Mitochondria oxidative metabolism and cell death in stroke

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ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Mitochondria oxidative metabolism and cell death in stroke Neil R Sims and Hakan Muyderman Centre for Neuroscience and Discipline of Medical Biochemistry Flinders


, Mitochondria oxidative metabolism and cell death in stroke. Neil R Sims Hakan Muyderman,PII S0925 4439 09 00214 2. DOI doi 10 1016 j bbadis 2009 09 003,Reference BBADIS 63006. To appear in BBA Molecular Basis of Disease,Received date 19 July 2009. Revised date 28 August 2009,Accepted date 8 September 2009.
Please cite this article as Neil R Sims Hakan Muyderman Mitochondria oxida . tive metabolism and cell death in stroke BBA Molecular Basis of Disease 2009 . doi 10 1016 j bbadis 2009 09 003, This is a PDF le of an unedited manuscript that has been accepted for publication . As a service to our customers we are providing this early version of the manuscript . The manuscript will undergo copyediting typesetting and review of the resulting proof. before it is published in its nal form Please note that during the production process. errors may be discovered which could a ect the content and all legal disclaimers that. apply to the journal pertain , ACCEPTED MANUSCRIPT. Mitochondria oxidative metabolism and cell death in stroke. Neil R Sims and Hakan Muyderman, Centre for Neuroscience and Discipline of Medical Biochemistry Flinders. Medical Science and Technology School of Medicine Flinders University . Adelaide South Australia Australia,Address for Correspondence NU. Professor Neil Sims,Discipline of Medical Biochemistry .
School of Medicine Flinders University ,GPO Box 2100 . Adelaide S A 5001 Australia,Email Neil Sims flinders edu au. Telephone 61 8 8204 4242,Fax 61 8 8374 0139, Running Title Mitochondria oxidative metabolism and cell death in stroke. Key words Mitochondria stroke focal ischemia energy metabolism necrosis apoptosis. Abbreviations AIF apoptosis inducing factor AKAP121 A kinase anchor protein 121 APAF 1 . apoptotic protease activating factor 1 IAPs inhibitor of apoptosis proteins JNK c Jun N terminal. kinase MCA middle cerebral artery Omi HtrA2 Omi stress regulated endoprotease high. temperature requirement protein A2 PARP poly ADP ribose polymerase Smac DIABLO second. mitochondria derived activator of caspase direct IAP binding protein of low pI t Bid truncated Bid. ACCEPTED MANUSCRIPT, Stroke most commonly results from occlusion of a major artery in the brain and typically leads to the. death of all cells within the affected tissue Mitochondria are centrally involved in the development of. this tissue injury due to modifications of their major role in supplying ATP and to changes in their. properties that can contribute to the development of apoptotic and necrotic cell death In animal models. of stroke the limited availability of glucose and oxygen directly impairs oxidative metabolism in severely. ischemic regions of the affected tissue and leads to rapid changes in ATP and other energy related. metabolites In the less severely ischemic penumbral tissue more moderate alterations develop in. these metabolites associated with near normal glucose use but impaired oxidative metabolism This. tissue remains potentially salvageable for at least the first few hours following stroke onset Early. restoration of blood flow can result in substantial recovery of energy related metabolites throughout the. affected tissue However glucose oxidation is markedly decreased due both to lower energy. requirements in the post ischemic tissue and limitations on the mitochondrial oxidation of pyruvate A. secondary deterioration of mitochondrial function subsequently develops that may contribute to. progression to cell loss Mitochondrial release of multiple apoptogenic proteins has been identified in. ischemic and post ischemic brain mostly in neurons Pharmacological interventions and genetic. modifications in rodent models strongly implicate caspase dependent and caspase independent apoptosis. and the mitochondrial permeability transition as important contributors to tissue damage particularly. when induced by short periods of temporary focal ischemia . ACCEPTED MANUSCRIPT,1 Introduction, Stroke is the primary cause of adult disability in developed countries and ranks only behind cancer and.
cardiac disease as a cause of death 1 2 Focal ischemia that results from occlusion of an artery in the. brain ischemic stroke accounts for more than 80 of all strokes 1 Unless rapidly reversed the. occlusion of a major artery usually produces tissue infarction in which affected parts of the brain exhibit. a non selective loss of all cells including neurons astrocytes oligodendrocytes microglia and endothelial. cells The size and location of these infarcts are important determinants of the long term functional. deficits resulting from ischemic stroke Mitochondria have been implicated as central players in the. development of ischemic cell death both through impairment of their normal role in generating much of. the ATP for neural cell function and as key mediators in cell death pathways This article reviews the. current understanding of the mitochondrial responses to focal cerebral ischemia and the contributions of. these organelles to tissue damage Additional aspects of this topic and further discussion of some of the. earlier studies can be found in previous reviews 3 6 . 2 Tissue damage in response to ischemic stroke, Occlusion of a major artery within the brain produces complex cellular changes that depend in part on the. severity of the ischemia that is generated and whether the occlusion is temporary or permanent Because. of the limited overlap in the perfusion territories of cerebral arteries severe ischemia develops in the. tissue immediately surrounding the occluded vessel Blood flow usually falls to less than 20 of normal. in this core or focal tissue 7 9 The resultant disruption to delivery of glucose and oxygen leads to. a greatly reduced ATP generation see section 4 1 1 Ionic gradients across the plasma membrane. quickly dissipate resulting in marked losses of intracellular potassium and large shifts of calcium into. cells 2 10 11 Because of contributions to perfusion from adjacent vessels a lesser ischemia develops. in tissue surrounding the core This penumbral or perifocal tissue typically exhibits reductions to. approximately 20 to 40 of normal flow 8 9 12 Neurons in the penumbra are electrically silent for. long periods a response associated with hyperpolarization of the plasma membrane 8 12 Note For. simplicity the term penumbra has been used throughout this review to describe tissue identified as. ACCEPTED MANUSCRIPT, receiving moderate ischemia even though criteria other than direct measurement of blood flow or plasma. membrane potential have commonly been used , Following permanent arterial occlusion infarcts initially develop in the core tissue but progress to. encompass both core and penumbral regions 13 14 The differences in the severity of the ischemia in. the core and penumbra mean that different mechanisms contribute to cell death Much of our. understanding of the cellular changes induced by focal ischemia comes from animal models of stroke and. from the effects of pharmacological treatments or genetic modifications on the damage that develops . Permanent or temporary occlusion of the middle cerebral artery MCA in rats or mice has commonly. been used for these investigations The present review focuses primarily on insights derived from such. animal models into changes in energy metabolism and mitochondrial properties within the first few hours. of stroke and their involvement in cell death , Many interventions during the initial few hours following the onset of stroke in these models can reduce. infarct volume particularly in the penumbra 2 15 Thus irreversible damage develops relatively. slowly in this region Consistent with this conclusion early restoration of blood flow can reduce the. tissue damage and functional deficits in animal models of stroke 16 17 and following a stroke in. humans 13 18 Indeed treatment with a thrombolytic agent to reverse arterial occlusion within the first. three hours following stroke onset provides the only approach in routine clinical use for limiting the acute. effects of this disorder in humans 13 18 Unfortunately because of the narrow therapeutic window . only a small proportion of those affected by stroke are currently treated with thrombolysis Spontaneous. reversal of arterial occlusion occurs within the first six hours in approximately 17 of ischemic stroke. patients and in approximately 40 to 50 by four days 19 Reperfusion beginning later than six hours. probably has limited effects on the tissue damage that develops Thus animal models involving. permanent arterial occlusion although less commonly investigated than temporary occlusion are likely to. be more relevant to the majority of ischemic stroke cases in humans . Treatments targeting a diverse range of cellular properties have been found to ameliorate tissue damage. and improve functional deficits in animal models of stroke 2 15 This suggests that the mechanisms. for cell loss involve interactions between multiple deleterious processes such that initial changes in one of. ACCEPTED MANUSCRIPT, these processes leads to more severe alterations in others Interruption of one of these initial responses is.
apparently able to disrupt or in some instances greatly delay the spiral of increasingly abnormal changes. that culminate in cell death Intriguingly treatments that reduce damage including those targeting. properties of specific cell populations preserve essentially all cells in the tissue that is salvaged A. smaller but still well demarcated infarct results Such a uniform demise of different cell populations is. not seen with many other insults and suggests a close interdependence of the different cell populations in. their responses to ischemia , Early studies demonstrated that pharmacological blockade of ionotropic glutamate receptors markedly. reduced ischemic damage 2 15 20 This effect is commonly ascribed to the involvement of an. excitotoxic process in which increases in glutamate release from neurons and astrocytes induced by the. ischemia cause an excessive calcium entry via these receptors and triggers other intracellular changes. leading to cell death However alternative mechanisms have also been suggested to explain the. protection by glutamate receptor antagonists including interference with the propogation of potentially. harmful spreading depression like depolarizations that develop in the penumbral tissue during arterial. occlusion 15 21 Abnormal intracellular calcium accumulations arising from calcium entry via ion. channels or transporters in addition to the ionotropic glutamate receptors have also been implicated in. triggering cell death 20 , Other changes identified as important in ischemia induced cell loss include oxidative stress particularly. involving nitric oxide and peroxynitrite and abnormal activation of enzymes such as poly ADP ribose. polymerase PARP and the calpains 2 15 Early reperfusion can limit the effects of some of these. changes but also adds to the complexity of the cellular responses that develop Oxidative stress is. promoted under these conditions and inflammatory responses arising both from resident microglia and. astrocytes as well as blood derived cells also become important 2 15 . 3 The nature of cell death in focal ischemia, Cell death resulting from cerebral ischemia was originally considered to be almost exclusively due to the. process of necrosis in which catastrophic events initiated by ischemia led to cellular changes culminating. in organelle swelling disruption of the plasma membrane and release of intracellular contents These. ACCEPTED MANUSCRIPT, features of cell death are usually seen in the vast majority of cells throughout the developing infarct 22 . Nonetheless a more complex picture began to emerge in the mid 1990 s with the identification of cells. that exhibited features of apoptosis including DNA fragmentation and the production of membrane. enclosed apoptotic bodies 23 24 Such changes are common features of cell death mediated by the. activation of caspases either via the intrinisic pathway or the extrinsic pathway 3 25 26 . Mitochondrial changes resulting in the release of proteins are central to the intrinsic pathway Fig 1 . These proteins lead to the activation of caspases particularly caspase 3 in brain which in turn induces. cellular changes including internucleosomal chromatin condensation and DNA fragmentation 3 25 27 . The role of the intrinsic pathway in focal ischemia is discussed in section 5 2 The extrinsic pathway is. triggered by the binding of specific ligands to plasma membrane cell death receptors This leads to. intracellular activation of caspase 8 and then of executioner capsases involved in cell death In the. extrinsic pathway the executioner caspase activation can occur without involvement of mitochondria 3 . 26 However caspase 8 activation can also cleave Bid to produce truncated Bid t Bid which initiates. the release of apoptogenic proteins from mitochondria under some conditions Caspase independent. forms of apoptosis Fig 1 which result from mitochondrial release of apoptosis inducing factor AIF . and perhaps other proteins 3 25 26 have also been implicated in focal ischemic damage see section. Cells exhibiting features of apoptosis typically peak in number at 24 hours or longer after stroke onset. 23 24 28 They are found scattered throughout the infarct following temporary or permanent occlusion. but are more prominent in tissue subject to less severe ischemia within the penumbra and are more. numerous in brains subjected to temporary ischemia lasting up to two hours 23 24 28 30 This form of. cell loss shows a closer association with tissue that is potentially salvageable and has attracted particular. attention as a target for neuroprotective therapies . Attempts to characterize the mechanisms underlying ischemic cell loss have been further complicated. with the recognition that necrosis also often involves specific patterns of cellular change that can develop. over many hours Furthermore these responses can be highly regulated or even programmed and are. potentially modifiable 26 31 32 Alterations contributing to cerebral ischemic damage including. increased intracellular calcium and oxidative stress have been identified as potential players in necrotic . ACCEPTED MANUSCRIPT, like programmed cell death However the extent to which such a programmed form of necrosis might.
contribute to focal ischemic damage is not currently known . 4 Mitochondrial function and ATP generation during cerebral ischemia and. reperfusion, Mitochondrial function in focal ischemia is altered as a direct consequence of the impaired delivery of. glucose and oxygen to the tissue and is further modified by changes in mitochondrial properties that. develop during ischemia or following reperfusion Limitations in the ability of cells to generate ATP can. exacerbate the cellular response to other insults and can greatly influence the cell death pathways that. develop Thus an understanding of the pattern of changes in cellular energy metabolism is essential to. fully elucidate the mechanisms leading to tissue damage in ischemia Furthermore because the. generation of ATP requires the integration of complex metabolic processes the characterization of. energy related metabolites and of the pathways involved in their production provides a useful indicator of. both the extent of preservation of essential cellular functions and the extent of cell damage or cell death in. the tissue ,4 1 Energy metabolism during ischemia, Table 1 summarizes alterations in the content of energy related metabolites and in the contributing. metabolic pathways in brain tissue during ischemia and following reperfusion An overview of the. relevant metabolic processes is provided in Figure 2 which further highlights the changes that develop in. penumbral tissue during the initial two to three hours of focal ischemia . 4 1 1 Core tissue , Within the severely ischemic core the large reductions in blood flow lead to impaired delivery of oxygen. and glucose and a mismatch between ATP use and production Glucose and ATP content falls markedly. during the first five minutes or so of arterial occlusion 33 ATP stabilizes at values approximately 15 to. 30 of those in non ischemic tissue for at least the first two hours of focal ischemia 33 36 The initial. rapid decrease in ATP content is associated with the major redistribution of ions across the plasma. ACCEPTED MANUSCRIPT, membrane of cells 10 11 and probably triggers this response 37 The adenylate energy charge ATP . 0 5 ADP ATP ADP AMP which measures the intracellular balance between ATP ADP and. AMP is also rapidly decreased and is maintained at values of approximately 0 4 to 0 5 during the initial. hours of focal ischemia much lower than values in normal brain of approximately 0 93 33 35 . Phosphocreatine in brain tissue provides a short term energy reserve allowing ATP to be regenerated. from ADP in a near equilibrium reaction catalysed by creatine kinase Phosphocreatine shows a similar. pattern of change to ATP rapidly falling to values less than 30 of normal 33 36 Limitations in the. availability of oxygen ensure that some of the glucose that does reach core tissue is metabolised via. glycolysis to lactate with an associated decrease in pH Lactate accumulates to values more than ten fold. that of non ischemic tissue 34 36 Reduced removal of the lactate because of the limited blood flow. probably also contributes to this increase ,4 1 2 Penumbral tissue.
A pattern of changes in energy metabolites similar to that in the ischemic core develops in the penumbral. tissue but the alterations are less severe Table 1 Figure 1 After two hours of ischemia . phosphocreatine is reduced to approximately 70 of non ischemic values and the adenylate energy. charge remains above 0 8 34 Larger decreases are seen in ATP with values approaching 50 of non . ischemic tissue at two hours of ischemia 34 Under ischemic conditions some of the ADP generated. from ATP hydrolysis is further metabolised to AMP and ATP 38 This reaction catalysed by adenylate. kinase normally helps to maintain ATP and meet short term energy demands in the brain In ischemic. tissue the AMP is further converted to inosine and hypoxanthine resulting in overall depletion of the. adenine nucleotide pool 38 The greater severity of the ATP loss compared with changes in other. energy related metabolites is to a large extent explained by this decrease in the total adenine nucleotide. Surprisingly glucose utilization in penumbral tissue as assessed from metabolism of deoxyglucose is. unchanged or even increased during the first two hours of ischemia 9 13 An increase in glucose. extraction from the blood helps to largely preserve the tissue glucose content 33 39 contributing to the. maintenance of glycolytic activity There is an increase in lactate within the penumbra to values many. ACCEPTED MANUSCRIPT, times higher than in normal brain but less than in the core regions 34 36 The accumulation of lactate. suggests that oxygen delivery is more severely restricted than that of glucose resulting in impaired. oxidative metabolism of pyruvate by the mitochondria Magnetic resonance spectroscopic analysis of. the products of isotopically labelled glucose provides support for this conclusion 40 41 In particular . these studies show reductions of more than 50 in the generation of isotopically labelled glutamate from. glucose This process which occurs predominantly in neurons 41 43 requires generation of pyruvate. via glycolysis metabolism of pyruvate to ketoglutarate via the tricarboxylic acid cycle and subsequent. conversion to glutamate Fig 2 Some caution is needed in interpreting these findings because of the. possible confounding effects of ischemia induced changes in the size of intermediate metabolite pools as. well as any moderate changes that may exist in delivery of the labelled precursors Nonetheless the. results strongly suggest markedly reduced oxidative metabolism of glucose in the penumbral tissue in. contrast to the preservation of glycolysis , The reduced oxidative metabolism in penumbral tissue means that there is unlikely to be reserve capacity. to deal with increases in energy requirements This conclusion is supported by comparisons of the. metabolic response to spreading depression like depolarizations that develop in the penumbra compared. with KCl induced spreading depression in normal brain 44 Similar proportional decreases in ATP and. phosphocreatine are induced by the advancing depolarization of the tissue in both situations However . the penumbral tissue shows much larger increases in lactate and a greatly reduced ability to restore the. ATP and phosphocreatine content These changes limit the capacity of the tissue to reverse changes. initiated by the redistribution of ions during the spreading depression increasing the likelihood of. deleterious consequences ,4 2 Energy metabolism following reperfusion. 4 2 1 Core tissue, The greatly impaired production of ATP the major redistribution of ions and derangement of other. metabolic properties in the ischemic core are incompatible with cell survival if they are not rapidly. reversed However the initial development of these changes within core tissue during the first five. minutes or so of arterial occlusion does not immediately produce irreversible cellular deterioration . ACCEPTED MANUSCRIPT, Restoration of blood flow during the first 30 to 60 minutes in rats and mice greatly limits the size of the.
infarcts that subsequently develop 16 17 and can completely block cell loss indicating that the. development of irreversible damage in neurons and other cells in the core tissue is delayed Even with. ischemic periods up to three hours which will ultimately lead to infarction there is often near complete. recovery of phosphocreatine to more than 90 of pre ischemic values and of the adenylate energy. charge or other measures of adenine nucleotide balance during the first two hours following reperfusion. 34 36 39 45 46 The recovery of these metabolic parameters requires the presence of intact and. functional cells that at least partially regain the complex metabolic activities and control processes. required to meet energy demands The concentration of ATP in core tissue recovers more slowly than. phosphocreatine or the adenylate energy charge following restoration of blood flow reaching 50 to 70 . of control values within the first hours This ongoing decrease in ATP is mostly due to the slow. resynthesis of the adenine nucleotide pool that was depleted during ischemia with lesser contributions. from an imbalance between ATP use and production , With further perfusion following longer ischemic periods that are sufficient to initiate infarct formation . the core tissue typically exhibits a secondary decline in energy related metabolites that is most likely. associated with final progression to the death of many cells 34 39 Such cell loss in the core tissue is. generally an inevitable consequence of ischemic periods lasting more than an hour but might not be. irreversibly determined in all parts of this tissue at the onset of reperfusion Large reductions in infarct. size exceeding 50 have been achieved with some treatments initiated early after reperfusion following. ischemic periods of at least two hours e g 47 50 Although the penumbra is the predominant site of. this protection the magnitude of the effects suggests that parts of the core tissue are also salvaged The. initial near complete restoration of energy metabolites on reperfusion is consistent with the possibility. that cells in parts of the core can still be rescued When temporary arterial occlusion exceeds three hours . reperfusion results in less complete restoration of energy metabolites and a more rapid onset of secondary. deterioration in the core regions indicating that many cells are much more severely compromised at the. time of reperfusion 39 , ACCEPTED MANUSCRIPT, The substantial restoration of the content of energy related metabolites is not an indication of comparable. recovery of the activity of energy generating metabolism At one hour of reperfusion following two. hours of ischemia in rats glucose utilization as assessed from deoxyglucose incorporation is reduced to. approximately 50 of normal values in tissue regions that formed the ischemic core 9 Furthermore . the lactate content remains many times higher than in normal tissue suggesting ongoing restrictions on the. oxidative metabolism of pyruvate 34 36 39 45 46 Consistent with these results the generation of. isotopically labelled glutamate from glucose is also markedly decreased 41 46 indicating greatly. reduced neuronal energy metabolism ,4 2 2 Penumbral tissue. Reperfusion in the penumbral tissue leads to complete or near complete recovery of phosphocreatine and. the adenine nucleotide balance within the first hour of reperfusion following ischemic periods lasting up. to three hours or even longer 34 39 45 46 The restoration of ATP content is less complete again. because of slow regeneration of the depleted adenine nucleotide pool A secondary disruption of energy. metabolites associated with gross disruption of cellular function typically occurs at six or more hours. after the initiation of reflow 39 The timing of these changes is broadly consistent with the finding in. human stroke that damage can be reduced and function improved if flow is restored within three hours. and perhaps after longer periods 8 18 , As in the core tissue the onset of reperfusion lead to reductions by approximately 40 in glucose use. assessed using deoxyglucose in the penumbra within the first hour a finding which contrasts with the. preservation of this activity during ischemia 9 Even larger reductions in the oxidative metabolism of. glucose develop in this tissue within the first hour of reperfusion as determined from the incorporation of. isotopic label from glucose into glutamate 41 46 Lactate is substantially decreased compared with the. large accumulations during ischemia However it usually remains significantly elevated following. ischemic insults of sufficient duration to generate infarcts encompassing the former penumbral tissue 34 . 46 but see also 36 41 consistent with ongoing restrictions in pyruvate oxidation Despite the size of. the reductions in oxidative glucose metabolism this change is not inevitably associated with the. ACCEPTED MANUSCRIPT, development of infarcts Similar metabolic decreases are also seen with shorter ischemic periods that.
generally do not result in infarcts within the reperfused penumbral tissue 46 . As indicated previously the isotopic labelling of glutamate from glucose primarily but not exclusively . reflects neuronal metabolism and provides one of only a few measures available to evaluate aspects of. metabolism selectively in this cell population 41 43 A selective measure of the oxidative metabolism. of astrocytes in the brain can also be obtained based on the incorporation of isotopic label from acetate to. glutamine 41 43 The selectivity results from the ability of glia but not neurons to take up acetate and. convert it to acetyl CoA 51 and from the almost exclusive localization of the enzyme catalysing. glutamine production glutamine synthetase in astrocytes 52 The production of isotopically labelled. glutamine from acetate is unchanged or even increased in the penumbra compared with normal tissue. during the first hour following reperfusion 41 53 This measure of metabolic activity continues to be. nearly fully preserved for at least four hours in reperfused penumbral tissue that is destined to become. infarcted 53 These results indicate that the majority of astrocytes remain viable in this tissue and. preserve important features of oxidative metabolism for extended periods following temporary ischemia . The finding of greatly reduced glucose conversion to glutamate but well preserved astrocytic acetate. metabolism could possibly indicate large differences in the functional preservation of astrocytes. compared with neurons during early reperfusion of penumbral tissue Alternatively the limitations on. glucose metabolism might be similar in the two cell populations but the decrease in glucose metabolism. results from the effects of cellular controls or other changes decreasing activity at steps prior to acetyl. CoA If so these restrictions on metabolism would be by passed by the use of acetate as the metabolic. precursor The latter explanation is supported by analyses using magnetic resonance spectroscopy of the. labelling patterns of individual carbons in glutamate and glutamine following injection of 13C glucose. 41 This approach allows a comparison of carbons entering the tricarboxylic acid cycle via the. anaplerotic reaction catalysed by pyruvate carboxylase which is specific to astrocytes and those entering. via pyruvate dehydrogenase which occurs in neurons and astrocytes The proportional contribution of. these two pathways is similar in reperfused penumbral tissue and in normal tissue 41 Thus glucose. metabolism is apparently similarly affected in both cell types following reperfusion of the penumbral. ACCEPTED MANUSCRIPT, The near complete restoration of phosphocreatine and the adenylate energy charge following reperfusion. in the penumbra despite marked decreases in activity of the relevant ATP generating metabolic pathways. from glucose implies that energy requiring functions are greatly reduced in the post ischemic brain This. could arise partly from decreases in neuronal activity that are induced during ischemia and persist for. long periods in post ischemic brain 54 55 A further likely major contributor to reductions in energy. use in post ischemic brain is the enzyme AMP activated protein kinase This kinase is activated by. many stimuli including ATP depletion and other changes produced by cerebral ischemia 56 It induces. multiple cellular alterations that reduce anabolic reactions and helps to restore energy balance The. activity of AMP activated protein kinase is increased by phosphorylation Long lasting increases in. phosphorylated AMP activated protein kinase are seen following reperfusion throughout the brain . including tissue from the ischemic penumbra non ischemic tissue and to a lesser extent core tissue 56 . 57 Interestingly inhibition of AMP activated kinase initiated at the time of occlusion or during early. reperfusion reduces infarct volume whereas an activator of this enzyme causes increased damage 57 58 . Protection is also seen in genetically modified mice that do not express the 2 isoform of AMP activated. protein kinase 58 Thus changes leading to activation of this enzyme are deleterious in post ischemic. brain even though they can be protective following a more mild insult . 4 3 Other mitochondrial changes during ischemia and reperfusion. The capacity of mitochondria for respiratory activity has been evaluated based on oxygen utilization in. preparations from brain tissue removed during focal ischemia and following reperfusion For samples. obtained during ischemia there is a progressive deterioration of the ability of the mitochondria to increase. activity of the electron transport chain in response to decreases in the proton gradient across the inner. mitochondrial membrane induced by the addition of ADP or an uncoupling agent 16 59 60 Basal. respiration is largely preserved By two hours of MCA occlusion in rats the ADP stimulated or. uncoupled respiration decreases by 45 to 60 in samples from core tissue Reductions of 15 to 40 are. seen in the penumbra This reduced respiratory capacity in the penumbral mitochondria could exacerbate. the effects of lower oxygen delivery and contribute to the decreases in oxidative metabolism in this.

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