol 1989;9:127–40.[Medline]
29. Hossmann K-A. Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. Brain Pathol 1994;4:23–36.[Medline]
30. Liu TH, Beckman JS, Freeman BA, et al. Polyethylene glycol–conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am J Physiol 1989;256:H589–93.[Medline]
31. Del Zoppo GJ, Schmid-Schönbein GW, Mori E, et al. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991;22:1276–83.[Abstract/Free Full Text]
32. Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic/ischemic neuronal death. Annu Rev Neurosci 1990;13:171–82.[Medline]
33. Silver IA, Erecinska M. Ion homeostasis in rat brain in vivo: intra- and extracellular Ca²⁺ and H⁺ in the hippocampus during recovery from short-term, transient ischemia. J Cereb Blood Flow Metab 1992;12:759–72.[Medline]
34. Gidö G, Kristián T, Siesjö B. Induced spreading depressions in energy-compromised neocortical tissue: calcium transients and histopathological correlates. Neurobiol Dis 1994;1:31–41.[Medline]
35. Cao X, Phillis J. -Phenyl-tert-butyl-nitrone reduces cortical infarct and edema in rats subjected to focal ischemia. Brain Res 1994;644:267–72.[Medline]
36. Zhao Q, Pahlmark K, Smith M-L, Siesjö B. Delayed treatment with the spin trap -phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol Scand 1994;152:349–50.[Medline]
37. Garcia J, Liu K, Yoshida Y, et al. Influx of leukocytes and platelets in an evolving brain infarct. Am J Pathol 1994;144:188–99.[Abstract]
38. Chen H, Chopp M, Zhang R, et al. Anti-CD 11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 1994;35:458–63.[Medline]
39. Matsuo Y, Onodera H, Shiga Y, et al. Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 1994;656:344–52.[Medline]
40. Mori E, del Zoppo G, Chambers D, et al. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 1992;23:712–8.[Abstract/Free Full Text]
41. Carney JM, Floyd RA. Protection against oxidative damage to CNS by a-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: a novel series of nonlipid free radical scavengers. J Mol Neurosci 1991;3:47–57.[Medline]
42. Floyd R. Role of oxygen free radicals in carcinogenesis and brain ischemia. FASEB J 1990;4:2587–97.[Abstract]
43. Oliver C, Starke-Reed P, Stadtman E, et al. Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion–induced injury to gerbil brain. Proc Natl Acad Sci USA 1990; 87:5144–7.[Abstract/Free Full Text]
44. Hallenbeck J. Inflammatory reactions at the blood-endothelial interface in acute stroke. In: Siesjö B, Wieloch T, eds. Advances in neurology. New York: Raven, 1995.

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