Focal Cerebral Ischemia: Pathophysiologic Mechanisms and Rationale for Future Avenues of Treatment
1987; Elsevier BV; Volume: 62; Issue: 1 Linguagem: Inglês
10.1016/s0025-6196(12)61523-7
ISSN1942-5546
AutoresFredric B. Meyer, Thoralf M. Sundt, Takehiko Yanagihara, Robert E. Anderson,
Tópico(s)Neurological Disease Mechanisms and Treatments
ResumoAlthough approximately 500,000 patients suffer from a stroke each year in the United States, treatment of these patients to date has consisted primarily of prevention, supportive measures, and rehabilitation. The modification of experimental cerebral infarction by new pharmacologic agents, along with encouraging results from the restoration of blood flow to areas of focal ischemia in both laboratory and clinical trials, suggests that a more aggressive approach might be considered in selected patients with acute stroke. Although approximately 500,000 patients suffer from a stroke each year in the United States, treatment of these patients to date has consisted primarily of prevention, supportive measures, and rehabilitation. The modification of experimental cerebral infarction by new pharmacologic agents, along with encouraging results from the restoration of blood flow to areas of focal ischemia in both laboratory and clinical trials, suggests that a more aggressive approach might be considered in selected patients with acute stroke. Despite new insights into the pathophysiologic mechanisms of cerebral infarction, the treatment of focal cerebral ischemia is usually limited to aggressive anticoagulation and supportive measures. This conservative approach may reflect both the lack of proven beneficial therapeutic measures and the question of applicability of experimental models to actual clinical situations.1Hossmann K-A Treatment of experimental cerebral ischemia.Cereb Blood Flow Metab. 1982; 2: 275-297Crossref Google Scholar In light of recent evidence in support of the efficacy of certain agents and the role of revascularization, the conventional treatment of focal cerebral ischemia should be critically reevaluated. In this article, we review the cause and pathophysiologic mechanisms of focal cerebral ischemia and consider the applicability of medical and surgical treatment modalities currently under laboratory investigation. Focal cerebral ischemia is a clinical entity distinct from global cerebral ischemia as observed, for example, in patients who have experienced cardiac arrest. The notable differences are that (1) patients with global ischemia have no collateral flow, and irreversible neuronal damage commences within 4 to 8 minutes under normothermic conditions;2Ames III, A Wright RL Kowada M Thurston JM Majno G Cerebral ischemia. II. The no-reflow phenomenon.Am J Pathol. 1968; 52: 437-453PubMed Google Scholar, 3Nemoto EM Hossmann K-A Cooper HK Post-ischemic hypermetabolism in cat brain.Stroke. 1981; 12: 666-676Crossref PubMed Google Scholar, 4Kabat H Dennis C Baker AB Recovery of function following arrest of the brain circulation.Am J Physiol. 1941; 132: 737-747Google Scholar, 5Hossmann K-A Olsson Y Suppression and recovery of neuronal function in transient cerebral ischemia.Brain Res. 1970; 22: 313-325Crossref PubMed Google Scholar (2) in focal ischemia, the trickle of flow from the collateral circulation leads to a more complex biochemical situation including the delivery of glucose under anaerobic conditions, which causes a profound acidosis; and (3) this potential for collateral flow in focal ischemia may facilitate possible reversal of neuronal damage after extended periods of ischemia. Therefore, the pathophysiologic features and treatment of global ischemia differ from those of focal ischemia and will not be considered further in this review. The pathophysiologic characteristics of focal cerebral ischemia can be analyzed in terms of thresholds of cerebral ischemia, metabolic derangements, and microcirculatory changes. In 1948, Kety and Schmidt6Kety SS Schmidt CF The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values.J Clin Invest. 1948; 27: 476-483Crossref PubMed Google Scholar first measured a normal cerebral blood flow (CBF) in humans of approximately 53 ml/100 g per min. Some 25 years later, two separate teams of investigators in Denmark and at the Mayo Clinic found, in patients undergoing carotid endarterectomy, that the threshold for brain electrical failure (attenuation in electroencephalograms) approximated 15 to 18 ml/100 g per min.7Sharbrough FW Messick Jr, JM Sundt Jr, TM Correlation of continuous electroencephalograms with cerebral blood flow measurements during carotid endarterectomy.Stroke. 1973; 4: 674-683Crossref PubMed Google Scholar, 8Trojaborg W Boysen G Relation between EEG, regional cerebral blood flow and internal carotid artery pressure during carotid endarterectomy.Electroencephalogr Clin Neurophysiol. 1973; 34: 61-69Abstract Full Text PDF PubMed Google Scholar Thereafter, in laboratory studies Branston and associates9Branston NM Symon L Crockard HA Pasztor E Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon.Exp Neurol. 1974; 45: 195-208Crossref PubMed Google Scholar showed that the somatosensory evoked potentials were suppressed when CBF was less than 15 ml/100 g per min. Thus, a threshold of electrical failure was quantitated at 15 to 18 ml/100 g per min, a range that has proved to be relatively constant in numerous animal models anesthetized with various agents.10Morawetz RB Crowell RH DeGirolami U Marcoux FW Jones TH Halsey JH Regional cerebral blood flow thresholds during cerebral ischemia.Fed Proc. 1979; 38: 2493-2494Google Scholar, 11Heiss W-D Hayakawa T Waltz AG Cortical neuronal function during ischemia: effects of occlusion of one middle cerebral artery on single-unit activity in cats.Arch Neurol. 1976; 33: 813-820Crossref PubMed Google Scholar In addition, a threshold of ionic failure was substantiated at approximately 10 ml/100 g per min. At this level of flow, investigators noted alterations in extracellular potassium and intracellular calcium, liberation of free fatty acids, disturbances in the water content of the brain, rapid depletion of adenosine triphosphate (ATP), and a profound intracellular acidosis12Astrup J Symon L Branston NM Lassen NA Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia.Stroke. 1977; 8: 51-57Crossref PubMed Google Scholar, 13Symon L Branston NM Chikovani O Ischemic brain edema following middle cerebral artery occlusion in baboons: relationship between regional cerebral water content and blood flow at 1 to 2 hours.Stroke. 1979; 10: 184-191Crossref PubMed Google Scholar, 14Astrup J Blennow G Nilsson B Effects of reduced cerebral blood flow upon EEG pattern, cerebral extracellular potassium, and energy metabolism in the rat cortex during bicuculline-induced seizures.Brain Res. 1979; 177: 115-126Crossref PubMed Scopus (12) Google Scholar, 15Branston NM Strong AJ Symon L Extracellular potassium activity, evoked potential and tissue blood flow: relationships during progressive ischaemia in baboon cerebral cortex.J Neurol Sei. 1977; 32: 305-321Abstract Full Text PDF Scopus (81) Google Scholar, 16Harris RJ Symon L Branston NM Bayhan M Changes in extracellular calcium activity in cerebral ischaemia.J Cereb Blood Flow Metab. 1981; 1: 203-209Crossref PubMed Google Scholar, 17Wieloch T Siesjö BK Ischemic brain injury: the importance of calcium, lipolytic activities, and free fatty acids.Pathol Biol (Paris). 1982; 30: 269-277Google Scholar, 18Meyer FB Anderson RE Sundt Jr, TM Yaksh TL Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate focal cortical ischemia in the rabbit.J Cereb Blood Flow Metab. 1986; 6: 71-78Crossref PubMed Google Scholar (Fig. 1). This threshold of ionic failure is presumed to be a CBF at which irreversible neuronal damage rapidly occurs. Although the tolerance of neuronal tissue for these low flows is unknown, a few studies suggest that after 3 to 4 hours, neuronal death is inevitable.10Morawetz RB Crowell RH DeGirolami U Marcoux FW Jones TH Halsey JH Regional cerebral blood flow thresholds during cerebral ischemia.Fed Proc. 1979; 38: 2493-2494Google Scholar, 18Meyer FB Anderson RE Sundt Jr, TM Yaksh TL Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate focal cortical ischemia in the rabbit.J Cereb Blood Flow Metab. 1986; 6: 71-78Crossref PubMed Google Scholar, 19Traupe H Heiss WD Umbach R Microflow and cortical neuronal function during temporary ischemia.J Cereb Blood Flow Metab. 1981; 1: 190-191Google Scholar, 20Sundt Jr, TM Grant WC Garcia JH Restoration of middle cerebral artery flow in experimental infarction.J Neurosurg. 1969; 31: 311-322Crossref PubMed Google Scholar, 21Crowell RM Olsson Y Klatzo I Ommaya A Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations.Stroke. 1970; 1: 439-448Crossref PubMed Google Scholar Between these two thresholds of electrical and ionic failure exists a small range of flow at which, despite functional loss, membrane homeostasis and structural integrity are maintained. This circumscribed range of CBF has been conceptualized in the term "ischemic penumbra"12Astrup J Symon L Branston NM Lassen NA Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia.Stroke. 1977; 8: 51-57Crossref PubMed Google Scholar, 22Symon L Branston NM Strong AJ Hope TD The concept of thresholds of ischaemia in relation to brain structure and function.J Clin Pathol. 1977; 30: 149-154Crossref Google Scholar, 23Astrup J Siesjö BK Symon L Thresholds in cerebral ischemia: the ischemic penumbra (editorial).Stroke. 1981; 12: 723-725Crossref PubMed Google Scholar, 24Heiss W-D Flow thresholds of functional and morphological damage of brain tissue.Stroke. 1983; 14: 329-331Crossref PubMed Google Scholar and explains why the potential for recovery exists in patients with acute focal ischemia if sufficient collateral flow is present to satisfy basic energy requirements. Some evidence suggests, however, that this "ischemic penumbra" is a dynamic state that will deteriorate over time (Fig. 1).18Meyer FB Anderson RE Sundt Jr, TM Yaksh TL Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate focal cortical ischemia in the rabbit.J Cereb Blood Flow Metab. 1986; 6: 71-78Crossref PubMed Google Scholar, 25Strong AJ Tomlinson BE Venables GS Gibson G Hardy JA The cortical ischaemic penumbra associated with occlusion of the middle cerebral artery in the cat. 2. Studies of histopathology, water content, and in vitro neurotransmitter uptake.J Cereb Blood Flow Metab. 1983; 3: 97-108Crossref Google Scholar Therefore, after acute occlusion of a vessel, the clinical outcome will reflect both the severity and the duration of reduced flow. The metabolic aberrations that occur at a CBF of approximately 10 ml/100 g per min are multifactorial and reflect both the rapid depletion of ATP and the accumulation of lactic acid due to the absence of oxidative phosphorylation (Fig. 2).26Michenfelder JD Sundt Jr, TM Cerebral ATP and lactate levels in the squirrel monkey following occlusion of the middle cerebral artery.Stroke. 1971; 2: 319-326Crossref Google Scholar One of the pathways that precipitate irreversible damage is currently thought to be an increase in intracellular calcium.27Schanne FAX Kane AB Young EE Farber JL Calcium dependence of toxic cell death: a final common pathway.Science. 1979; 206: 700-702Crossref PubMed Google Scholar, 28Farber JL Chien KR Mittnacht Jr, S The pathogenesis of irreversible cell injury in ischemia.Am J Pathol. 1981; 102: 271-281PubMed Google Scholar, 29Siesjö BK Cell damage in the brain: a speculative synthesis.J Cereb Blood Flow Metab. 1981; 1: 155-185Crossref PubMed Google Scholar, 30Siesjö BK Cerebral circulation and metabolism.J Neurosurg. 1984; 60: 883-908Crossref PubMed Google Scholar, 31Yanagihara T McCall JT Ionic shift in cerebral ischemia.Life Sei. 1982; 30: 1921-1925Crossref Scopus (6) Google Scholar Failure of ATP-dependent Na+-K+ transport, and the resultant increased extracellular K+, will depolarize the neuronal membrane. This situation results in opening of voltage-sensitive calcium channels and an increase in intracellular free calcium (Fig. 3).17Wieloch T Siesjö BK Ischemic brain injury: the importance of calcium, lipolytic activities, and free fatty acids.Pathol Biol (Paris). 1982; 30: 269-277Google Scholar This influx of calcium is enhanced by failure of the ATP-dependent Na+-Ca+ antiport system, failure of the ATP-dependent sequestration of Ca+ by the endoplasmic reticulum, and electrophoretic accumulation of calcium by mitochondria, which will uncouple oxidative phosphorylation.32Ginsberg MD Mela L Wrobel-Kuhl K Reivich M Mitochondrial metabolism following bilateral cerebral ischemia in the gerbil.Ann Neurol. 1977; 1: 519-527Crossref PubMed Google Scholar, 33Nowicki JP MacKenzie ET Young AR Brain ischaemia, calcium and calcium antagonists.Pathol Biol. 1982; 30: 282-288Google Scholar, 34Rehncrona S Mela L Siesjö BK Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia.Stroke. 1979; 10: 437-446Crossref PubMed Google Scholar This uncountered increase in intracellular calcium is thought to activate phospholipase A and C, which will attack membrane phospholipids with the production of free fatty acids.29Siesjö BK Cell damage in the brain: a speculative synthesis.J Cereb Blood Flow Metab. 1981; 1: 155-185Crossref PubMed Google Scholar, 30Siesjö BK Cerebral circulation and metabolism.J Neurosurg. 1984; 60: 883-908Crossref PubMed Google Scholar This loss of membrane phospholipids will increase the permeability of neuronal and mitochondrial membranes, which will further alter calcium homeostasis with additional detrimental effects on oxidative phosphorylation. The accumulated free fatty acids, especially arachidonic acid, may be oxidized along the cyclooxygenase and lipoxygenase pathways in incomplete ischemia. The end result would be the accumulation of prostaglandins, leukotrienes, and possibly free radicals.29Siesjö BK Cell damage in the brain: a speculative synthesis.J Cereb Blood Flow Metab. 1981; 1: 155-185Crossref PubMed Google Scholar, 30Siesjö BK Cerebral circulation and metabolism.J Neurosurg. 1984; 60: 883-908Crossref PubMed Google Scholar, 35Yoshida S Inoh S Asano T Sano K Kubota M Shima-zaki H Ueta N Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain: lipid peroxidation as a possible cause of postischemic injury.J Neurosurg. 1980; 53: 323-331Crossref PubMed Google Scholar, 36Demopoulos HB Flamm ES Pietronigro DD Seligman ML The free radical pathology and the microcirculation in the major central nervous system disorders.Acta Physiol Scand [Suppl]. 1980; 492: 91-119PubMed Google Scholar Thromboxane A2 is a potent vasoconstrictor, leukotrienes alter membrane permeability and cause vasoconstriction, and free radicals, if present, would attack membranes.35Yoshida S Inoh S Asano T Sano K Kubota M Shima-zaki H Ueta N Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain: lipid peroxidation as a possible cause of postischemic injury.J Neurosurg. 1980; 53: 323-331Crossref PubMed Google Scholar, 36Demopoulos HB Flamm ES Pietronigro DD Seligman ML The free radical pathology and the microcirculation in the major central nervous system disorders.Acta Physiol Scand [Suppl]. 1980; 492: 91-119PubMed Google Scholar, 37Wolfe LS Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids.J Neurochem. 1982; 38: 1-14Crossref PubMed Google Scholar Therefore, inhibition of voltage-sensitive calcium channels by calcium antagonists might attenuate the foregoing cascade of events.Fig. 3Demonstration of transient increase of sodium (closed circles) and calcium (closed triangles) contents (μg/g dry tissue) and decrease of potassium (open circles) content after occlusion of right common carotid artery for 30 minutes and subsequent recirculation in the gerbil. Those alterations became sustained after occlusion for 180 minutes and subsequent recirculation. Water content (%) is shown with cross marks, whereas magnesium content is shown with open triangles. Results are expressed as percentage of the value of right cerebral hemisphere as compared with left cerebral hemisphere based on four experiments (mean ± SEM) for each time interval. P values (*** = <0.01; ** = 0.01<P<0.05; * = 0.05<P<0.1) are based on Student t test by comparison with percentage values (right versus left) from normal gerbils.(Modified from Yanagihara and McCall.31Yanagihara T McCall JT Ionic shift in cerebral ischemia.Life Sei. 1982; 30: 1921-1925Crossref Scopus (6) Google Scholar By permission of Pergamon Journals, Ltd.)View Large Image Figure ViewerDownload (PPT) The importance of intracellular acidosis during focal ischemia must also be emphasized. As seen in Figure 1, 10 minutes after occlusion of the middle cerebral artery in the rabbit, intracellular brain pH declines to 6.64 in comparison with the preocclusion value of 7.01. This finding is a direct reflection of the fourfold increase in lactic acid that occurs during the first minutes of severe ischemia (Fig. 2).26Michenfelder JD Sundt Jr, TM Cerebral ATP and lactate levels in the squirrel monkey following occlusion of the middle cerebral artery.Stroke. 1971; 2: 319-326Crossref Google Scholar Intracellular brain pH then decreases to 6.08 during the next 4 hours, a reflection of the accumulation of both lactic acid and free fatty acids.26Michenfelder JD Sundt Jr, TM Cerebral ATP and lactate levels in the squirrel monkey following occlusion of the middle cerebral artery.Stroke. 1971; 2: 319-326Crossref Google Scholar, 38Kuwashima J Nakamura K Fujitani B Kadokawa T Yoshida K Shimizu M Relationship between cerebral energy failure and free fatty acid accumulation following prolonged brain ischemia.Jpn J Pharmacol. 1978; 28: 277-287Crossref Google Scholar This intracellular acidosis has the following detrimental effects: denaturing of proteins with loss of enzymatic function, increasing glial edema that compromises potential collateral flow, suppressing regeneration of the reduced form of nicotinamide-adenine dinucleotide, and possibly increasing production of free radicals.39Rehncrona S Rosén I Siesjö BK Excessive cellular acidosis: an important mechanism of neuronal damage in the brain?.Acta Physiol Scand. 1980; 110: 435-437Crossref PubMed Google Scholar, 40Siesjö BK Bendek G Koide T Westerberg E Wieloch T Influence of acidosis on lipid peroxidation in brain tissues in vitro.J Cereb Blood Flow Metab. 1985; 5: 253-258Crossref PubMed Google Scholar, 41Siesjö BK Lactic acidosis in the brain: occurrence, triggering mechanisms and pathophysiological importance.Ciba Found Symp. 1982; 87: 77-100Google Scholar, 42Welsh FA O'Connor MJ Marcy VR Spatacco AJ Johns RL Factors limiting regeneration of ATP following temporary ischemia in cat brain.Stroke. 1982; 13: 234-242Crossref PubMed Google Scholar In focal ischemia, the continued delivery of glucose under anaerobic conditions will increase production of lactic acid. The initial circulatory changes noted after vessel occlusion are a darkening of the venous blood and then a decrease in the velocity of flow through veins and venules. Aggregation of blood elements (sludging or particulate flow) results from a reduction in the shearing forces that tend to keep cells dispersed.43Knisely MH Bloch EH Eliot TS Warner L Sludged blood.Science. 1947; 106: 431-440Crossref PubMed Google Scholar, 44Little JR Kerr FWL Sundt Jr, TM Microcirculatory obstruction in focal cerebral ischemia: relationship to neuronal alterations.Mayo Clin Proc. 1975; 50: 264-270Google Scholar Consequently, blood viscosity and resistance to flow increase. Measurements of the caliber of arteries and arterioles reveal an immediate slight increase. At a variable time after occlusion, cortical pallor develops, the earliest indication of severe ischemia (Fig. 4). When this pallor extends to an area underlying an artery or arteriole, a spasm occurs in that vessel.45Sundt Jr, TM Waltz AG Cerebral ischemia and reactive hyperemia: studies of cortical blood flow and microcirculation before, during, and after temporary occlusion of middle cerebral artery of squirrel monkeys.Circ Res. 1971; 28: 426-433Crossref PubMed Google Scholar The mechanism of this ischemia-induced secondary vasospasm is unclear, but the cause has been postulated to be either an increase in extracellular K+, which would lead to vascular smooth muscle contraction, or an influx of Ca+ into smooth muscle cells. An increase in membrane permeability to Ca+ could result from opening of K+ depolarized calcium channels, interaction of surface receptors with an extracellular messenger such as serotonin or norepinephrine, or activation of 3′,5′-guanosine monophosphate.46Sundt Jr, TM Davis DH Reactions of cerebrovascular smooth muscle to blood and ischemia: primary versus secondary vasospasm.in: Wilkins RH Cerebral Arterial Spasm. Williams & Wilkins, Baltimore1980: 244-250Google Scholar With restoration of flow to a region of ischemia, the aforementioned chain of events is reversed. The venous blood becomes bright red, particulate flow in the venules is no longer observed, the cortex recolorizes, and, finally, the major vessels resume their normal caliber. Often a true hyperemia develops, with dilatation of conducting vessels in the cortex that were not noted in the normal state. This hyperemia is probably a function of vasomotor paralysis, partially a result of excessive lactic acidosis. During this paralysis, cortical perfusion is directly related to blood pressure.47Waltz AG Red venous blood: occurrence and significance in ischemic and nonischemic cerebral cortex.J Neurosurg. 1969; 31: 141-148Crossref Google Scholar In addition to the intravascular obstruction described (sludging), microcirculatory changesoccur—the "no-reflow phenomenon," as first described by Ames and colleagues2Ames III, A Wright RL Kowada M Thurston JM Majno G Cerebral ischemia. II. The no-reflow phenomenon.Am J Pathol. 1968; 52: 437-453PubMed Google Scholar in a model of global ischemia. They postulated that ischemic endothelial damage resulted in impairedvascular filling because of capillary obstruction, after which neurons were then damaged. Electron microscopic demonstration of "endothelial blebs" supported this concept.48Fischer EG Ames III, A Hedley-Whyte ET O'Gorman S Reassessment of cerebral capillary changes in acute global ischemia and their relationship to the "no-reflow phenomenon.".Stroke. 1977; 8: 36-39Crossref PubMed Google Scholar Crowell and Olsson49Crowell RM Olsson Y Impaired microvascular filling after focal cerebral ischemia in monkeys.J Neurosurg. 1972; 36: 303-309Crossref PubMed Google Scholar extended this "no-reflow" concept to focal cerebral ischemia by demonstrating impaired vascular filling after transient occlusion of the middle cerebral artery. Inthe "no-reflow phenomenon," ischemic endothelial damage was postulated to precede neuronal injury. Alternatively, research by Little and colleagues44Little JR Kerr FWL Sundt Jr, TM Microcirculatory obstruction in focal cerebral ischemia: relationship to neuronal alterations.Mayo Clin Proc. 1975; 50: 264-270Google Scholar demonstrated that, during focal ischemia, neuronal alterations precede impaired vascular filling and that, at least initially, microvascular obstruction is not the primary determinant of irreversible neuronal damage. One of the primary acute reactions of the brain parenchyma to injury is swelling. Ischemic edema has been divided into an early cytotoxic (intracellular), and a late vasogenic (extracellular) phase. Cytotoxic edema initially involves perivascular glial cells, a finding that suggests that it is secondary to alterations in permeability rather than tothe lack of energy substrate.20Sundt Jr, TM Grant WC Garcia JH Restoration of middle cerebral artery flow in experimental infarction.J Neurosurg. 1969; 31: 311-322Crossref PubMed Google Scholar, 50Little JR Sundt Jr, TM Kerr FWL Neuronal alterations in developing cortical infarction: an experimental study in monkeys.J Neurosurg. 1974; 40: 186-198Crossref Google Scholar Lactic acidosis seems to have a critical role in glial edema.39Rehncrona S Rosén I Siesjö BK Excessive cellular acidosis: an important mechanism of neuronal damage in the brain?.Acta Physiol Scand. 1980; 110: 435-437Crossref PubMed Google Scholar The major detrimental effect of this edema is the impingement on potential collateral flow (Fig. 5). Accordingly, Iannotti and colleagues51Iannotti F Hoff JT Schielke GP Brain tissue pressure in focal cerebral ischemia.J Neurosurg. 1985; 62: 83-89Crossref Google Scholar demonstrated an increase in local tissue pressure in core regions of ischemia commencing within 10 minutes after occlusion of the middle cerebral artery. Corresponding to this increase in tissue pressure was a progressive decline in local CBF. These events occurred early, before the eventual rise in intracranial pressure, and were considered to be a result of local cytotoxic edema. Vasogenic edema occurs hours to days after vessel occlusion and is secondary to irreversible ischemic endothelial damage. The end result is breakdown of the blood-brain barrier and extravasation of plasma into the extracellular compartment.52Olsson Y Crowell RM Klatzo I The blood-brain barrier to protein tracers in focal cerebral ischemia and infarction caused by occlusion of the middle cerebral artery.Acta Neuropathol (Berl). 1971; 18: 89-102Crossref Scopus (19) Google Scholar, 53Plum F Posner JB Alvord Jr, EC Edema and necrosis in experimental cerebral infarction.Arch Neurol. 1963; 9: 563-570Crossref Google Scholar Subsequently, the intracranial pressure increases, the extent depending on the volume of the infarct. In turn, secondary effects such as tentorial herniation may occur. For determination of the reversibility of cerebralischemia, morphologic assessment of ischemic damage is important. Morphologic damage soon after the onset of ischemia, however, has not been well elucidated because of relative insensitivity of conventional histologic methods. Recent investigations at our institution have demonstrated that the immunohistochemical technique for identifying neuron-enriched or neuron-specific proteins is very sensitive for detection of ischemic and post-ischemic damage.54Yanagihara T Yoshimine T Morimoto K Yamamoto K Homburger HA Immunohistochemical investigation of cerebral ischemia in gerbils.J Neuropathol Exp Neurol. 1985; 44: 204-215Crossref PubMed Google Scholar, 55Yoshimine T Morimoto K Brengman JM Homburger HA Mogami H Yanagihara T Immunohistochemical investigation of cerebral ischemia during recirculation.J Neurosurg. 1985; 63: 922-928Crossref PubMed Google Scholar For example, in the gerbil, ischemic lesions of the hippocampus can be identified within 4 minutes after occlusion of a posterior communicating artery (Fig. 6). Approximately 3 minutes later, these ischemic lesions become irreversible. In contrast, a period of 10 minutes of ischemiawas necessary before lesions could be detected in the thalamus.56Yamamoto K Yoshimine T Homburger HA Yanagihara T Immunohistochemical investigation of regional cerebral ischemia in the gerbil: occlusion of the posterior communicating artery.Brain Res. 1986; 371: 244-252Crossref Google Scholar These immunohistochemical techniques can be combined with other investigative methods. For example, a recent study that used immunohistochemical and quantitative autoradiographic procedures57Matsumoto M Hatakeyama T Yanagihara T Combination of cerebral blood flow measurement and immunohistochemical technique in cerebral ischemia (abstract).Stroke. 1986; 17: 137Google Scholar demonstrated regional differences in tissue vulnerability to CBF of 10 ml/100 g per min or less. Furthermore, immunohistochemically identified vulnerable sites have been analyzed with transmission electron microscopy and immunoelectron microscopy.58Yamamoto K Yanagihara T Immunoelectronmicroscopic investigation of cerebral ischemia in gerbils (abstract).J Neuropathol Exp Neurol. 1985; 44: 337Crossref Google Scholar, 59Yamamoto K Morimoto K Yanagihara T Cerebral ischemia in the gerbil: transmission electronmicroscopic and immunoelectronmicroscopic investigation.Brain Res. 1986; 384: 1-10Crossref PubMed Google Scholar Dendritic terminals seem to be most vulnerable, and ischemic damage subsequently extends proximally toward neuronal cellbodies. Both variations in tissue vulnerability and the sensitivity of dendrites to ischemia may reflect an increased number of calcium channels at these locations. Herein we will discuss the treatment options that either are of historical interest or seemto be most promising for attenuating neuronal injury during focal ischemia. Certain agents that alleviate damage in global ischemia are of minimal benefit in focal ischemia—for example, hypothermia and platelet antagonists. Conversely, some therapeutic measures (such as barbiturates) may attenuate damage in focal but not in global ischemia. Therefore, this review is highly selective and reflects our opinions in regard to specific regimens and their actions in focal ischemia only. Those agents that are most familiar to us because of our own investigations are emphasized; in addition, several other review articles are recommended to provide alternative perspectives on this subject.60Selman WR Spetzler RF Therapeutics for focal cerebral ischemia.Neurosurgery. 1980; 6: 446-452Crossref PubMed Google Scholar, 61Diaz FG Ausman JI Experimental cerebral ischemia.Neurosurgery. 1980; 6: 436-445Crossref PubMed Google Scholar Increasing collateral f
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