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The Ischemic Cascade and Mediators of Ischemic Injury

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The Ischemic Cascade and Mediators of Ischemic Injury Handbook of Clinical Neurology, Vol. 92 (3rd series) Stroke, Part I M. Fisher, Editor # 2009 Elsevier B.V. All rights reserved Chapter 2 The ischemic cascade and mediators of ischemic injury MATTHIAS ENDRES 1 *, ULRICH DIRNAGL1, AND MICHAEL A. MOSKOWITZ 2 1Charite´-Universit atsmedizin€ Berlin, Berlin, Germany 2Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA Cerebr ovascula r disease ranks secon d as the cause of that cel l d eat h ev olve s in a tem po ral and sp ati al c onti - death worldwid e; morta lity over the first year after first nuu m ( Ast ru p et a l., 19 81 ). Al mo st im med iate ly aft er stroke is approx imately 20%. The econom ic and soci al vess el oc clus io n, an isc he mic core is d efi ne d th at is burde ns of stroke, however , are not conse quences of dest in ed to die irr e spec tiv e of ther a peu tic in ter ven - morta lity; they are impose d by the large major ity of tio ns u nles s b lood flo w is rapi d ly rest ore d. Su rro un d- stroke patients who survive but are physical ly and men - ing thi s core li es the pe numb ra, whi ch is fun cti on ally tally disable d by stroke- induced brain dam age ( Stroke sil ent b ut met abo li cal ly sti ll ac tiv e an d he nce sal va ge- Progr ess Rev iew Gr oup, 2002 ). able . Ear ly rep erf usio n is th e maj or tar g et of mos t Stroke is a heteroge neous disease and ref ers to an exp eri men tal int er vent io ns, to rend er cel ls in the pe n- umbrel la of condi tions. In the Wester n world, ischem ic umbr a resi sta n t to cel l d eat h. Im po rta ntl y, ho wev e r, stroke com prises 80–85% , whi le pri mary intrac erebral the pe numb ra is dy nam ic: ind eed , ov er ti me the ‘co re hem orrhages , subarachn oida l hem orrhages , and sinus grow s at the co st o f the pen umbr a ’ an d pre viou sly thromb osis accou nt for the remainin g 15–20% . By con- viab le b rai n be com es in far cte d ti ss ue ( Gi nsb erg et al. , trast , hemorrh agic stroke may com prise up to 50% of all 199 9) (F ig. 2 .1). strokes in Asia. Ischemic stroke is caused by a transi ent or permane nt reduc tion of blood flow restricted to the 2.2. Active cell death mechanisms territor y of a cerebra l artery—ty pically by emb olic or thromb otic occlusi on. In any case, ischem ic stroke Although the exact timing and cellular path ways are eventual ly resu lts in the death and dysfunct ion of brain incomplet ely under stood it is common ly believed that cells. Central to our current understandi ng of stroke mechanism s actively promot ing cel l deat h are trig- path ophysiol ogy is evidence derived from animal mod- gered after stroke ( Lo et al., 200 5). Ce ll death occur s els. Mimicking the condi tion of ischem ic str oke are by a necrotic path way charact erized by ischemic or mode ls of foca l cere bral ischem ia. Th e most frequent ly edematous cell changes, by an apopt otic path way with used species are rodents such as mice and rats bu t also a number of morphological (e.g., apoptotic bodies, bleb- othe r mamm als, includin g dogs, cat s, and sheep as well bing), biochemical (e.g., DNA laddering), pharma- as primates (Lo et al., 2003 ). cological, and molecular characteristics (e.g., activation of caspases), or by autophagocytosis. A number of dif- 2.1. Temporal and spatial events after stroke:ferent stages of the cell death process and major patho- the concept of an ischemic penumbra physiological pathways have emerged from the literature (Dirnagl et al., 1999; Lo et al., 2005). First Not all b rai n cel ls die im med iat e ly a fte r a n isc he mic comes an induction stage with energy failure, increase str o ke. Ev er sinc e Ast rup fir st int rod uce d the con cept of intracellular calcium, and release of excitatory of a n isc he mic p enu mbr a, i.e. a p eri les ion al area tha t amino acids (Lipton et al., 1999). This in turn triggers su rrou nds th e isc he mic core , it is g ene ral ly acc epte d the activation of downstream perpetrators of ischemic *Correspondence to: Priv.-Doz. Dr M. Endres, Klinik und Poliklinik fu¨r Neurologie, Charite´-Universita¨tsmedizin Berlin, Campus Mitte, Schumannstrasse. 20/21, D-10117 Berlin, Germany. E-mail: [email protected], Tel: þ49 .30. 450 .56 0. 257 , Fax: þ49.30.450.560.932. 32 M. ENDRES ET AL. Morphology Biochemistry Ionic failure Infarction Anoxic depolarization Glucose utilization ↓ Glutamate release CORE Glucose utilization A Protein synthesis ↓ Inflammation Acidosis and MBR Oxygen extraction Apoptosis U Selective gene expression PEN Fig. 2.1. The ischemic penumbra. A brain region of low perfusion in which cells have lost their membrane potential terminally (“core”) is surrounded by an area in which intermediate perfusion prevails (“penumbra”)(from Dirnagl et al., 1999). damage, including free radical and peroxynitrite pro- 2.3. Excitotoxicity, energy failure, and duction, calpain, phospholipases, and poly-ADP- ionic imbalance ribose polymerase activation. Concomitantly, apopto- tic pathways are initiated. Waves of peri-infarct Brain is one of the most metabolically active organs depolarization further compromise the energy balance and depends almost exclusively upon oxidative phos- of ischemic neurons in the penumbra. Inflammation phorylation for energy. It is exquisitely sensitive to then amplifies tissue damage. Secondary stages of disturbances in oxygen and glucose supply (Siesjo, cell death may involve long-term changes in macro- 1978; Hansen, 1985; Erenciska and Silver, 1989). Fol- molecules and other key metabolites. All these events lowing focal ischemia there is a profound deprivation are potential targets for therapeutic interventions of oxygen and glucose. Available evidence suggests (Fig. 2.2). that gray and white matter both suffer immediate loss Energy failure Peri-infarct depolarization Glu Glu Na+ K+ Depolari- Glu Ca2+ zation Glu K+ Glu + Na Cell Glu Glutamate swelling 2+ release Ca Mitochondrial damage Enzyme- induction DNA damage Free radicals Membrane NO Apoptosis degradation Inflammatory mediators Microglial Leukocyte activation infiltration Fig. 2.2. Simplified overview of pathophysiological mechanisms in the focally ischemic brain (from Dirnagl et al., 1999). THE ISCHEMIC CASCADE AND MEDIATORS OF ISCHEMIC INJURY 33 of function with anoxia (Stys et al., 1992). Within as robust as focal ischemia (Kondo et al., 1997; Fuji- minutes both neuronal and non-neuronal cells become mura et al., 1998, 1999). Mice overexpressing superox- depolarized (e.g., anoxic depolarization) and voltage- ide dismutase have reduced injury following focal dependent calcium channels are activated (Martin ischemia, giving support to the notion that interven- et al., 1994; Paschen, 2000). Depolarization also tions aimed at enhancing endogenous repair mechan- induces the release of (predominantly excitatory) neu- ism may be attractive therapeutic targets for ischemic rotransmitters from presynaptic terminals into the stroke (Kinouchi et al., 1991; Sheng et al., 1999). synaptic cleft (Zipfel et al., 1999). In particular, bind- In addition to reactive free oxygen species, nitrosa- ing of glutamate to ionotropic N-methyl-d-aspartate tive stress contributes to tissue damage. Nitric oxide (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoazole (NO) itself may play both beneficial and deleterious propionic acid (AMPA) receptors promotes excessive roles during brain ischemia depending upon when calcium influx. In turn, increased intracellular calcium and where it is produced. NO is synthesized from levels act as universal second and third messenger L-arginine by several isoforms of NO synthase (NOS; to trigger an array of downstream phospholipases i.e. NOS I, II, and III). In situations of increased oxida- and proteases that degrade membrane and proteins tive stress NO reacts with superoxide anions to gener- essential for cellular integrity (such as actin, spectrin, ate the highly reactive and cytotoxic peroxynitrite, laminin, etc.; Chen et al., 1998; Furukawa et al., which may damage virtually every cellular component 1997; Endres et al., 1999). Calcium ions and other ions (Beckman and Koppenol, 1997; Iadecola, 1997). Dur- also enter mitochondria through the mitochondrial per- ing ischemia constitutive, calcium-dependent neuronal meability transition pore, causing dysfunction and type I NOS (nNOS) may be activated via calcium mitochondrial swelling. Moreover, sodium and chlor- influx. Within minutes after induction of focal cerebral ide enter neurons via channels for monovalent ions ischemia cortical NO levels may rise from 10 nmol/L (e.g., the AMPA receptor) passively followed by to 2 mmol/L (Dalkara and Moskowitz, 1994). In addi- water. The ensuing intracellular (‘cytotoxic’) edema tion, inducible (type II) NOS (iNOS), which is cal- may negatively impact perfusion in the peri-infarct cium/calmodulin-independent and is not normally region. Imbalances of other ions are also important: present in healthy brain tissue, is induced after brain for example, large amounts of zinc that are stored in ischemia in non-neuronal cells such as microglia and vesicles of excitatory neurons become released upon leukocytes, but also astrocytes and endothelial cells.
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