Biology of ischemic cerebral cell death
Identifieur interne : 002382 ( Istex/Corpus ); précédent : 002381; suivant : 002383Biology of ischemic cerebral cell death
Auteurs : Daniel L. Small ; Paul Morley ; Alastair M. BuchanSource :
- Progress in Cardiovascular Diseases [ 0033-0620 ] ; 1999.
Abstract
With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 185-207
Url:
DOI: 10.1016/S0033-0620(99)70002-2
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Small</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author><author><name sortKey="Morley, Paul" sort="Morley, Paul" uniqKey="Morley P" first="Paul" last="Morley">Paul Morley</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author><author><name sortKey="Buchan, Alastair M" sort="Buchan, Alastair M" uniqKey="Buchan A" first="Alastair M." last="Buchan">Alastair M. Buchan</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:B48DF05771726B4024DF8B7FF69521CDBEC43EF3</idno><date when="1999" year="1999">1999</date><idno type="doi">10.1016/S0033-0620(99)70002-2</idno><idno type="url">https://api-v5.istex.fr/document/B48DF05771726B4024DF8B7FF69521CDBEC43EF3/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">002382</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002382</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Biology of ischemic cerebral cell death</title><author><name sortKey="Small, Daniel L" sort="Small, Daniel L" uniqKey="Small D" first="Daniel L." last="Small">Daniel L. Small</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author><author><name sortKey="Morley, Paul" sort="Morley, Paul" uniqKey="Morley P" first="Paul" last="Morley">Paul Morley</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author><author><name sortKey="Buchan, Alastair M" sort="Buchan, Alastair M" uniqKey="Buchan A" first="Alastair M." last="Buchan">Alastair M. Buchan</name><affiliation><mods:affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Progress in Cardiovascular Diseases</title><title level="j" type="abbrev">YPCAD</title><idno type="ISSN">0033-0620</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">42</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="185">185</biblScope><biblScope unit="page" to="207">207</biblScope></imprint><idno type="ISSN">0033-0620</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0033-0620</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 185-207</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Daniel L. 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Buchan</name><affiliations><json:string>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</json:string></affiliations></json:item></author><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. 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Saunders Company</p></availability><date>1999</date></publicationStmt><notesStmt><note>Address reprint requests to Daniel L. Small, PhD, Institute for Biological Sciences, National Research Council of Canada, Building M-54, Montreal Road, Ottawa, Ontario, Canada K1A 0R6; email: Dan.Small@nrc.ca.</note><note type="content">Section title: Cerebrovascular Disease</note><note type="content">TABLE 1: Molecular Biology of Glutamate Receptors</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Biology of ischemic cerebral cell death</title><author xml:id="author-0000"><persName><forename type="first">Daniel L.</forename><surname>Small</surname></persName><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Paul</forename><surname>Morley</surname></persName><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Alastair M.</forename><surname>Buchan</surname></persName><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation></author><idno type="istex">B48DF05771726B4024DF8B7FF69521CDBEC43EF3</idno><idno type="DOI">10.1016/S0033-0620(99)70002-2</idno><idno type="PII">S0033-0620(99)70002-2</idno></analytic><monogr><title level="j">Progress in Cardiovascular Diseases</title><title level="j" type="abbrev">YPCAD</title><idno type="pISSN">0033-0620</idno><idno type="PII">S0033-0620(05)X7016-5</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999"></date><biblScope unit="volume">42</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="185">185</biblScope><biblScope unit="page" to="207">207</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1999</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 185-207</p></abstract></profileDesc><revisionDesc><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/B48DF05771726B4024DF8B7FF69521CDBEC43EF3/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier doc found" wicri:toSee="Elsevier, no converted or simple article"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 5.0.1//EN//XML" URI="art501.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity></istex:docType><istex:document><article docsubtype="fla" xml:lang="en"><item-info><jid>YPCAD</jid><aid>042018</aid><ce:pii>S0033-0620(99)70002-2</ce:pii><ce:doi>10.1016/S0033-0620(99)70002-2</ce:doi><ce:copyright type="full-transfer" year="1999">W.B. Saunders Company</ce:copyright></item-info><ce:floats><ce:table id="tab1" colsep="0" rowsep="0" frame="topbot"><ce:label>TABLE 1</ce:label><ce:caption><ce:simple-para>Molecular Biology of Glutamate Receptors</ce:simple-para></ce:caption><tgroup cols="6"><colspec colname="col1" colsep="0"></colspec><colspec colname="col2" colsep="0"></colspec><colspec colname="col3" colsep="0"></colspec><colspec colname="col4" colsep="0"></colspec><colspec colname="col5" colsep="0"></colspec><colspec colname="col6" colsep="0"></colspec><thead><row rowsep="1"><entry namest="col1" nameend="col3" align="center">Ionotropic</entry><entry namest="col4" nameend="col6" align="center">Metabotropic</entry></row><row rowsep="1"><entry>NMDA</entry><entry align="center">AMPA<ce:sup>flip/flop</ce:sup></entry><entry align="center">KA</entry><entry align="center">Group I</entry><entry align="center">Group II</entry><entry align="center">Group III</entry></row></thead><tbody><row><entry>NR1<ce:inf>XXX</ce:inf></entry><entry align="center">GluR1</entry><entry align="center">KA1</entry><entry align="center">mGluR1<ce:inf>a-e</ce:inf></entry><entry align="center">mGluR2</entry><entry align="center">mGluR4<ce:inf>a,b</ce:inf></entry></row><row><entry>NR3*</entry><entry align="center">GluR2<ce:sup>R/G,Q/R</ce:sup></entry><entry align="center">KA2</entry><entry align="center">mGluR5<ce:inf>a,b</ce:inf></entry><entry align="center">mGluR3</entry><entry align="center">mGluR6</entry></row><row><entry></entry><entry align="center">GluR3<ce:sup>R/G</ce:sup></entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry><entry align="center">mGluR7<ce:inf>a,b</ce:inf></entry></row><row><entry>NR2A</entry><entry align="center">GluR4<ce:sup>R/G</ce:sup></entry><entry align="center">GluR5<ce:sup>Q/R</ce:sup></entry><entry align="center"></entry><entry align="center"></entry><entry align="center">mGluR8</entry></row><row><entry>NR2B</entry><entry align="center"></entry><entry align="center">GluR6<ce:sup>Q/R,I/V,Y/C</ce:sup></entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry></row><row><entry>NR2C</entry><entry align="center"></entry><entry align="center">GluR7</entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry></row><row><entry>NR2D</entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry><entry align="center"></entry></row><row><entry namest="col1" nameend="col6">*NR3A previously known as NR-L and X1.</entry></row></tbody></tgroup><ce:legend><ce:simple-para>Note: Subscripts and superscripts denote splice variants.</ce:simple-para></ce:legend></ce:table></ce:floats><head><ce:article-footnote><ce:label>☆</ce:label><ce:note-para>Address reprint requests to Daniel L. Small, PhD, Institute for Biological Sciences, National Research Council of Canada, Building M-54, Montreal Road, Ottawa, Ontario, Canada K1A 0R6; email: <ce:inter-ref xlink:href="mailto:dan.small@nrc.ca">Dan.Small@nrc.ca.</ce:inter-ref></ce:note-para></ce:article-footnote><ce:dochead><ce:textfn>Cerebrovascular Disease</ce:textfn></ce:dochead><ce:title>Biology of ischemic cerebral cell death</ce:title><ce:author-group><ce:author><ce:given-name>Daniel L.</ce:given-name><ce:surname>Small</ce:surname></ce:author><ce:author><ce:given-name>Paul</ce:given-name><ce:surname>Morley</ce:surname></ce:author><ce:author><ce:given-name>Alastair M.</ce:given-name><ce:surname>Buchan</ce:surname></ce:author><ce:affiliation><ce:textfn>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</ce:textfn></ce:affiliation></ce:author-group><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K<ce:sup>+</ce:sup>, Na<ce:sup>+</ce:sup>, and Ca<ce:sup>2+</ce:sup> channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca<ce:sup>2+</ce:sup> dynamics, Ca<ce:sup>2+</ce:sup>-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. Saunders Company</ce:simple-para><ce:simple-para>Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 185-207</ce:simple-para></ce:abstract-sec></ce:abstract></head><body><ce:sections><ce:para>February 17, 1999 marks a turning point for the treatment of stroke in Canada. Almost 3 years after the American Food and Drug Administration approved the clot-dissolving drug, tissue plasminogen activator, alteplase (tPA) (brand name Activase; Genentech, San Francisco, CA), for use in the treatment of ischemic stroke, Health Canada has followed suit with approval in Canada. tPA is not a panacea for cerebrovascular disease but for the lucky handful of people with an ischemic stroke (85%) who are seen and diagnosed with a computed tomography (CT) scan within the critical 3 hour window after symptom onset, there is now hope. Because a recent Canadian study reported the median time to examination was 9.7 hours from arrival at hospital,<ce:cross-ref refid="bib1"><ce:sup>1</ce:sup></ce:cross-ref> and that in most community hospitals neither neurological consultation nor CT scanning are readily available, it is unlikely that tPA will be a viable therapy for stroke for some time, at least not until the current state of stroke care is radically overhauled. This underscores the importance of further research of the basic mechanisms underlying neuronal damage in the wake of an ischemic episode. It is tempting to speculate that the future of stroke treatment lies in combination therapy with agents targeting an early restoration of blood flow followed by attempts to halt or reverse the cascade of neuronal damage and then subsequently enhancing the regenerative and trophic abilities of the infarcted area.</ce:para><ce:para>As tools to help better understand the pathophysiological mechanisms underlying stroke in man, animal models of stroke have been developed that can be grouped into 2 main types; global and focal ischemia. In global ischemia models the lack of blood flow is transient (5-30 min) but complete or nearly complete (<5% of normal in cortex) during this time.<ce:cross-ref refid="bib2"><ce:sup>2</ce:sup></ce:cross-ref> If blood flow is not restored within 30 minutes, widespread pannecrosis ensues and there is no functional recovery of the tissue. After reperfusion within 30 minutes there is selective neuronal death of pyramidal neurons in the CA1 region of the hippocampus and in layers 3, 5, and 6 of the neocortex as well as cerebellar Purkinje neurons and medium-sized striatal neurons.<ce:cross-ref refid="bib3"><ce:sup>3</ce:sup></ce:cross-ref> The sensitivity of these neurons to ischemia differs between brain regions as does the time course of cell death. CA1 pyramidal neurons are more sensitive to ischemia than striatal neurons but after a severe global ischemic insult (30 min) the more resistant striatal neurons begin to die after just 3 to 12 hours of reperfusion whereas the more sensitive CA1 neurons remain viable for 2 to 3 days before succumbing to the insult.<ce:cross-ref refid="bib3"><ce:sup>3</ce:sup></ce:cross-ref> This model most closely represents the clinical situation of a cardiac arrest or near drowning. Although this situation represents a very small proportion of clinical strokes, the basic mechanisms underlying the pathophysiology of the animal model correlate well with what is known about those underlying clinical strokes.</ce:para><ce:para>The focal models are a closer representation of the clinical situation in which there is a localized, more prolonged (60-90 min) ischemic period resulting from the occlusion of an individual cerebral blood vessel. The resulting blood flow pattern is more complex and is not as severe as in the global model of ischemia. There is a central core region, closest to the occluded vessel, which results in immediate pannecrosis if reperfusion is not reestablished within 60 minutes of the occlusion. Surrounding the edge of the core is a region referred to as the penumbra, which is hypoperfused and is at risk of dying but can be salvaged with increased perfusion and/or pharmacological intervention. If no intervention occurs, the tissue at risk will begin to die within 3 to 4 hours of reperfusion. This cell loss is restricted to neurons; glial cells do not die. If the occlusion is extended beyond 60 minutes the penumbra evolves to become core and spreads outward with time.</ce:para><ce:para>Because it is not the purpose of this article to review animal models of cerebral ischemia we refer the reader to excellent reviews on the subject for details of these models including differences between 4- and 2-vessel occlusion models of global ischemia, and differences between transient and permanent occlusions in focal models using threads, clips, sutures or embolic clots.<ce:cross-refs refid="bib2 bib4 bib5 bib6 bib7"><ce:sup>2,4-7</ce:sup></ce:cross-refs> Recently, mouse models of cerebral ischemia have been developed to take advantage of genetically altered animals.</ce:para><ce:section><ce:section-title>The excitotoxicity theory</ce:section-title><ce:para>Within seconds of the onset of ischemia, the decline in blood flow and the accompanying loss of oxygen supply result in a reduction of high-energy metabolites such as adenosine triphosphate (ATP) and phosphocreatine.<ce:cross-refs refid="bib8 bib9 bib10"><ce:sup>8-10</ce:sup></ce:cross-refs> The combination of ATP breakdown and compensatory activation of anaerobic glycolysis during ischemia leads to an increase in the levels of inorganic phosphate, lactate, and H<ce:sup>+</ce:sup> formation causing cellular acidification. The depletion of neuronal ATP also leads to a loss of cellular Na<ce:sup>+</ce:sup> gradients which are normally maintained by the ATP-dependent membrane Na<ce:sup>+</ce:sup>-K<ce:sup>+</ce:sup> pump.<ce:cross-ref refid="bib8"><ce:sup>8</ce:sup></ce:cross-ref> The resulting depolarization triggers Ca<ce:sup>2+</ce:sup> influx through voltage-sensitive Ca<ce:sup>2+</ce:sup> channels that further depolarizes the membrane and stimulates the release of massive amounts of the excitatory neurotransmitter glutamate into the extracellular space.<ce:cross-refs refid="bib9 bib10 bib11"><ce:sup>9-11</ce:sup></ce:cross-refs> Neurons are normally exposed to brief pulses of glutamate because excess extracellular glutamate is actively returned to presynaptic terminals and glial cells.<ce:cross-ref refid="bib9"><ce:sup>9</ce:sup></ce:cross-ref> During ischemia, however, the energy-dependent mechanisms responsible for glutamate re-uptake are impaired, hence extracellular glutamate levels can approach 100 μM.<ce:cross-ref refid="bib12"><ce:sup>12</ce:sup></ce:cross-ref> This elevation of extracellular glutamate causes a prolonged and excessive activation of membrane glutamate receptors, further stimulating Ca<ce:sup>2+</ce:sup> influx (Fig 1).<ce:cross-ref refid="bib9"><ce:sup>9</ce:sup></ce:cross-ref><ce:display><ce:figure id="fig1"><ce:label>Fig. 1</ce:label><ce:caption><ce:simple-para>Schematic illustration of cell surface mediators of excitotoxicity cascade.</ce:simple-para></ce:caption> <ce:link locator="gr1"></ce:link></ce:figure></ce:display>Even ambient glutamate concentrations may be neurotoxic in energy-deprived cells.<ce:cross-ref refid="bib13"><ce:sup>13</ce:sup></ce:cross-ref> Glutamate induces further Ca<ce:sup>2+</ce:sup> influx through the activation of Ca<ce:sup>2+</ce:sup> channels secondary to the transmitter-evoked depolarization of the membrane.<ce:cross-ref refid="bib9"><ce:sup>9</ce:sup></ce:cross-ref> These events all occur during ischemia and in the very early period of reperfusion. Extracellular glutamate levels return to normal shortly after reperfusion has been initiated.<ce:cross-ref refid="bib14"><ce:sup>14</ce:sup></ce:cross-ref> Then, in the hours to days after ischemia, there is a disruption of Ca<ce:sup>2+</ce:sup> homeostasis that leads to the activation of a series of Ca<ce:sup>2+</ce:sup>-dependent processes, activation of kinases, induction of immediate early genes, and mitochondrial dysfunction (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>), all of which culminate in secondary injury and eventually cell death.</ce:para></ce:section><ce:section><ce:section-title>Mechanisms of cell death</ce:section-title><ce:para>The mechanisms of ischemic neuronal death have not been fully defined and the relative contribution of apoptotic and necrotic processes remains controversial.<ce:cross-ref refid="bib15"><ce:sup>15</ce:sup></ce:cross-ref> Necrotic cell death is characterized by cell swelling, membrane disruption, and random DNA breaks, whereas apoptotic death involves chromatin condensation, internucleosomal DNA fragmentation, blebbing of the plasma membrane, and the appearance of apoptotic bodies.<ce:cross-ref refid="bib16"><ce:sup>16</ce:sup></ce:cross-ref> Rapid neuronal death after ischemia, such as occurs in the ischemic core, is necrotic, whereas delayed neuronal death in the penumbral region may be apoptotic. Some of the hallmarks of apoptotic death, like DNA fragmentation<ce:cross-refs refid="bib17 bib18"><ce:sup>17,18</ce:sup></ce:cross-refs> and apoptotic bodies<ce:cross-ref refid="bib19"><ce:sup>19</ce:sup></ce:cross-ref> have been reported in ischemic neurons, however most neuronal death does not show classical apoptotic morphology. The conventional categorization of all cell death as being either apoptotic or necrotic may not be appropriate for ischemic cell death. Instead, it may involve a molecular and biochemical hybrid along the apoptosis-necrosis continuum.<ce:cross-ref refid="bib15"><ce:sup>15</ce:sup></ce:cross-ref></ce:para><ce:para>Several genes that promote apoptosis have been identified including p53, myc, bax, bcl-x<ce:inf>L</ce:inf>, bcl-x<ce:inf>s</ce:inf> and mcl-1 as well as genes such as bcl-2 and p35, which prevent apoptosis.<ce:cross-ref refid="bib20"><ce:sup>20</ce:sup></ce:cross-ref> These genes may also be involved in neuronal death after cerebral ischemia. For example, p53 and myc levels are elevated and bcl-2 levels are reduced after ischemia.<ce:cross-refs refid="bib21 bib22 bib23 bib24"><ce:sup>21-24</ce:sup></ce:cross-refs> p53 knockout mice show reduced damage in response to focal insults<ce:cross-ref refid="bib23"><ce:sup>23</ce:sup></ce:cross-ref> whereas transgenic mice overexpressing bcl-2 were resistant to ischemic damage in focal and global models.<ce:cross-refs refid="bib25 bib26"><ce:sup>25,26</ce:sup></ce:cross-refs></ce:para><ce:para>The signalling pathways contributing to ischemic neuronal death will be discussed later based on the cellular localization of the events, ie, cell surface, intracellular, or intercellular. Cell surface signalling events include the activities of both voltage- and ligand-gated ion channels including K<ce:sup>+</ce:sup>, Na<ce:sup>+</ce:sup>, and Ca<ce:sup>2+</ce:sup> channels, ionotropic and metabotropic glutamate and gamma-aminobutyric acid (GABA) receptors, and adenosine receptors. All of these cell surface receptors contribute to the pathophysiology of ischemic cell death.</ce:para></ce:section><ce:section><ce:section-title>Cell surface signalling</ce:section-title><ce:para>Neuronal excitability is the result of an imbalance of ions across a cell's membrane. During ischemia this imbalance is disrupted and the altered Ca<ce:sup>2+</ce:sup> homeostasis mediates an excitotoxic cascade culminating over hours to days. The cascade of events leading to this death can be divided into 3 stages.<ce:cross-refs refid="bib27 bib28"><ce:sup>27,28</ce:sup></ce:cross-refs> The initial stage is the ischemic period itself (5-30 min for global and 60-90 min for focal) during which ionic gradients collapse. Much is known about the nature of the metabolic failure, however, the only neuroprotective strategy available at this time is to restore perfusion with tPA. The second stage is the reperfusion period in which there is a recovery of the cell's energy state, ion homeostasis, and basic physiological functions. The second stage lasts for hours to days and is the time for neuroprotective strategies designed to prevent the death of postischemic neurons. Finally, there is the third stage in which there is another energy failure accompanied, eventually, by cell death. Because it is too late to affect protection at this stage, trophic responses in which regenerative capacities can be enhanced are the best therapeutic approach.</ce:para><ce:section><ce:section-title>Potassium channels</ce:section-title><ce:para>K<ce:sup>+</ce:sup> channels are a major contributor to a cell's resting potential and their activation helps to maintain a hyperpolarized resting membrane potential. It should not be surprising, then, that K<ce:sup>+</ce:sup> efflux occurs much sooner after the onset of ischemia than either the Na<ce:sup>+</ce:sup> or Ca<ce:sup>2+</ce:sup> influx, which does not occur until ATP levels have fallen by more than 50%.<ce:cross-ref refid="bib28"><ce:sup>28</ce:sup></ce:cross-ref> There are a number of different types of K<ce:sup>+</ce:sup> channels. The metabolic nature of an ischemic insult suggests that ATP-sensitive K<ce:sup>+</ce:sup> channels, which are activated by a decrease in ATP, would be one of the first channels to respond during ischemia. In hypoxic rats, the early K<ce:sup>+</ce:sup> efflux in the dorsal hippocampus could be blocked by pretreatment with 4-aminopyridine (4-AP) a blocker of voltage-activated K<ce:sup>+</ce:sup> channels found predominantly in the dendritic portion of hippocampal pyramidal neurons.<ce:cross-ref refid="bib29"><ce:sup>29</ce:sup></ce:cross-ref> At later times after ischemia, other K<ce:sup>+</ce:sup> channels are activated including the Ca<ce:sup>2+</ce:sup>-activated K<ce:sup>+</ce:sup> channels,<ce:cross-ref refid="bib30"><ce:sup>30</ce:sup></ce:cross-ref> activated by an increase in intracellular Ca<ce:sup>2+</ce:sup> and the ATP-sensitive K<ce:sup>+</ce:sup> channels.<ce:cross-refs refid="bib31 bib32 bib33"><ce:sup>31-33</ce:sup></ce:cross-refs> Astrocytes attempt to buffer this increase in [K<ce:sup>+</ce:sup>]<ce:inf>e</ce:inf>. They switch to anaerobic glycolysis and swell 5 to 10 times their normal size. Eventually, astrocytes are no longer able to cope with the increase in [K<ce:sup>+</ce:sup>]<ce:inf>e</ce:inf> and they lyse.<ce:cross-ref refid="bib28"><ce:sup>28</ce:sup></ce:cross-ref> These events all occur during the first stage of ischemia. There is little known regarding the behavior or expression of K<ce:sup>+</ce:sup> channels in the second stage but given their role in in vitro neuronal apoptosis,<ce:cross-ref refid="bib34"><ce:sup>34</ce:sup></ce:cross-ref> a closer examination of these channels is warranted. The development of therapeutic agents targeting K<ce:sup>+</ce:sup> channels in the brain will not be easy. Specificity will be a problem because K<ce:sup>+</ce:sup> channels are ubiquitously expressed throughout the body.</ce:para></ce:section><ce:section><ce:section-title>Sodium channels</ce:section-title><ce:para>Na<ce:sup>+</ce:sup> channels also play an important role in neuronal excitability and they are as widely expressed as K<ce:sup>+</ce:sup> channels. While Na<ce:sup>+</ce:sup> channels have received little attention by those studying ischemia in gray matter, they have been extensively studied in ischemic white matter.<ce:cross-refs refid="bib35 bib36"><ce:sup>35,36</ce:sup></ce:cross-refs> Because of the differences in the mechanisms underlying excitation in white matter, it would be surprising if the mechanisms of ischemic death were the same in white matter and gray matter. In cerebral ischemia there is a pronounced Na<ce:sup>+</ce:sup> influx at the end of the first stage of ischemia (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>). This is coincident with the Ca<ce:sup>2+</ce:sup> influx and the anoxic depolarization associated with energy failure. Although problems of specificity exist for therapeutic agents targeting Na<ce:sup>+</ce:sup> channels, there is evidence using local anesthetics that suggests inhibition of Na<ce:sup>+</ce:sup> channels is neuroprotective. The Na<ce:sup>+</ce:sup> channel blocker, tetrodotoxin (TTX), markedly delayed anoxic depolarization and extracellular acidosis in an isolated perfused rat brain<ce:cross-ref refid="bib37"><ce:sup>37</ce:sup></ce:cross-ref> and improved the recovery of evoked population spikes in anoxic rat hippocampal slices.<ce:cross-ref refid="bib38"><ce:sup>38</ce:sup></ce:cross-ref> TTX and the local anesthetics (lidocaine and procaine) are not clinically useful because of their systemic toxicity.<ce:cross-ref refid="bib39"><ce:sup>39</ce:sup></ce:cross-ref> Some anticonvulsants that inhibit Na<ce:sup>+</ce:sup> channels are neuroprotective <ce:italic>in vivo</ce:italic>. Lamotrigine and its derivatives BW1003C87 and BW619C89 are protective in models of focal<ce:cross-refs refid="bib40 bib41 bib42"><ce:sup>40-42</ce:sup></ce:cross-refs> and global<ce:cross-refs refid="bib43 bib44 bib45"><ce:sup>43-45</ce:sup></ce:cross-refs> ischemia. Similarly, the Na<ce:sup>+</ce:sup> channel blockers riluzole and its derivative RP66055 are also protective in both focal<ce:cross-refs refid="bib46 bib47 bib48"><ce:sup>46-48</ce:sup></ce:cross-refs> and global<ce:cross-ref refid="bib49"><ce:sup>49</ce:sup></ce:cross-ref> models of cerebral ischemia. The role of Na<ce:sup>+</ce:sup> channels in cerebral ischemic death should not be over emphasized because the agents mentioned previously are not selective. Riluzole antagonizes N-methyl-D-aspartate (NMDA) receptors<ce:cross-ref refid="bib50"><ce:sup>50</ce:sup></ce:cross-ref> and lamotrigine and its derivatives inhibit Ca<ce:sup>2+</ce:sup> channels.<ce:cross-ref refid="bib51"><ce:sup>51</ce:sup></ce:cross-ref> Furthermore, many of the Na<ce:sup>+</ce:sup> channel antagonists exhibit severe cardiovascular effects that eliminate them as therapeutic agents for the treatment of stroke.<ce:cross-ref refid="bib52"><ce:sup>52</ce:sup></ce:cross-ref></ce:para></ce:section><ce:section><ce:section-title>Calcium channels</ce:section-title><ce:para>Ca<ce:sup>2+</ce:sup> channels have received a lot of attention in studies of cerebral ischemia because Ca<ce:sup>2+</ce:sup> influx and the disruption of Ca<ce:sup>2+</ce:sup> homeostasis play an important role in ischemic cell death (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>). In addition to the Ca<ce:sup>2+</ce:sup> influx through voltage-gated Ca<ce:sup>2+</ce:sup> channels, a much larger portion of the influx occurs through ligand-gated ion channels.</ce:para><ce:para>Of the voltage-gated Ca<ce:sup>2+</ce:sup> channels there are primarily 5 types, L, T, N, R, and P/Q, which are defined by their subunit molecular biology and pharmacology.<ce:cross-refs refid="bib53 bib54 bib55"><ce:sup>53-55</ce:sup></ce:cross-refs> The L-type are represented by the α<ce:inf>1</ce:inf> gene products C, D, and S and are blocked specifically by dihydropyridines, phenylalkylamines, and benzothiazepines.<ce:cross-ref refid="bib56"><ce:sup>56</ce:sup></ce:cross-ref> The T-type has recently been cloned and is composed of the α<ce:inf>1</ce:inf> gene products G and H and they are blocked by Ni<ce:sup>2+</ce:sup> and mibefradil.<ce:cross-refs refid="bib57 bib58"><ce:sup>57,58</ce:sup></ce:cross-refs> The R-type is represented by the α<ce:inf>1</ce:inf> gene product E and like the T-type is blocked by Ni<ce:sup>2+</ce:sup>.<ce:cross-refs refid="bib54 bib55"><ce:sup>54,55</ce:sup></ce:cross-refs> The N-type is represented by the α<ce:inf>1</ce:inf> gene product B and is blocked specifically by conotoxins from marine snails.<ce:cross-refs refid="bib53 bib54 bib55"><ce:sup>53-55</ce:sup></ce:cross-refs> The P- and Q-types are represented by the α<ce:inf>1</ce:inf> gene product A and are blocked by conotoxin MVIIC and agatoxin from the venom of the funnel web spider.<ce:cross-refs refid="bib53 bib54 bib55"><ce:sup>53-55</ce:sup></ce:cross-refs> N-, P-, and Q-type channels are primarily involved in neurotransmitter release.<ce:cross-ref refid="bib59"><ce:sup>59</ce:sup></ce:cross-ref> L-type channels are thought to activate gene responses<ce:cross-ref refid="bib60"><ce:sup>60</ce:sup></ce:cross-ref> because they are located mainly on the cell bodies of neurons and to a lesser degree on dendrites.<ce:cross-ref refid="bib61"><ce:sup>61</ce:sup></ce:cross-ref> Much of the insight on the role of the various Ca<ce:sup>2+</ce:sup> channel subtypes in ischemic neuronal injury comes from studies using pharmacological agents.</ce:para><ce:para>Dihydropyridines have been used with limited success in animal models of cerebral ischemia. Nimodipine, chosen for its high blood brain barrier permeability, is neuroprotective in some models of focal<ce:cross-refs refid="bib62 bib63 bib64"><ce:sup>62-64</ce:sup></ce:cross-refs> and global<ce:cross-ref refid="bib65"><ce:sup>65</ce:sup></ce:cross-ref> ischemia but isradipine<ce:cross-ref refid="bib66"><ce:sup>66</ce:sup></ce:cross-ref> and AT-227<ce:cross-ref refid="bib67"><ce:sup>67</ce:sup></ce:cross-ref> failed to reduce lesion volume in focal models of ischemia. Ca<ce:sup>2+</ce:sup> channel antagonists SB201823 and SB206284 are neuroprotective in both focal and global models of ischemia<ce:cross-refs refid="bib68 bib69 bib70 bib71"><ce:sup>68-71</ce:sup></ce:cross-refs> but are not specific for any one type of Ca<ce:sup>2+</ce:sup> channel.<ce:cross-ref refid="bib18"><ce:sup>18</ce:sup></ce:cross-ref> Although the systemic cardiovascular effects and poor blood brain barrier permeability of many of the L-type Ca<ce:sup>2+</ce:sup> channel blockers<ce:cross-ref refid="bib72"><ce:sup>72</ce:sup></ce:cross-ref> has precluded their being successful in animal models of cerebral ischemia, increased [<ce:sup>3</ce:sup>H]-nimodipine binding associated with regions of severe blood flow reductions in focal<ce:cross-ref refid="bib73"><ce:sup>73</ce:sup></ce:cross-ref> and global ischemia<ce:cross-ref refid="bib74"><ce:sup>74</ce:sup></ce:cross-ref> provide evidence supporting a role for L-type Ca<ce:sup>2+</ce:sup> channels in cerebral ischemia. Several clinical trials using Ca<ce:sup>2+</ce:sup> channel antagonists have shown no neuroprotective efficacy.<ce:cross-ref refid="bib75"><ce:sup>75</ce:sup></ce:cross-ref></ce:para><ce:para>Because of the importance of glutamate in ischemia, the Ca<ce:sup>2+</ce:sup> channels involved in glutamate release provide an attractive therapeutic target. The conotoxin, SNX-111, which specifically blocks N-type channels, is neuroprotective in both focal<ce:cross-refs refid="bib76 bib77 bib78"><ce:sup>76-78</ce:sup></ce:cross-refs> and global<ce:cross-refs refid="bib76 bib79 bib80"><ce:sup>76,79,80</ce:sup></ce:cross-refs> models of ischemia. Antagonists of Q-type (SNX-230), and P-type (daurisoline), Ca<ce:sup>2+</ce:sup> channels failed to provide neuroprotection against ischemia.<ce:cross-refs refid="bib79 bib81"><ce:sup>79,81</ce:sup></ce:cross-refs> Although the efficacy of SNX-111 was impressive in animal models, this efficacy was not translated into success in clinical trials for the treatment of stroke. As with K<ce:sup>+</ce:sup> and Na<ce:sup>+</ce:sup> channel antagonists, agents targeting voltage-gated Ca<ce:sup>2+</ce:sup> channels will be faced with the problem of specificity because of the ubiquitous expression of these channels.</ce:para></ce:section></ce:section><ce:section><ce:section-title>Ligand-gated receptors/channels</ce:section-title><ce:section><ce:section-title>Ionotropic glutamate receptors</ce:section-title><ce:para>Glutamate is the principle mediator of ischemic neuronal damage and, as such, has been the focus of much attention in efforts to understand the pathophysiology of cerebral ischemia. Glutamate acts on both ionotropic and metabotropic receptors. The ionotropic receptors are ligand-gated ion channels and the metabotropic receptors are linked via G-proteins to the cAMP and IP<ce:inf>3</ce:inf> second messenger systems. The ionotropic receptors are further subdivided into 3 types based on their pharmacology: NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA). Of these types there exist several more subtypes based on structural/functional classifications (Table 1). <ce:float-anchor refid="tab1"></ce:float-anchor>Glutamate receptors are activated during ischemia when glutamate levels rise several-fold (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>).<ce:cross-ref refid="bib12"><ce:sup>12</ce:sup></ce:cross-ref> Despite the fact that glutamate levels return to normal shortly after reperfusion is initiated,<ce:cross-ref refid="bib14"><ce:sup>14</ce:sup></ce:cross-ref> glutamate receptor activation is an important mediator of ischemic neuronal death.</ce:para><ce:para>NMDA receptors may be the major source of the lethal postischemic Ca<ce:sup>2+</ce:sup> influx after ischemia. NMDA receptors are composed of NR1 and NR2A-D subunits. Their functional characteristics are determined by the receptors specific combination of NR1 and NR2 subunits (<ce:cross-ref refid="tab1">Table 1</ce:cross-ref>). There are also modulatory sites on the NMDA receptor for glycine, Mg<ce:sup>2+</ce:sup> and polyamines. There is a plethora of NMDA receptor antagonists that act at these sites. The neuroprotective efficacy of competitive (AP-7, dCPP-ene, CGS 19755) and noncompetitive pore site (MK-801, ketamine, CNS 1102, dextrorphan, memantine, remacemide), glycine site (ACEA 1021, felbamate), and polyamine site (eliprodil, CP-101, 606) NMDA receptor antagonists have been assessed in both global and focal models of cerebral ischemia.<ce:cross-ref refid="bib82"><ce:sup>82</ce:sup></ce:cross-ref> Although some studies show neuroprotection, others do not. The NMDA receptor antagonists generally offer greater protection in focal models than in global models.<ce:cross-ref refid="bib82"><ce:sup>82</ce:sup></ce:cross-ref> Because some NMDA receptor antagonists lower body temperature and affect cerebral blood flow, it is critical to control these variables to ensure protection is because of the antagonists action. NMDA receptor antagonists show neurobehavioral, neuronal vacuolation, and cardiovascular side effects, which have resulted in the failure of numerous large scale clinical trials like those for Cerestat, Selfotel, and eliprodil to name a few.</ce:para><ce:para>AMPA receptors are composed of GluR1-4 subunits that determine their functional properties. The presence of a GluR2 subunit renders an AMPA channel impermeable to Ca<ce:sup>2+</ce:sup>. Activation of AMPA receptors after ischemia allows Na<ce:sup>+</ce:sup> influx that contributes to the depolarization of the neuron and to the influx of Ca<ce:sup>2+</ce:sup> through Ca<ce:sup>2+</ce:sup> channels. AMPA receptor antagonists are few in number relative to NMDA receptor antagonists yet they offer greater protection against cerebral ischemia.<ce:cross-refs refid="bib82 bib83"><ce:sup>82,83</ce:sup></ce:cross-refs> Several quinoxalinedione competitive AMPA receptor antagonists (NBQX [2,3-dihydroxy-6-nitro-7-sulfamoylbanzo(f)guinoxaline], PNQX 1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido(3,4-f)guinoxaline-2,3-dione, YM90K, YM872) and noncompetitive AMPA receptor modulators (GYKI 52466) have shown robust neuroprotective efficacy in focal and global models.<ce:cross-refs refid="bib82 bib84"><ce:sup>82,84</ce:sup></ce:cross-refs> Unfortunately, some act as antagonists at the NMDA receptor glycine site, and almost all quinoxalinediones are relatively insoluble in water resulting in nephrotoxicity. A second generation of compounds produced by Yamanouchi Pharmaceuticals, exhibiting greater solubility has been tested in animal models<ce:cross-refs refid="bib85 bib86 bib87 bib88"><ce:sup>85-88</ce:sup></ce:cross-refs> and is now in phase II clinical trials for stroke. KA receptors probably do not play a large role in ischemic cell death. The neuroprotective quinoxalinediones have a 100-fold selectivity for AMPA receptors over KA receptors.<ce:cross-ref refid="bib89"><ce:sup>89</ce:sup></ce:cross-ref> The ischemia resistant CA3 region of the hippocampus has an abundance of KA receptors and neuroprotection has not been shown by any KA receptor-selective antagonists.<ce:cross-ref refid="bib90"><ce:sup>90</ce:sup></ce:cross-ref></ce:para><ce:para>The role of glutamate receptors in cerebral ischemia is further supported by numerous studies that describe ischemia-induced changes in glutamate receptor expression. In the hippocampus there is a selective decrease in NMDA-R1 mRNA in the CA1 region<ce:cross-ref refid="bib91"><ce:sup>91</ce:sup></ce:cross-ref> and a decrease in mRNA and protein expression of both NMDA NR2A and NR2B subunits in CA1 and dentate gyrus regions early after ischemia<ce:cross-refs refid="bib92 bib93"><ce:sup>92,93</ce:sup></ce:cross-refs> but a recovery of NR2A and NR2B mRNA in dentate at later times.<ce:cross-ref refid="bib93"><ce:sup>93</ce:sup></ce:cross-ref> Although still controversial, there may be a postischemic increase in the expression of Ca<ce:sup>2+</ce:sup>-permeable AMPA receptors resulting from a decrease in the expression of the GluR2 subunit.<ce:cross-refs refid="bib94 bib95 bib96 bib97"><ce:sup>94-97</ce:sup></ce:cross-refs> This could lead to the lethal postischemic Ca<ce:sup>2+</ce:sup> influx that occurs in vulnerable neurons. This observation is consistent with the neuroprotection obtained by Buchan et al<ce:cross-ref refid="bib98"><ce:sup>98</ce:sup></ce:cross-ref> administering NBQX as late as 12 hours after ischemia. Ischemia induced changes in glutamate receptor subunits have led to a search for subunit selective antagonists that would show greater specificity than currently available drugs.</ce:para></ce:section><ce:section><ce:section-title>Metabotropic glutamate receptors</ce:section-title><ce:para>Interest in the role of metabotropic glutamate receptors in ischemia has grown recently. The metabotropic glutamate receptor subtypes, mGluR1-8, are grouped into 3 main families (<ce:cross-ref refid="tab1">Table 1</ce:cross-ref>). Group I receptors are linked to phospholipase C and groups II and III are negatively linked to adenylate cyclase.<ce:cross-ref refid="bib99"><ce:sup>99</ce:sup></ce:cross-ref> Although the in vitro data suggest that activation of group I receptors exacerbates damage and activation of group II receptors ameliorates damage (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>),<ce:cross-refs refid="bib100 bib101"><ce:sup>100,101</ce:sup></ce:cross-refs> the results of the in vivo data are mixed. In global ischemia the group I/II agonist (1S, 3R)-ACPD significantly increased neuronal death<ce:cross-ref refid="bib102"><ce:sup>102</ce:sup></ce:cross-ref> whereas the related compound, AP-3, was protective.<ce:cross-ref refid="bib103"><ce:sup>103</ce:sup></ce:cross-ref> In focal ischemia, (1S, 3R)-ACPD was shown to be protective.<ce:cross-ref refid="bib104"><ce:sup>104</ce:sup></ce:cross-ref> The selective group II agonist LY354740 failed to protect against either focal<ce:cross-ref refid="bib105"><ce:sup>105</ce:sup></ce:cross-ref> or global<ce:cross-ref refid="bib106"><ce:sup>106</ce:sup></ce:cross-ref> ischemia but [(S)-4C3HPG], a group I antagonist/group II agonist, significantly protected gerbil CA1 neurons in focal<ce:cross-ref refid="bib107"><ce:sup>107</ce:sup></ce:cross-ref> and global<ce:cross-ref refid="bib108"><ce:sup>108</ce:sup></ce:cross-ref> ischemia. As with the ionotropic glutamate receptors, postischemic subunit expression alterations have been reported. After 24 hours of reperfusion following global ischemia, there is an increase in the expression of mGluR2 and mGluR4 mRNA and a decrease in mGluR5.<ce:cross-ref refid="bib109"><ce:sup>109</ce:sup></ce:cross-ref></ce:para></ce:section><ce:section><ce:section-title>GABA receptors</ce:section-title><ce:para>As with glutamate, ischemia results in a 2-fold increase in extracellular GABA.<ce:cross-refs refid="bib110 bib111"><ce:sup>110,111</ce:sup></ce:cross-refs> The increase is not as large as that of glutamate and does not persist as long.<ce:cross-refs refid="bib110 bib111"><ce:sup>110,111</ce:sup></ce:cross-refs> GABA has the opposite effect of glutamate on neuronal excitation. GABA receptors are both ionotropic, GABA<ce:inf>A</ce:inf>, and metabotropic, GABA<ce:inf>B</ce:inf> (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>). The ionotropic GABA receptors are composed of 17 different α, β, δ, and γ subunits.<ce:cross-ref refid="bib112"><ce:sup>112</ce:sup></ce:cross-ref> Agonists for both types of receptors are neuroprotective against ischemia.<ce:cross-ref refid="bib113"><ce:sup>113</ce:sup></ce:cross-ref> The majority of GABAergic neurons in the hippocampus are interneurons, which are spared after ischemia and seem to provide protection to neighboring cells.<ce:cross-ref refid="bib114"><ce:sup>114</ce:sup></ce:cross-ref> Any protection of these GABAergic neurons would be anticipated to aid the survival of the more vulnerable pyramidal neurons.</ce:para><ce:para>GABA uptake inhibitors are neuroprotective,<ce:cross-ref refid="bib114"><ce:sup>114</ce:sup></ce:cross-ref> as are many GABAergic agents like diazepam, phenobarbitol, valproic acid, baclofen, and muscimol.<ce:cross-refs refid="bib115 bib116 bib117"><ce:sup>115-117</ce:sup></ce:cross-refs> GABA<ce:inf>B</ce:inf> receptors are linked via G-proteins to second messengers and are predominantly located on presynaptic nerve terminals. GABA<ce:inf>B</ce:inf> receptor activation appears to block the release of excitatory neurotransmitters.<ce:cross-refs refid="bib118 bib119 bib120 bib121"><ce:sup>118-121</ce:sup></ce:cross-refs> Activation of these receptors with agonists like baclofen is neuroprotective in both focal<ce:cross-ref refid="bib113"><ce:sup>113</ce:sup></ce:cross-ref> and global<ce:cross-ref refid="bib118"><ce:sup>118</ce:sup></ce:cross-ref> models of ischemia. GABA modulators, like chlormethiazole, which facilitate chloride influx through the GABA receptor are neuroprotective in focal<ce:cross-ref refid="bib122"><ce:sup>122</ce:sup></ce:cross-ref> and global<ce:cross-refs refid="bib123 bib124"><ce:sup>123,124</ce:sup></ce:cross-refs> models and phase III clinical trials for chlormethiazole in stroke have recently been completed.</ce:para><ce:para>Like glutamate receptors, ischemia induces changes in GABA receptor subunits. Because of the number of different possible molecular subunits that can combine to form a heteromeric GABA channel complex, recent work has only scratched the surface in terms of looking at altered subunit expression after ischemia. There is an early decrease in the expression of the predominant adult subunits α<ce:inf>1</ce:inf> and β<ce:inf>2</ce:inf> in all regions of the hippocampus, but expression recovers in the resistant CA3 and dentate gyrus regions.<ce:cross-refs refid="bib125 bib126"><ce:sup>125,126</ce:sup></ce:cross-refs> At the same time, there is a decrease in the functionality of both GABA<ce:inf>A</ce:inf><ce:cross-ref refid="bib127"><ce:sup>127</ce:sup></ce:cross-ref> and GABA<ce:inf>B</ce:inf><ce:cross-ref refid="bib128"><ce:sup>128</ce:sup></ce:cross-ref> receptors. Interestingly, however, there have been recent observations that there is an increase in the expression of the fetal subunits α<ce:inf>2</ce:inf> and α<ce:inf>3</ce:inf><ce:cross-ref refid="bib129"><ce:sup>129</ce:sup></ce:cross-ref> in a global model of ischemia and an increase in α<ce:inf>4</ce:inf> subunit mRNA expression in focal ischemia.<ce:cross-ref refid="bib130"><ce:sup>130</ce:sup></ce:cross-ref> It remains to be seen whether these changes in message are translated into changes in protein and function and whether or not they can be exploited to improve neurological outcome after ischemia.</ce:para></ce:section><ce:section><ce:section-title>Adenosine receptors</ce:section-title><ce:para>Cerebral ischemia also causes an efflux of the inhibitory neuromodulator adenosine from neurons.<ce:cross-refs refid="bib131 bib132"><ce:sup>131,132</ce:sup></ce:cross-refs> Adenosine levels can rise up to 150-fold in the rat brain after transient ischemia because of the metabolism of ATP.<ce:cross-ref refid="bib133"><ce:sup>133</ce:sup></ce:cross-ref> After ischemia, adenosine A<ce:inf>1</ce:inf>, A<ce:inf>2</ce:inf>, and A<ce:inf>3</ce:inf> receptors desensitize and there is a decrease in their receptor numbers and coupling to G-proteins.<ce:cross-ref refid="bib134"><ce:sup>134</ce:sup></ce:cross-ref> An elevation of adenosine levels protects against ischemia, however the mechanism of this action is not fully understood (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>).<ce:cross-ref refid="bib133"><ce:sup>133</ce:sup></ce:cross-ref> Adenosine acts on presynaptic adenosine receptors to inhibit excitatory amino acid release, to hyperpolarize cell membranes and to decrease Ca<ce:sup>2+</ce:sup> influx.<ce:cross-refs refid="bib131 bib135 bib136"><ce:sup>131,135,136</ce:sup></ce:cross-refs> It also increases blood flow, activates presynaptic K<ce:sup>+</ce:sup> channels, increases glucose transport, reduces free radical formation and activates cellular antioxidant defense systems.<ce:cross-refs refid="bib131 bib135 bib136"><ce:sup>131,135,136</ce:sup></ce:cross-refs> Interestingly, there is some evidence for adenosine acting on A<ce:inf>1</ce:inf> receptors via K<ce:inf>ATP</ce:inf> channels in the mediation of ischemic preconditioning in the hippocampus.<ce:cross-ref refid="bib137"><ce:sup>137</ce:sup></ce:cross-ref> Administration of adenosine receptor agonists like 2-chloroadenosine or the A<ce:inf>1</ce:inf> receptor selective agonist N<ce:sup>6</ce:sup>-R-phenylisopropyl adenosine protect neurons from ischemic insults.<ce:cross-refs refid="bib132 bib138"><ce:sup>132,138</ce:sup></ce:cross-refs> In contrast, adenosine receptor antagonists make ischemic damage worse.<ce:cross-ref refid="bib139"><ce:sup>139</ce:sup></ce:cross-ref> Drugs targeting the enzymes involved in adenosine production, adenosine kinase, and adenosine deaminase, and blockers of adenosine transporters have also been assessed.<ce:cross-ref refid="bib132"><ce:sup>132</ce:sup></ce:cross-ref> Although the first 2 approaches have not been successful, the use of the adenosine transport inhibitor propentofylline increases adenosine release after ischemia and reduces damage.<ce:cross-ref refid="bib132"><ce:sup>132</ce:sup></ce:cross-ref></ce:para></ce:section></ce:section><ce:section><ce:section-title>Intracellular signalling events</ce:section-title><ce:para>In this section, intracellular signalling events will be discussed including alterations in cytosolic and subcellular Ca<ce:sup>2+</ce:sup> dynamics and the alteration of Ca<ce:sup>2+</ce:sup>-dependent kinases and immediate early genes.</ce:para><ce:section><ce:section-title>Neuronal calcium homeostasis</ce:section-title><ce:para>Neurons have an intracellular Ca<ce:sup>2+</ce:sup> content in the mM range, similar to the concentration in extracellular fluid (1 mM), yet they maintain their resting [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> at around 100 nM.<ce:cross-ref refid="bib140"><ce:sup>140</ce:sup></ce:cross-ref> The difference between Ca<ce:sup>2+</ce:sup> content and [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> is because the majority of the Ca<ce:sup>2+</ce:sup> sequestered in intracellular storage organelles. The electrochemical gradient across the cell membrane that drives Ca<ce:sup>2+</ce:sup> into neurons is maintained by the low Ca<ce:sup>2+</ce:sup> permeability of the membrane and by Ca<ce:sup>2+</ce:sup> extrusion processes. The net [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> is determined by a variety of factors including Ca<ce:sup>2+</ce:sup> influx through ligand- and voltage-gated Ca<ce:sup>2+</ce:sup> channels, sequestration by internal storage organelles such as the mitochondria or endoplasmic reticulum, and Ca<ce:sup>2+</ce:sup> extrusion.<ce:cross-refs refid="bib140 bib141 bib142"><ce:sup>140-142</ce:sup></ce:cross-refs> Ca<ce:sup>2+</ce:sup> efflux occurs via a high-affinity Ca<ce:sup>2+</ce:sup>-activated ATPase and a low-affinity Na<ce:sup>+</ce:sup>/Ca<ce:sup>2+</ce:sup> exchanger driven by the plasma membrane Na<ce:sup>+</ce:sup> gradient (<ce:cross-ref refid="fig1">Fig 1</ce:cross-ref>).<ce:cross-ref refid="bib140"><ce:sup>140</ce:sup></ce:cross-ref> Neurons also possess Ca<ce:sup>2+</ce:sup>-binding proteins which rapidly buffer Ca<ce:sup>2+</ce:sup>.<ce:cross-ref refid="bib143"><ce:sup>143</ce:sup></ce:cross-ref></ce:para><ce:para>Physiological stimuli use small, transient increases in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> but Ca<ce:sup>2+</ce:sup> overload can initiate a cascade of events that lead to the death of the neuron during ischemia.<ce:cross-refs refid="bib141 bib142 bib144"><ce:sup>141,142,144</ce:sup></ce:cross-refs> A few minutes after the onset of focal or global ischemia, neuronal [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> rises because of the impairment of energy-dependent membrane transport systems and possibly because of the release of Ca<ce:sup>2+</ce:sup> from internal stores.<ce:cross-refs refid="bib145 bib146 bib147 bib148"><ce:sup>145-148</ce:sup></ce:cross-refs> This is followed by a larger rise in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> coincident with depolarization of the plasma membrane.<ce:cross-refs refid="bib145 bib146 bib147 bib148"><ce:sup>145-148</ce:sup></ce:cross-refs> Depolarization triggers Ca<ce:sup>2+</ce:sup> influx through Ca<ce:sup>2+</ce:sup> channels possibly contributing to the lethal Ca<ce:sup>2+</ce:sup> influx, and also stimulating the release of glutamate. NMDA receptors are thought to be a major source of the postischemic [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> elevation.<ce:cross-ref refid="bib149"><ce:sup>149</ce:sup></ce:cross-ref></ce:para><ce:para>Because of a limited amount of Ca<ce:sup>2+</ce:sup> in the extracellular fluid, ischemia causes only a 150% increase in Ca<ce:sup>2+</ce:sup> content.<ce:cross-ref refid="bib150"><ce:sup>150</ce:sup></ce:cross-ref> The loss of ATP and acidosis, however, prevents the sequestration of Ca<ce:sup>2+</ce:sup>, leading to increases in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> from 0.1 μM to 30 μM.<ce:cross-refs refid="bib145 bib146"><ce:sup>145,146</ce:sup></ce:cross-refs> The magnitude of the [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> increases may be greater in selectively vulnerable neurons, such as those in the CA1 region.<ce:cross-ref refid="bib151"><ce:sup>151</ce:sup></ce:cross-ref> Within 6 to 8 minutes of ischemia, the [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> in cells in the CA1 region rises to as high as 300 μM.<ce:cross-refs refid="bib145 bib146 bib147 bib148"><ce:sup>145-148</ce:sup></ce:cross-refs> In the resistant cells in the CA3 region, the [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> only increases to 10 μM.<ce:cross-ref refid="bib147"><ce:sup>147</ce:sup></ce:cross-ref> These changes in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> are accompanied by reciprocal changes in extracellular [Ca<ce:sup>2+</ce:sup>].<ce:cross-ref refid="bib148"><ce:sup>148</ce:sup></ce:cross-ref> Ischemia-induced changes in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> are affected significantly by brain glucose concentrations and pH, with low blood glucose producing a faster and larger increase in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf>.<ce:cross-ref refid="bib148"><ce:sup>148</ce:sup></ce:cross-ref> Attenuation of the rise in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> with permeant Ca<ce:sup>2+</ce:sup> chelators, such as 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid (BAPTA), reduces infarction volume and preserves neurons.<ce:cross-ref refid="bib151"><ce:sup>151</ce:sup></ce:cross-ref> It is not known why some regions of the brain are more vulnerable to ischemia and Ca<ce:sup>2+</ce:sup> overload than others. Vulnerability may be associated with differences in the number, type, and localization of glutamate receptors and to the ability of neurons to handle the ischemia-induced Ca<ce:sup>2+</ce:sup> overload. Neurons of the CA3 region may survive ischemia because they can conserve energy to deal with the Ca<ce:sup>2+</ce:sup> overload, whereas the metabolic failure in the CA1 region renders the neurons incapable of coping with this excess Ca<ce:sup>2+</ce:sup> and the cells die.<ce:cross-ref refid="bib152"><ce:sup>152</ce:sup></ce:cross-ref> NMDA receptor antagonists inhibit Ca<ce:sup>2+</ce:sup> accumulation in CA1 neurons<ce:cross-refs refid="bib145 bib146"><ce:sup>145,146</ce:sup></ce:cross-refs> and reduce the fall in extracellular [Ca<ce:sup>2+</ce:sup>] following ischemia.<ce:cross-ref refid="bib153"><ce:sup>153</ce:sup></ce:cross-ref> The neuroprotective efficacy of NMDA receptor antagonists in global ischemia, however, is controversial.<ce:cross-ref refid="bib154"><ce:sup>154</ce:sup></ce:cross-ref> Normal ischemia-induced [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> responses occur in hypothermia-protected neurons.<ce:cross-ref refid="bib155"><ce:sup>155</ce:sup></ce:cross-ref> AMPA receptor activation allows an influx of Na<ce:sup>+</ce:sup>, depolarizing the membrane, thus allowing also Ca<ce:sup>2+</ce:sup> influx through NMDA receptor channels and Ca<ce:sup>2+</ce:sup> channels.</ce:para><ce:para>The buffering of [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> by Ca<ce:sup>2+</ce:sup>-binding proteins may regulate neuronal vulnerability in ischemia. Neurons in different brain regions contain different Ca<ce:sup>2+</ce:sup>-binding proteins including calmodulin, parvalbumin, calbindin, calretinin, and S100.<ce:cross-ref refid="bib156"><ce:sup>156</ce:sup></ce:cross-ref> There is no clear link, however, between neuronal immunoreactivity for Ca<ce:sup>2+</ce:sup>-binding proteins and vulnerability to ischemia.<ce:cross-refs refid="bib156 bib157"><ce:sup>156,157</ce:sup></ce:cross-refs></ce:para><ce:para>Following an elevation of [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf>, the Na<ce:sup>+</ce:sup>-Ca<ce:sup>2+</ce:sup> exchanger uses the electrochemical gradient for Na<ce:sup>+</ce:sup> that is maintained by the Na<ce:sup>+</ce:sup>-K<ce:sup>+</ce:sup> pump to exchange extracellular Na<ce:sup>+</ce:sup> for intracellular Ca<ce:sup>2+</ce:sup> until normal [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> is restored. In ischemia, the loss of ATP inhibits the Na<ce:sup>+</ce:sup>-K<ce:sup>+</ce:sup> pump<ce:cross-ref refid="bib8"><ce:sup>8</ce:sup></ce:cross-ref> and the resulting accumulation of Na<ce:sup>+</ce:sup> may reverse the Na<ce:sup>+</ce:sup>-Ca<ce:sup>2+</ce:sup> exchanger.<ce:cross-ref refid="bib158"><ce:sup>158</ce:sup></ce:cross-ref> Inhibiting or reversing the Na<ce:sup>+</ce:sup>-Ca<ce:sup>2+</ce:sup> pump is neuroprotective suggesting the exchanger contributes to the lethal elevation of [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf>.<ce:cross-ref refid="bib159"><ce:sup>159</ce:sup></ce:cross-ref></ce:para><ce:para>Neurons contain a variety of internal Ca<ce:sup>2+</ce:sup> stores that can be activated by inositol triphosphate (IP<ce:inf>3</ce:inf>), caffeine, ryanodine, glutamate, and hypoxia.<ce:cross-ref refid="bib160"><ce:sup>160</ce:sup></ce:cross-ref> In gerbil hippocampal neurons, up to two thirds of the ischemia-induced Ca<ce:sup>2+</ce:sup> surge may be caused by release from internal stores and the remaining one third from Ca<ce:sup>2+</ce:sup> influx.<ce:cross-ref refid="bib161"><ce:sup>161</ce:sup></ce:cross-ref> Dantrolene, which blocks Ca<ce:sup>2+</ce:sup> release from these internal stores, reduces the ischemia-induced release of Ca<ce:sup>2+</ce:sup> and protects neurons after transient forebrain ischemia.<ce:cross-ref refid="bib162"><ce:sup>162</ce:sup></ce:cross-ref></ce:para><ce:para>With reperfusion there is a restoration of the levels of energy metabolites and the ionic gradients.<ce:cross-ref refid="bib142"><ce:sup>142</ce:sup></ce:cross-ref> The recovery of energy metabolites is the same in vulnerable and resistant neurons and extracellular [Ca<ce:sup>2+</ce:sup>] returns to normal values in 2 phases. With repolarization, extracellular Ca<ce:sup>2+</ce:sup> rapidly increases to about 70% of normal, followed by a slower return to preischemic levels over the next hour.<ce:cross-refs refid="bib145 bib146 bib147"><ce:sup>145-147</ce:sup></ce:cross-refs> The elevated [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> is reversed by active transport of Ca<ce:sup>2+</ce:sup> across endoplasmic reticulum, plasma, and mitochondrial membranes.<ce:cross-refs refid="bib145 bib146 bib147"><ce:sup>145-147</ce:sup></ce:cross-refs> A few hours after the insult, the vulnerable CA1, but not CA3 cells, may see a secondary increase in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf>.<ce:cross-refs refid="bib145 bib146"><ce:sup>145,146</ce:sup></ce:cross-refs> The secondary overload correlates with cell death suggesting a link between neurotoxicity and the irreversible loss of Ca<ce:sup>2+</ce:sup> homeostasis or the release of Ca<ce:sup>2+</ce:sup> from the overloaded mitochondria.<ce:cross-ref refid="bib163"><ce:sup>163</ce:sup></ce:cross-ref> Some Ca<ce:sup>2+</ce:sup> influx pathways may be more important during ischemia than others, or the source of Ca<ce:sup>2+</ce:sup> may differ at different stages of ischemia and in cells with different sensitivities to damage. Many questions remain to be answered. Neurotoxicity may be related to many factors including the kinds of receptors activated, the source of the Ca<ce:sup>2+</ce:sup>, the severity and duration of ischemia, the duration and persistence of the [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> surge, and the intrinsic susceptibility of the neurons.</ce:para></ce:section><ce:section><ce:section-title>Subcellular Ca<ce:sup>2+</ce:sup> dynamics</ce:section-title><ce:para>Spatial and temporal variations of [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> allow independent regulation of the various Ca<ce:sup>2+</ce:sup>-dependent processes. [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> responses are restricted to specific regions of neurons because of the clustering and nonuniform distribution of ion channels and ligand-gated receptors and to the selective localization of Ca<ce:sup>2+</ce:sup> pumps and exchangers and Ca<ce:sup>2+</ce:sup>-binding proteins.<ce:cross-ref refid="bib164"><ce:sup>164</ce:sup></ce:cross-ref> Distinct Ca<ce:sup>2+</ce:sup> signalling patterns can occur in the cytoplasm, nucleus, endoplasmic reticulum, (ER) and mitochondria.</ce:para><ce:para>ER [Ca<ce:sup>2+</ce:sup>] is controlled by ryanodine and IP<ce:inf>3</ce:inf> receptors that release Ca<ce:sup>2+</ce:sup> from the ER into the cytoplasm and a Ca<ce:sup>2+</ce:sup>-ATPase that pumps Ca<ce:sup>2+</ce:sup> from the cytoplasm into the ER.<ce:cross-refs refid="bib165 bib166"><ce:sup>165,166</ce:sup></ce:cross-refs> Disturbances of Ca<ce:sup>2+</ce:sup> homeostasis may contribute to ischemic damage because a depletion of ER Ca<ce:sup>2+</ce:sup> triggers apoptosis.<ce:cross-refs refid="bib166 bib167"><ce:sup>166,167</ce:sup></ce:cross-refs> Studies to date show that Ca<ce:sup>2+</ce:sup> uptake into the ER is impaired after ischemia, ischemic cell damage is reduced by dantrolene that blocks the release of Ca<ce:sup>2+</ce:sup> from the ER, and free radicals deplete ER Ca<ce:sup>2+</ce:sup>.<ce:cross-ref refid="bib167"><ce:sup>167</ce:sup></ce:cross-ref> Therefore, therapies aimed at increasing ER Ca<ce:sup>2+</ce:sup> content after ischemia should be explored.</ce:para><ce:para>Nuclear Ca<ce:sup>2+</ce:sup> may be regulated independently of the cytosolic pool. Nuclear pores restrict the movement of molecules with a molecular weight greater than 20 kD so small changes in neuronal [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> are directly transferred to the nucleus whereas larger changes (>300 nM) are attenuated.<ce:cross-ref refid="bib168"><ce:sup>168</ce:sup></ce:cross-ref> Like the ER, nuclei contain a Ca<ce:sup>2+</ce:sup> pump, IP<ce:inf>3</ce:inf>-sensitive Ca<ce:sup>2+</ce:sup> channels, a cyclic ADP-ribose-modulated channel and calmodulin.<ce:cross-refs refid="bib169 bib170"><ce:sup>169,170</ce:sup></ce:cross-refs> The role of nuclear Ca<ce:sup>2+</ce:sup> in controlling neuronal death processes through Ca<ce:sup>2+</ce:sup>-dependent nuclear endonucleases is a subject of great interest.<ce:cross-ref refid="bib170"><ce:sup>170</ce:sup></ce:cross-ref> Increasing nuclear [Ca<ce:sup>2+</ce:sup>] affects Ca<ce:sup>2+</ce:sup>-activated gene expression mediated by the cAMP-response element (CRE) and the CRE-binding protein (CREB), whereas increasing cytoplasmic [Ca<ce:sup>2+</ce:sup>] activates transcription through the serum-response element (SRE).<ce:cross-ref refid="bib171"><ce:sup>171</ce:sup></ce:cross-ref> The role of nuclear Ca<ce:sup>2+</ce:sup> in the regulation of Ca<ce:sup>2+</ce:sup>-dependent nuclear processes and ischemia-induced neuronal death has yet to be elucidated</ce:para><ce:para>Mitochondria have increasingly been implicated as major players in ischemic damage.<ce:cross-refs refid="bib172 bib173 bib174 bib175"><ce:sup>172-175</ce:sup></ce:cross-refs> Normally, mitochondria generate the ATP necessary for the production of pyruvate from glucose. A large membrane potential across mitochondria is formed by the movement of protons, products of mitochondrial respiration, out of the mitochondrial matrix.<ce:cross-ref refid="bib175"><ce:sup>175</ce:sup></ce:cross-ref> Although a large amount of Ca<ce:sup>2+</ce:sup> is stored in the mitochondria, their role in buffering Ca<ce:sup>2+</ce:sup> under physiological conditions is small.<ce:cross-ref refid="bib172"><ce:sup>172</ce:sup></ce:cross-ref> The negative membrane potential of the inner mitochondrial membrane provides the driving force for the uptake of Ca<ce:sup>2+</ce:sup> into mitochondria and efflux occurs by a 2Na<ce:sup>+</ce:sup>/Ca<ce:sup>2+</ce:sup> antiporter.<ce:cross-refs refid="bib172 bib173 bib174 bib175"><ce:sup>172-175</ce:sup></ce:cross-refs></ce:para><ce:para>After ischemia, electron transport is disrupted, which stops ATP production causing pyruvate to be reduced to lactate with the production of H<ce:sup>+</ce:sup>.<ce:cross-refs refid="bib172 bib175"><ce:sup>172,175</ce:sup></ce:cross-refs> When [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> is very high after ischemia, mitochondria become the major Ca<ce:sup>2+</ce:sup> buffering system.<ce:cross-refs refid="bib173 bib174"><ce:sup>173,174</ce:sup></ce:cross-refs> The mitochondrial Ca<ce:sup>2+</ce:sup> content increases from 1 to 3 nmol/mg protein to 6 to 9 nmol/mg protein after 24 hours of reperfusion.<ce:cross-ref refid="bib173"><ce:sup>173</ce:sup></ce:cross-ref> During ischemia the loss of oxidative metabolism means there is no energy to maintain the membrane potential required to drive Ca<ce:sup>2+</ce:sup> uptake into the mitochondria. During the early period of reperfusion mitochondrial Ca<ce:sup>2+</ce:sup> content increases in all affected regions, however, when oxidative metabolism returns and the mitochondrial membrane potential is restored, large increases in mitochondrial Ca<ce:sup>2+</ce:sup> content occur.<ce:cross-refs refid="bib175 bib176"><ce:sup>175,176</ce:sup></ce:cross-refs> When mitochondria become overloaded with Ca<ce:sup>2+</ce:sup> they undergo a permeability transition of the inner mitochondrial membrane (MPT), release Ca<ce:sup>2+</ce:sup>, swell, become uncoupled, lose the ability to produce ATP, and the cell dies.<ce:cross-ref refid="bib176"><ce:sup>176</ce:sup></ce:cross-ref> MPT occurs because of the opening of a large pore that allows the movement of molecules of molecular weight less than 1500. Cyclosporin A, which prevents the opening of the MPT, protects against CA1 death after global ischemia.<ce:cross-ref refid="bib177"><ce:sup>177</ce:sup></ce:cross-ref> Mitochondria also produce hydroxyl radicals and, in swollen mitochondria, the increased radical production activates the MPT.<ce:cross-ref refid="bib172"><ce:sup>172</ce:sup></ce:cross-ref> If the [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf> returns to normal, mitochondria release their Ca<ce:sup>2+</ce:sup> and then it is pumped out of the neuron.<ce:cross-ref refid="bib176"><ce:sup>176</ce:sup></ce:cross-ref> Many of the key events in apoptotic cell death involve mitochondria.<ce:cross-refs refid="bib176 bib177 bib178 bib179"><ce:sup>176-179</ce:sup></ce:cross-refs> For example, cytochrome c is an important enzyme for oxidative phosphorylation that is released in response to Bax, oxidants and mitochondrial Ca<ce:sup>2+</ce:sup> overload. Once released, cytochrome c interacts with deoxyadenosine triphosphate and binds to Apaf-1 to activate caspase-9. The activated caspase-9 then activates caspase-3 to induce apoptotic cell death.<ce:cross-refs refid="bib174 bib180"><ce:sup>174,180</ce:sup></ce:cross-refs></ce:para></ce:section><ce:section><ce:section-title>Kinases</ce:section-title><ce:para>The protein tyrosine and serine/threonine kinases such as protein kinase A (PKA), the Ca<ce:sup>2+</ce:sup>/phospholipid-dependent kinase C (PKC) and the Ca<ce:sup>2+</ce:sup>/calmodulin-dependent kinase II (CaMKII) are part of a family of signalling enzymes that affect cell proliferation, differentiation, secretion, and death. They participate in the major signalling pathway used by growth factor receptors that are important for cell growth and survival. Their activities are also altered after focal and global cerebral ischemia where they may contribute to the development of ischemic neuronal damage.<ce:cross-ref refid="bib181"><ce:sup>181</ce:sup></ce:cross-ref> After ischemia there is a rapid increase in kinase activity that is sometimes accompanied by a translocation to the plasma membrane or nucleus where target proteins are phosphorylated. The activation phase is followed by a long lasting loss of activity in affected brain regions.<ce:cross-refs refid="bib182 bib183 bib184 bib185"><ce:sup>182-185</ce:sup></ce:cross-refs> Studies using activators and inhibitors of PKC in ischemia models have been somewhat inconclusive because of the lack of selective pharmacological agents, so the role of PKC in ischemic neuronal death remains unclear. Reduction of PKC activity by staurosporine, however, was protective in the rat and gerbil<ce:cross-ref refid="bib186"><ce:sup>186</ce:sup></ce:cross-ref> and dextrorphan treatment that maintained PKC and CaMKII activities was neuroprotective in a global model.<ce:cross-ref refid="bib187"><ce:sup>187</ce:sup></ce:cross-ref></ce:para><ce:para>More recently, the activity of many other kinases have been reported to be modulated by cerebral ischemia. For example, the cyclin-dependent protein kinase 5 (CDK5), which regulates the neuronal cytoskeleton, is increased after ischemia<ce:cross-ref refid="bib188"><ce:sup>188</ce:sup></ce:cross-ref> and the c-Jun NH2-terminal kinase (JNK1), which conveys signals from the cytosol to the nucleus, translocates to the nucleus during ischemia without activation and then it is activated during reperfusion by SAPK/ERK kinase (SEK1) in the nucleus.<ce:cross-ref refid="bib189"><ce:sup>189</ce:sup></ce:cross-ref> The activity of casein kinase II (CKII), a kinase involved in cell proliferation and survival, decreases in vulnerable brain regions after ischemia<ce:cross-ref refid="bib190"><ce:sup>190</ce:sup></ce:cross-ref> and the mitogen-activated protein (MAP) kinase is tyrosine phosphorylated and activated immediately after ischemia.<ce:cross-ref refid="bib191"><ce:sup>191</ce:sup></ce:cross-ref> The role of these various kinases in ischemic cell death and survival remains to be elucidated.</ce:para></ce:section><ce:section><ce:section-title>Proteases</ce:section-title><ce:para>The excessive postischemic elevation of cytosolic Ca<ce:sup>2+</ce:sup> can activate degradative proteolytic enzymes, including the family of cytosolic proteases called calpains.<ce:cross-ref refid="bib192"><ce:sup>192</ce:sup></ce:cross-ref> Proteolysis of cellular proteins is an important component of neurodegeneration. Calpain I (μ-calpain) and II (m-calpain) are found throughout the brain and are activated by Ca<ce:sup>2+</ce:sup> at neutral pH. Calpain activity is also regulated by the endogenous inhibitor calpastatin which forms a complex with calpain limiting its proteolytic activity.<ce:cross-ref refid="bib192"><ce:sup>192</ce:sup></ce:cross-ref> Activated calpains hydrolyze peptide bonds in cytoskeletal and structural proteins (spectrin, MAP2, actin, tubulin, tau, microtubules, neurofilaments), membrane proteins (epidermal growth factor receptor, glutamate receptors, ryanodine receptor), and other regulatory and signalling proteins (protein kinase C, G-proteins, calcineurin, calpain, calmodulin-binding proteins) (Fig 2).<ce:cross-ref refid="bib193"><ce:sup>193</ce:sup></ce:cross-ref><ce:display><ce:figure><ce:label>Fig. 2</ce:label><ce:caption><ce:simple-para>Calpain modulation and substrates in ischemic cell death.</ce:simple-para></ce:caption> <ce:link locator="gr2"></ce:link></ce:figure></ce:display>Uncontrolled proteolysis destroys the plasma membrane and kills the cell. In focal and global ischemia, calpain degrades the structural protein spectrin in neurons before cell loss.<ce:cross-refs refid="bib194 bib195"><ce:sup>194,195</ce:sup></ce:cross-refs> Inhibitors of calpain activity are neuroprotective in both focal and global models of cerebral ischemia.<ce:cross-refs refid="bib196 bib197 bib198"><ce:sup>196-198</ce:sup></ce:cross-refs></ce:para><ce:para>A family of cysteine proteases called caspases also have important functions in cell death.<ce:cross-ref refid="bib199"><ce:sup>199</ce:sup></ce:cross-ref> Two of the members of this family are caspase-1 (interleukin-1β-converting enzyme or ICE) and caspase-3. Caspases cleave a variety of intracellular substrates and caspase-3 activity is increased after ischemia suggesting the active involvement of caspase in ischemic neuronal death.<ce:cross-ref refid="bib200"><ce:sup>200</ce:sup></ce:cross-ref> Caspase-1 knockout mice and transgenic mice expressing a dominant negative mutant caspase-1 gene are resistant to ischemic neuronal damage.<ce:cross-refs refid="bib201 bib202"><ce:sup>201,202</ce:sup></ce:cross-refs> Similarly, the caspase inhibitors zDEVD-fmk and zVAD-fmk reduce caspase activity and protect neurons from ischemic damage.<ce:cross-refs refid="bib203 bib204"><ce:sup>203,204</ce:sup></ce:cross-refs></ce:para></ce:section><ce:section><ce:section-title>Stress genes and immediate early genes</ce:section-title><ce:para>Cerebral ischemia rapidly and transiently increases the expression of immediate early genes (IEGs) and stress genes.<ce:cross-ref refid="bib205"><ce:sup>205</ce:sup></ce:cross-ref> The heat shock protein hsp70 is a marker of brain injury whose expression is elevated in the first 24 hours after the insult.<ce:cross-refs refid="bib205 bib206"><ce:sup>205,206</ce:sup></ce:cross-refs> In focal models, hsp70 immunoreactivity is seen in endothelial cells in the infarct, in neurons, and possibly glia cells in the peri-infarct region.<ce:cross-ref refid="bib207"><ce:sup>207</ce:sup></ce:cross-ref> Other stress proteins such as glucose regulated protein (grp78), hsp27, hsp47, and hsp72 are induced with similar temporal patterns as hsp70.<ce:cross-ref refid="bib208"><ce:sup>208</ce:sup></ce:cross-ref> It is not known if postischemic changes in stress genes are caused by structural damage mediated by proteases, endonucleases or lipases, metabolic changes, or oxidative damage.<ce:cross-ref refid="bib209"><ce:sup>209</ce:sup></ce:cross-ref></ce:para><ce:para>Focal and global ischemia also produce rapid increases in the expression of the IEGs c-fos,<ce:cross-refs refid="bib205 bib210 bib211"><ce:sup>205,210,211</ce:sup></ce:cross-refs> jun-B,<ce:cross-refs refid="bib206 bib210 bib212"><ce:sup>206,210,212</ce:sup></ce:cross-refs> c-jun,<ce:cross-refs refid="bib206 bib210 bib213"><ce:sup>206,210,213</ce:sup></ce:cross-refs> jun D,<ce:cross-refs refid="bib210 bib212"><ce:sup>210,212</ce:sup></ce:cross-refs> Krox-20,<ce:cross-ref refid="bib213"><ce:sup>213</ce:sup></ce:cross-ref> Krox 24,<ce:cross-ref refid="bib214"><ce:sup>214</ce:sup></ce:cross-ref> and TIS-1,<ce:cross-ref refid="bib214"><ce:sup>214</ce:sup></ce:cross-ref> which may play a role in neuroprotection. After a focal insult, c-fos and jun-B mRNA are increased in neuronal nuclei throughout the cortex of the affected hemisphere.<ce:cross-ref refid="bib206"><ce:sup>206</ce:sup></ce:cross-ref> The c-FOS protein was elevated for up to 4 days outside the ischemic core in the injured hemisphere.<ce:cross-ref refid="bib215"><ce:sup>215</ce:sup></ce:cross-ref> <ce:italic>In vivo</ce:italic> studies have established that c-fos expression can be triggered by Ca<ce:sup>2+</ce:sup> influx through voltage-sensitive Ca<ce:sup>2+</ce:sup> channels.<ce:cross-ref refid="bib216"><ce:sup>216</ce:sup></ce:cross-ref> The role of IEGs may be to activate other secondary response genes. For example, c-fos and c-jun can bind to and activate AP-1 sites on genes that subsequently increase the expression of neurotrophic genes.<ce:cross-ref refid="bib217"><ce:sup>217</ce:sup></ce:cross-ref> It has not been established if the induction of a specific combination of IEGs is indicative of neuronal survival or eventual cell death.</ce:para></ce:section><ce:section><ce:section-title>Ischemic preconditioning (ischemic tolerance)</ce:section-title><ce:para>Brief episodes of nonlethal ischemia or cortical spreading depression induced by dural application of potassium chloride increase the tolerance of the brain to subsequent lethal global or focal insults.<ce:cross-refs refid="bib218 bib219 bib220"><ce:sup>218-220</ce:sup></ce:cross-refs> Ischemic preconditioning requires a perturbation of neuronal energy metabolism and an interval between the conditioning event and the lethal ischemia to allow for gene expression and new-protein synthesis.<ce:cross-ref refid="bib221"><ce:sup>221</ce:sup></ce:cross-ref> The degree of protection is determined by the duration of the preconditioning event and the delay to the subsequent ischemia.<ce:cross-refs refid="bib218 bib220"><ce:sup>218,220</ce:sup></ce:cross-refs> Preconditioning does not alter ischemic blood flow<ce:cross-ref refid="bib219"><ce:sup>219</ce:sup></ce:cross-ref> but may reduce cerebral glucose metabolism<ce:cross-ref refid="bib222"><ce:sup>222</ce:sup></ce:cross-ref> and reduce the ischemia-induced rise in extracellular glutamate.<ce:cross-ref refid="bib223"><ce:sup>223</ce:sup></ce:cross-ref> The mechanism(s) by which preconditioning promotes neuronal survival is unknown. Tolerance phenomenon may elevate hsp72, promote Ca<ce:sup>2+</ce:sup> influx, and activate immediate early genes.<ce:cross-refs refid="bib224 bib225"><ce:sup>224,225</ce:sup></ce:cross-refs></ce:para></ce:section></ce:section><ce:section><ce:section-title>Intercellular signalling events</ce:section-title><ce:para>Several mechanisms have been proposed to explain the pathophysiology of ischemic neuronal death including free radical formation and activation of the immune system. In this section we review these intercellular mechanisms that contribute to ischemic cell death.</ce:para><ce:section><ce:section-title>Cytokines</ce:section-title><ce:para>Inflammatory and immunological responses, which involve the infiltration of leukocytes and activation of macrophages, contribute to the pathogenesis of cerebral ischemia.<ce:cross-refs refid="bib226 bib227"><ce:sup>226,227</ce:sup></ce:cross-refs> Astrocytes, microglia, and endothelial cells are activated by ischemia and begin to produce cytokines.<ce:cross-ref refid="bib227"><ce:sup>227</ce:sup></ce:cross-ref> Cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) are responsible for the accumulation of inflammatory cells in the injured brain and affect the survival of damaged neurons. In ischemia, cytokines attract leukocytes and stimulate the production of adhesion molecules on leukocytes and endothelial cells.<ce:cross-ref refid="bib228"><ce:sup>228</ce:sup></ce:cross-ref> Leukocytes promote infarction through their toxic by-products, phagocytic actions, and by the immune reaction. Cytokines are induced by 1 hour after reperfusion following transient focal ischemia and remain elevated for up to 5 days.<ce:cross-refs refid="bib229 bib230 bib231"><ce:sup>229-231</ce:sup></ce:cross-refs> IL-1 receptor antagonists attenuate infarct size<ce:cross-refs refid="bib232 bib233"><ce:sup>232,233</ce:sup></ce:cross-refs> whereas injection of IL-1β or TNFα into the lateral ventricle increases infarct volume.<ce:cross-ref refid="bib234"><ce:sup>234</ce:sup></ce:cross-ref> IL-1 also increases damage by increasing heart rate and blood pressure, arachidonic acid release, and enhancing the synthesis of nitric oxide.<ce:cross-refs refid="bib227 bib235"><ce:sup>227,235</ce:sup></ce:cross-refs> Other cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), and transforming growth factor β (TGF-β) show similar expression profiles after ischemia and may also contribute to ischemic damage.<ce:cross-refs refid="bib227 bib236"><ce:sup>227,236</ce:sup></ce:cross-refs> Determining the importance of these cytokines will be dependent on the development of specific antagonists.</ce:para></ce:section><ce:section><ce:section-title>Adhesion molecules</ce:section-title><ce:para>Cytokines rapidly induce the expression of the adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial cell adhesion molecule-1 (ELAM-1 or E-selectin), and monocyte chemoattractant protein-1 (MCP-1). Adhesion molecules are expressed in low amounts under normal conditions but during ischemia their expression is increased on the surfaces of leukocytes and endothelial cells.<ce:cross-refs refid="bib237 bib238"><ce:sup>237,238</ce:sup></ce:cross-refs> This response is critical for the docking of leukocytes to endothelial cells, which starts their transendothelial migration process. There is also evidence for increased expression of adhesion molecules on astrocytes after ischemia that may promote leukocyte migration. ICAM-1 expression is elevated within 1 to 4 hours of reperfusion.<ce:cross-refs refid="bib239 bib240 bib241 bib242"><ce:sup>239-242</ce:sup></ce:cross-refs> Mice deficient in ICAM-1 have smaller infarcts after focal insults<ce:cross-ref refid="bib243"><ce:sup>243</ce:sup></ce:cross-ref> and intravenous administration of anti-ICAM-1 antibodies reduces infarct volume even when they are administered after the insult.<ce:cross-ref refid="bib244"><ce:sup>244</ce:sup></ce:cross-ref> MCP-1, a specific attractant for monocytes, is elevated later than ICAM-1 at the time when monocyte infiltration occurs.<ce:cross-ref refid="bib245"><ce:sup>245</ce:sup></ce:cross-ref></ce:para></ce:section><ce:section><ce:section-title>Nitric oxide</ce:section-title><ce:para>The free radical nitric oxide (NO) is made from L-arginine by nitric oxide synthase (NOS) (Fig 3). <ce:display><ce:figure id="fig3"><ce:label>Fig. 3</ce:label><ce:caption><ce:simple-para>Formation of superoxide and hydroxyl radicals. Abbreviations: SOD, superoxide dismutase; NOS, nitric oxide synthase.</ce:simple-para></ce:caption> <ce:link locator="gr3"></ce:link></ce:figure></ce:display>After cerebral ischemia NO levels are elevated, probably because of increased activity of the constitutive neuronal NOS and inducible NOS in reactive astrocytes and neutrophils that have migrated to the infarcted tissue.<ce:cross-refs refid="bib246 bib247"><ce:sup>246,247</ce:sup></ce:cross-refs> NO reacts with superoxide to produce the highly toxic peroxynitrite anion (ONOO<ce:sup>−</ce:sup>). NOS activity is enhanced by the postischemic elevation of Ca<ce:sup>2+</ce:sup>. In the ischemic brain, NO exacerbates brain damage by reducing neuronal energy production by inhibiting glycolytic and mitochondrial enzymes, by increasing DNA damage, and, through the conversion of superoxide to peroxynitrite, increasing the levels of toxic free radicals.<ce:cross-ref refid="bib248"><ce:sup>248</ce:sup></ce:cross-ref> In focal ischemia the NOS inhibitors N<ce:sup>G</ce:sup>-nitro-L-arginine methyl ester (L-NAME), N-nitro-L-arginine (L-NA), and aminoguanidine are neuroprotective.<ce:cross-refs refid="bib249 bib250"><ce:sup>249,250</ce:sup></ce:cross-refs> Under some conditions increased NO production is neuroprotective.<ce:cross-ref refid="bib251"><ce:sup>251</ce:sup></ce:cross-ref> These effects may be because of NO-induced vasodilation. The differential effects of neuronal, endothelial, and inducible NOS on infarction are not fully understood. Although neuronal NOS knockout mice show a reduction in infarct volume, endothelial NOS knockout mice show increased damage.<ce:cross-refs refid="bib252 bib253"><ce:sup>252,253</ce:sup></ce:cross-refs> The type of NOS induced may be dependent on the type of ischemia.<ce:cross-ref refid="bib254"><ce:sup>254</ce:sup></ce:cross-ref> In addition, the neuroprotective actions of the peptide basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) may be mediated through NO.<ce:cross-ref refid="bib255"><ce:sup>255</ce:sup></ce:cross-ref></ce:para></ce:section><ce:section><ce:section-title>Free radicals</ce:section-title><ce:para>Reactive oxygen species are important pathophysiological mediators of ischemia-induced toxicity (<ce:cross-ref refid="fig3">Fig 3</ce:cross-ref>).<ce:cross-ref refid="bib256"><ce:sup>256</ce:sup></ce:cross-ref> Oxygen radicals like superoxide (O<ce:inf>2</ce:inf><ce:sup>−</ce:sup>), peroxynitrite (NO<ce:inf>2</ce:inf><ce:sup>−</ce:sup>), hydrogen peroxide (H<ce:inf>2</ce:inf>O<ce:inf>2</ce:inf>), and the hydroxyl radical (OH<ce:sup>−</ce:sup>) are normally produced in very-low amounts by activated microglia and endothelial cells as products of mitochondrial metabolism.<ce:cross-ref refid="bib257"><ce:sup>257</ce:sup></ce:cross-ref> Additionally, free radicals can be formed from the metabolism of dopamine to OH<ce:sup>−</ce:sup> and by the Fenton reaction in which iron and manganese catalyze the conversion of H<ce:inf>2</ce:inf>O<ce:inf>2</ce:inf> to OH<ce:sup>−</ce:sup>.<ce:cross-refs refid="bib257 bib258"><ce:sup>257,258</ce:sup></ce:cross-refs> Excessive free radical production causes the peroxidation of lipids, proteins, and nucleic acids. Cells protect themselves from free radical damage using enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic (vitamin C and E) inactivation, and degradation.<ce:cross-refs refid="bib257 bib258"><ce:sup>257,258</ce:sup></ce:cross-refs> During ischemia, and especially during reperfusion, these radicals may be produced to such an extent that endogenous antioxidant systems are overwhelmed.<ce:cross-ref refid="bib259"><ce:sup>259</ce:sup></ce:cross-ref> Compared with resistant regions, vulnerable brain regions produce more radicals and are less able to scavenge these radicals. Ischemic insults upregulate the expression of free radical scavenging enzyme mRNAs and proteins.<ce:cross-ref refid="bib260"><ce:sup>260</ce:sup></ce:cross-ref> Pharmacological upregulation of free radical scavenging enzymes can reduce infarct volumes.<ce:cross-ref refid="bib261"><ce:sup>261</ce:sup></ce:cross-ref> Overexpression of radical scavenging enzymes in transgenic mice also reduces ischemic damage.<ce:cross-ref refid="bib262"><ce:sup>262</ce:sup></ce:cross-ref> Reactive oxygen species also serve as mediators of apoptosis.<ce:cross-ref refid="bib263"><ce:sup>263</ce:sup></ce:cross-ref></ce:para></ce:section><ce:section><ce:section-title>Growth factors</ce:section-title><ce:para>After cerebral ischemia the brain shows upregulation of the expression of many growth factors including bFGF and brain-derived neurotrophic factor (BDNF). bFGF acts through high-affinity tyrosine-kinase receptors to promote neuronal survival and axonal outgrowth. After transient forebrain ischemia, bFGF and bFGF receptor expression are increased in reactive astrocytes.<ce:cross-ref refid="bib264"><ce:sup>264</ce:sup></ce:cross-ref> Intravenous or intracerebral delivery of bFGF after cerebral ischemia dramatically reduces infarction.<ce:cross-ref refid="bib265"><ce:sup>265</ce:sup></ce:cross-ref> bFGF crosses the blood-brain barrier and protects cells in the ischemic penumbra.<ce:cross-ref refid="bib266"><ce:sup>266</ce:sup></ce:cross-ref> The mechanism of bFGF's neuroprotective actions are not known, but may involve alterations in the expression of the genes for antiapoptotic molecules and free radical scavenging enzymes.<ce:cross-refs refid="bib267 bib268"><ce:sup>267,268</ce:sup></ce:cross-refs></ce:para><ce:para>BDNF is a member of the neurotrophin gene family that promotes neuronal survival through the Trk B protein-tyrosine kinase signal transducing receptor.<ce:cross-ref refid="bib269"><ce:sup>269</ce:sup></ce:cross-ref> Global and focal ischemic insults induce the elevation of BDNF mRNA and protein levels in ischemia-resistant brain regions and induce a reduction in the vulnerable regions.<ce:cross-refs refid="bib270 bib271"><ce:sup>270,271</ce:sup></ce:cross-refs> These observations suggest a neuroprotective action of endogenous BDNF. The protective action of BDNF is also supported by the observation that intraventricular injection of BDNF ameliorates CA1 damage after transient forebrain ischemia.<ce:cross-ref refid="bib272"><ce:sup>272</ce:sup></ce:cross-ref> The effectiveness of BDNF may be mediated in part by blocking the excessive postischemic increase in [Ca<ce:sup>2+</ce:sup>]<ce:inf>i</ce:inf>, attenuating Ca<ce:sup>2+</ce:sup>-activated processes and increasing the expression of Ca<ce:sup>2+</ce:sup>-binding proteins, which could help buffer the toxic Ca<ce:sup>2+</ce:sup> influx.<ce:cross-ref refid="bib273"><ce:sup>273</ce:sup></ce:cross-ref></ce:para><ce:para>Although there are very few studies using other growth factors, neurotrophin-4/5,<ce:cross-ref refid="bib274"><ce:sup>274</ce:sup></ce:cross-ref> ciliary neurotrophic factor (CNTF)<ce:cross-ref refid="bib275"><ce:sup>275</ce:sup></ce:cross-ref> and insulin-like growth factor-I (IGF-I)<ce:cross-ref refid="bib276"><ce:sup>276</ce:sup></ce:cross-ref> are all neuroprotective.</ce:para></ce:section></ce:section><ce:section><ce:section-title>Conclusions</ce:section-title><ce:para>This article has described many of the underlying events and mechanisms of ischemic cell death and in doing so has attempted to illustrate the spatial and temporal complexity of this neurotoxic cascade. The design of new therapeutic agents for stroke is dependent on a thorough understanding of these processes. Effective stroke therapies may indeed require targeting several points in the neurotoxic cascade in a specific temporal sequence. Such a combination therapy may begin with the immediate administration of clot-dissolving tPA, followed by a Ca<ce:sup>2+</ce:sup> channel blocker, a glutamate receptor antagonist, an antioxidant, or a kinase inhibitor. In the latter stages of treatment, growth factors could be administered to preserve the integrity of remaining tissue and assist in neuronal regeneration and rehabilitation. The overall goal is to reduce disability and enhance quality of life for stroke survivors.</ce:para></ce:section></ce:sections><ce:acknowledgment><ce:section-title>Acknowledgements</ce:section-title><ce:para>Supported in part by a Heart and Stroke Foundation of Ontario grant #NA3680 awarded to Paul Morley and a Heart and Stroke Foundation of Alberta grant and an Alberta Heritage Foundation grant awarded to Alastair M. 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of ischemic cerebral cell death</title></titleInfo><name type="personal"><namePart type="given">Daniel L.</namePart><namePart type="family">Small</namePart><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul</namePart><namePart type="family">Morley</namePart><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alastair M.</namePart><namePart type="family">Buchan</namePart><affiliation>Receptor and Ion Channels Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, and Clinical Neurosciences, University of Calgary, Foothills Hospital, Calgary, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+-dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 185-207</abstract><note>Address reprint requests to Daniel L. Small, PhD, Institute for Biological Sciences, National Research Council of Canada, Building M-54, Montreal Road, Ottawa, Ontario, Canada K1A 0R6; email: Dan.Small@nrc.ca.</note><note type="content">Section title: Cerebrovascular Disease</note><note type="content">TABLE 1: Molecular Biology of Glutamate Receptors</note><relatedItem type="host"><titleInfo><title>Progress in Cardiovascular Diseases</title></titleInfo><titleInfo type="abbreviated"><title>YPCAD</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">199911</dateIssued></originInfo><identifier type="ISSN">0033-0620</identifier><identifier type="PII">S0033-0620(05)X7016-5</identifier><part><date>199911</date><detail type="issue"><title>Cerebrovascular Disease</title></detail><detail type="volume"><number>42</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue pages"><start>175</start><end>233</end></extent><extent unit="pages"><start>185</start><end>207</end></extent></part></relatedItem><identifier type="istex">B48DF05771726B4024DF8B7FF69521CDBEC43EF3</identifier><identifier type="DOI">10.1016/S0033-0620(99)70002-2</identifier><identifier type="PII">S0033-0620(99)70002-2</identifier><accessCondition type="use and reproduction" contentType="copyright">©1999 W.B. Saunders Company</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>W.B. Saunders Company, ©1999</recordOrigin></recordInfo></mods></metadata></istex></record>Pour manipuler ce document sous Unix (Dilib)
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