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Reperfusion Brain Injury Focus on Cellular Bioenergetics Reperfusion brain injury Focus on cellular bioenergetics Svetlana Pundik, MD, ABSTRACT MS Energy production for the maintenance of brain function fails rapidly with the onset of ischemia Kui Xu, PhD and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is Sophia Sundararajan, strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced MD, PhD production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in re- versible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during Correspondence & reprint requests to Dr. Pundik: and after ischemia are discussed. Because mitochondrial function can be compromised by de- [email protected] rangements at more than one of the susceptible sites on this organelle, we propose that a combi- nation therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology® 2012;79 (Suppl 1):S44–S51 GLOSSARY ATP ϭ adenosine triphosphate; DAMP ϭ danger-associated molecular pattern molecule; MPTP ϭ mitochondrial permeability transition pore; ROS ϭ reactive oxygen species; SAINT ϭ Stroke-Acute Ischemic NXY Treatment; SEF ϭ secondary energy failure; STAIR ϭ Stroke Therapy Academic Industry Roundtable; TNF␣ ϭ tumor necrosis factor-␣. Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis. The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellu- lar milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other support- ing cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia. In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a From Case Western Reserve University (S.P., K.X., S.S.), Cleveland Veterans Affairs Medical Center (S.P.), and University Hospitals Case Medical Center (S.S.), Cleveland, OH. Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article. S44 © 2012 American Academy of Neurology Figure 1 A schematic of key ischemia and reperfusion-induced processes leading to mitochondrial dysfunction and cell death multitude of energy-dependent cellular pro- ration of ischemia is a major determinant of the cesses critical to cellular homeostasis and brain magnitude of the pathophysiologic response, function.1–3 Parenthetically, most physiologic and time of the ischemic episode cannot be processes within the cell are either directly or in- overemphasized when discussing the outcome directly impacted by the loss of energy. The im- following stroke. mediate consequence of diminished energy Restoring blood flow to the brain elicited reserves is perturbation of membrane electro- multiple cellular and physiologic events, and chemical gradients, leading to depolarization. it was initially expected that reperfusion The influx of sodium, calcium, and chloride would simply be a reversal of the ischemia- into the intracellular space and potassium efflux induced disruption of the cellular milieu to result in increased intracellular water and cyto- re-establish function; however, this clearly is toxic brain edema.4 Depolarization increases in- not the case. Experimental evidence shows tracellular calcium, activating transcription that reperfusion triggers a set of unique, po- factors, phospholipases, endonucleases, and pro- tentially pathologic events including, for ex- teases and leading to deranged intracellular sig- ample, increased prostaglandin synthesis, naling, compromised cellular function, and loss elevated production of second messengers, in- of structural integrity.5 Depolarization also trig- flammation, and mitochondrial dysfunction, gers excessive release of glutamate, which results as indicated by elevated reactive oxygen spe- in an increased activation of glutamate receptors cies (ROS) and the opening of the mitochon- and an additional influx of calcium, accentuat- drial permeability transition pore (MPTP).9–13 ing cellular injury.6 The cascade of ischemic It is our contention that if the bioenergetics of events disrupts cellular homeostasis, and if not the brain are not normalized, the tissue will reversed, it causes tissue necrosis. If reflow is ini- die, and rectifying the other potentially tiated in a timely fashion, however, tissue recov- pathogenic events would be of little value. In ers. Early reperfusion with thrombolytics is the spite of the collapse of cellular homeostasis only US Food and Drug Administration–ap- during ischemia, the brain has the capacity to proved treatment for ischemic stroke.7,8 The du- re-establish energy metabolism and then to Neurology 79 (Suppl 1) September 25, 2012 S45 counteract the ischemia-induced events, lead- depletion and neuronal death during reperfu- ing to the restoration of function if reperfu- sion.16 Of interest, there is evidence of selec- sion occurs within certain time constraints. In tive delayed neuronal death phenomenon this context, it has been a challenge to deter- following cardiac arrest and resuscitation in mine which of the reflow events unrelated to humans.17 bioenergetics are pathologic, vs those that are In the second model, delayed secondary merely epiphenomenal. loss of bioenergetics (i.e., SEF) and cell death The central event to the evolution of irre- have been demonstrated in a focal model of versible mitochondrial injury appears to be reversible ischemia. The middle cerebral ar- the formation of MPTP.14 The MPTP, when tery in the rat was transiently occluded for 2 open, becomes permeable to ions and large hours, and energy stores of the ischemic core Ͻ molecules ( 1,500 Kd), disrupting the mito- and surrounding region (i.e., penumbra) were chondrial electrochemical gradient necessary variably depleted.18,19 Upon reperfusion, the to drive oxidative phosphorylation and ATP concentration of ATP in the cerebral cortex 10 synthesis. Although the MPTP is present in was transiently restored, only to fail several the normal brain and subtle reversible open- hours later (figure 2). In contrast, levels of ings of the pore are detectable even at the early glucose remain elevated, as levels of ATP de- stages of reperfusion, evidence suggests that creased, indicating the ATP effect was unre- the massive pore opening is the final irrevers- lated to changes in substrate availability. 15 ible step in the evolution of brain damage. These findings have been confirmed by sev- From the literature, there is evidence to sug- eral laboratories, which also found that the gest that mitochondrial dysfunction is associ- magnitude of the changes was more pro- ated with free radical formation, calcium nounced in the ischemic core than in the pen- overload, and inflammation during reflow, umbra.18,19 Noticeably, there was a complete which may contribute to the massive opening restoration of blood flow in both models of of the MPTP.11 These will be discussed below ischemia, suggesting that deprivation of glu- with the idea that concerted interventions in cose and oxygen was unlikely to be the precip- these factors may produce neuroprotection. itating cause of secondary energy depletion One factor that generally has been overlooked and cell death. is that partial recovery of bioenergetics of the tissue is transiently evident upon reperfusion, From the experimental results on ischemic and if the compromised energy metabolism and reperfusion events, our current knowl- persists, secondary energy failure (SEF) is edge of the pathophysiology of ischemia can manifested and cell death ensues. be summarized as follows. First, cessation of Evidence for the existence of reflow- mitochondrial
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