Pathophysiology of Focal Cerebral Ischemia: a Therapeutic Perspective Wade S. Smith, MD, PhD The pathophysiology of cerebral ischemia is best understood in animal models of stroke. Within minutes of interrupted blood flow, mitochondria are deprived of substrate, which prevents adenosine triphosphate generation and results in membrane depolarization. This leads to increased intracellular calcium and sodium concentration followed by generation of free radicals and initiation of apoptosis. Glutamate release from ischemic neurons contributes to cellular damage. Each step in this complex, interdependent series of events offers a potential point to intervene and prevent neuronal death. Although many human trials in acute stroke therapy have had disappointing results, many promising therapies are in the pipeline, including hypothermia and free-radical inhibitors. Herein, the author discusses the pathophysiology of focal cerebral ischemia as has been revealed in rodent models and reviews the major human trials according to treatment mechanism. J Vasc Interv Radiol 2004; 15:S3–S12 Abbreviations: ATP ϭ adenosine triphosphate, MCA ϭ middle cerebral artery, NMDA ϭ N-methyl-d-aspartate, PARP ϭ poly (adenosine diphosphate ribose) polymerase BRAIN tissue is exquisitely sensitive tissue that has been reperfused. Un- more resilient than gray matter. In ad- to ischemia such that even brief isch- derstanding these processes better dition, certain populations of cerebral emia to cerebral neurons can initiate a should lead to new therapies for miti- neurons are selectively vulnerable to complex sequence of events that ulti- gating stroke. ischemia, as in hippocampal CA1 cells mately culminate in cellular death. Herein, I focus on focal ischemia compared with dentate granule cells Ischemia of cerebral tissue and cellular pathophysiology because this is most and cerebral neurons compared with death underlie all forms of stroke, in- relevant to human ischemic stroke. brain stem neurons. Infarction is a his- cluding focal ischemia (as in embolic Important distinctions between this tologic finding applied to a region of occlusion of the middle cerebral artery and other forms of ischemia will be brain that has been injured by isch- [MCA]), global ischemia (as in cardiac discussed where relevant. Data from emia. The region of infarction appears arrest), and, likely, intraparenchymal human neuroprotection and revascu- pale on brain slices stained with hema- hemorrhage. In addition, it overlaps larization trials will be discussed to toxylin and eosin and, at microscopy, with the processes of neuronal dam- illustrate what has been translated shows edema and cellular swelling age in closed head injury and sub- from the laboratory to human stroke. but initially no loss of cellular ele- arachnoid hemorrhage. Conversely, This article is necessarily limited in ments. The area of stroke in animal there are remarkable differences in the scope; the interested reader is referred models is defined by this region, and causes of cell death between global to the comprehensive review of isch- the volume of stroke is measured by ischemia and focal ischemia, and, emic cell death by Lipton (1) and a integrating areas of infarction over within focal ischemia, there are impor- review of potential neuroprotective multiple brain slices. Infarct volume re- tant processes that are unique to the strategies in ischemia and trauma (2). I duction is a reduction in this volume will not address the fascinating topic following some intervention. The re- of neural regeneration following isch- gion of infarction in humans can be emia, so the interested reader is re- From the Department of Neurology, University of visualized with diffusion-weighted California, San Francisco, 505 Parnassus Avenue, ferred elsewhere (3). magnetic resonance (MR) imaging (4). San Francisco, California 94143-0114. Received Jan- In focal ischemia, a central region of uary 30, 2003; revision requested April 23; revision DEFINITION OF TERMS AND brain tissue is infarcted rapidly; this received July 16; accepted July 17. Address corre- region is called the core of the infarct. spondence to W.S.S.; E-mail: wssmith@itsa. CONCEPTS ucsf.edu. The ischemic region around the core is Ischemia is defined as a reduction in called the ischemic penumbra. The pro- The author is a scientific advisor and holds stock in Radiant Medical Corporation and Renovis, Inc. cerebral blood flow sufficient to alter cesses of cellular injury and death are cerebral function. Different brain re- remarkably different in these two re- © SIR, 2004 gions have different thresholds for gions and will be discussed below. DOI: 10.1097/01.RVI.0000108687.75691.0C ischemia, with white matter being An ischemic neuron does not nec- S3 S4 • Pathophysiology of Focal Cerebral Ischemia January 2004 JVIR essarily die. The process of cellular that of permanent MCA occlusion (apoptotic bodies). This is followed by death happens long after ischemia and when temporary MCA recanalization a stereotypical loss of cellular architec- infarction, typically 2 to 3 days in ro- is allowed beyond 2 to 3 hours. There- ture (which takes several days) that dent models (1). Cellular death has fore, in most cases, human MCA oc- involves the activity of caspases (fam- clearly occurred when cytoskeletal clusion is probably best modeled with ily of cysteine proteases) and other en- breakdown occurs, but a cell may be permanent cerebral ischemia models. zyme systems. Necrotic cell death is committed to death long before obvi- Because the current basis of emergent more common with more extreme lev- ous morphologic change is observable. stroke treatment is vessel recanaliza- els of ischemia, whereas apoptotic cell In focal ischemia, cellular death is of- tion, however, both permanent and death is more common with less se- ten accompanied by necrosis, in which reperfusion models are relevant for vere insults. Thus, the core tissue of an cytoskeletal elements, edema, and in- human stroke therapy. infarct dies with a necrotic process, flammatory cells are found. Cells may Brain injury and neuronal death ne- and, depending on the location within also die by means of programmed cell cessitates at least 1 to 2 minutes of the penumbra, cells die by means of death or apoptosis. Apoptosis is a com- focal vascular occlusion. In animal either method, with apoptosis more plex process by which a neuron that models, blood flow is most greatly re- common for cells further away from has experienced even a transient insult duced in a central region of brain (in- the core. will begin to degrade its nucleus and farct “core”) and in a graded fashion initiate a self-destruct sequence that centrifugally from the core (“penum- happens days later. Although apopto- bra”). Cerebral blood flow decreases Process of Cerebral Infarction and sis likely exists to help the developing to less than 15% of baseline within the Cellular Death brain make appropriate connections, it core, which leads to reductions in may also have an important role in adenosine triphosphate (ATP) levels Within minutes of vascular occlu- mature and degenerating brain and is to 25% of baseline. Cerebral blood sion, brain tissue is deprived of glu- the subject of intense research. flow decreases to between 15% and cose and oxygen and the acidic by- 40% by definition in penumbral re- products of metabolism accumulate. gions, and ATP levels decrease to be- Although the exact sequence of events PATHOPHYSIOLOGY OF tween 50% and 70% of control within is debatable, what follows is a likely FOCAL CEREBRAL ISCHEMIA minutes of vessel occlusion. All neu- sequence of events responsible for the early damage to neurons. This se- The Core and Penumbral Regions of rons within the core region will infarct quence of events is summarized in the Infarction despite experiencing an increase in ATP levels to two-thirds of normal Figure. This loss of substrate and de- There are two major categories of and return of normal oxygen partial crease in pH level leads to cessation of experimental ischemia: (a) global hyp- pressure if the duration of ischemia is the electron transport chain activity oxia and/or ischemia models and (b) 30 minutes or more. Some neurons within mitochondria, which results in focal ischemia models. In global hyp- within the penumbra will die as well; a rapid decline in ATP concentration. Loss of ATP leads to failure of the oxia and/or ischemia models, typi- as the duration of focal ischemia ϩ ϩ cally two or four cervical vessels to the lengthens, the size of the infarct will Na ,K -ATPase, which results in a marked intracellular increase in intra- brain are temporarily interrupted and increase so that after 2 to 3 hours of ϩ cellular Na concentration. Persistent circulation restored after some delay. focal ischemia in rodents, the size of ϩ depolarization allows Ca2 entry, and In focal ischemia models, the MCA is the infarct will be equal to that found ϩ higher intracellular Na levels reduce typically occluded either permanently with permanent vascular occlusion. ϩ ϩ or temporarily to allow reperfusion The process by which the penumbra is the efficacy of the 2Na -Ca2 sym- port, which further increases intracel- (5). destroyed is the focus of most isch- ϩ Herein, I will focus on the patho- emia research, as prevention of this lular Ca2 . Because the membrane po- physiology of brain cell death in focal infarct growth with intervention tential reaches the electrical threshold ischemia models because human isch- would be expected to salvage neuro- for discharge, neurons inside the core emic stroke is best modeled with both nal tissue. Several strategies are suc- infarct exhibit ischemic discharges permanent and reperfusion models of cessful for protecting against penum- whereby they fire repetitively, releas- stroke. Following typical embolic vas- bral destruction, fostering the concept ing their transmitters locally and at cular occlusion in humans, there is of “neuroprotection.” distant targets. These ischemic depo- spontaneous thrombolysis and spon- Cells die by means of two major larizations further exacerbate energy taneous recanalization that occurs but methods: necrosis and apoptosis.