The mitochondrial uncoupler 2,4‐dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia
Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic ne...
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| Veröffentlicht in: | Journal of neurochemistry 2005-09, Vol.94 (6), p.1676-1684 |
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| container_title | Journal of neurochemistry |
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| creator | Korde, Amit S. Pettigrew, L. Creed Craddock, Susan D. Maragos, William F. |
| description | Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ‘upstream’ targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia–reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function. |
| doi_str_mv | 10.1111/j.1471-4159.2005.03328.x |
| format | Article |
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Creed ; Craddock, Susan D. ; Maragos, William F.</creator><creatorcontrib>Korde, Amit S. ; Pettigrew, L. Creed ; Craddock, Susan D. ; Maragos, William F.</creatorcontrib><description>Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ‘upstream’ targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia–reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/j.1471-4159.2005.03328.x</identifier><identifier>PMID: 16045446</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>2,4-Dinitrophenol - pharmacology ; Animals ; Biological and medical sciences ; Brain ; calcium ; Calcium Signaling - drug effects ; Calcium Signaling - physiology ; Cerebral Infarction - drug therapy ; Cerebral Infarction - physiopathology ; Cerebral Infarction - prevention & control ; Cytochromes c - metabolism ; cytochrome c ; Cytoprotection - drug effects ; Cytoprotection - physiology ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease Models, Animal ; Homeostasis - drug effects ; Homeostasis - physiology ; Ischemic Attack, Transient - drug therapy ; Ischemic Attack, Transient - metabolism ; Ischemic Attack, Transient - physiopathology ; laser Doppler flowmetry ; Male ; Medical sciences ; Mitochondria - drug effects ; Mitochondria - metabolism ; mitochondrial membrane potential ; Nerve Degeneration - drug therapy ; Nerve Degeneration - physiopathology ; Nerve Degeneration - prevention & control ; Neurology ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neuroprotective Agents - pharmacology ; Oxidative Stress - drug effects ; Oxidative Stress - physiology ; oximetry ; Rats ; Rats, Sprague-Dawley ; reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rodents ; Stroke ; Tissues ; Uncoupling Agents - pharmacology ; Vascular diseases and vascular malformations of the nervous system</subject><ispartof>Journal of neurochemistry, 2005-09, Vol.94 (6), p.1676-1684</ispartof><rights>2006 INIST-CNRS</rights><rights>2005 International Society for Neurochemistry</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4908-6f435174d206c07161eaca3accc00fb2b26ab3bb98709c1da29d32bf72fa5dad3</citedby><cites>FETCH-LOGICAL-c4908-6f435174d206c07161eaca3accc00fb2b26ab3bb98709c1da29d32bf72fa5dad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1471-4159.2005.03328.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1471-4159.2005.03328.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17062611$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16045446$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Korde, Amit S.</creatorcontrib><creatorcontrib>Pettigrew, L. Creed</creatorcontrib><creatorcontrib>Craddock, Susan D.</creatorcontrib><creatorcontrib>Maragos, William F.</creatorcontrib><title>The mitochondrial uncoupler 2,4‐dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ‘upstream’ targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia–reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.</description><subject>2,4-Dinitrophenol - pharmacology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain</subject><subject>calcium</subject><subject>Calcium Signaling - drug effects</subject><subject>Calcium Signaling - physiology</subject><subject>Cerebral Infarction - drug therapy</subject><subject>Cerebral Infarction - physiopathology</subject><subject>Cerebral Infarction - prevention & control</subject><subject>Cytochromes c - metabolism</subject><subject>cytochrome c</subject><subject>Cytoprotection - drug effects</subject><subject>Cytoprotection - physiology</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Disease Models, Animal</subject><subject>Homeostasis - drug effects</subject><subject>Homeostasis - physiology</subject><subject>Ischemic Attack, Transient - drug therapy</subject><subject>Ischemic Attack, Transient - metabolism</subject><subject>Ischemic Attack, Transient - physiopathology</subject><subject>laser Doppler flowmetry</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>mitochondrial membrane potential</subject><subject>Nerve Degeneration - drug therapy</subject><subject>Nerve Degeneration - physiopathology</subject><subject>Nerve Degeneration - prevention & control</subject><subject>Neurology</subject><subject>Neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - physiology</subject><subject>oximetry</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rodents</subject><subject>Stroke</subject><subject>Tissues</subject><subject>Uncoupling Agents - pharmacology</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EotPCKyALCVYkXDuOkyxYoBG_qmBT1pZjO41HiT3YDm13PAL7vh1PgsOMqGCFN77y_e7x0T0IYQIlyeflriSsIQUjdVdSgLqEqqJteX0Pbf407qMNAKVFBYyeoNMYdwCEM04eohPCgdWM8Q26vRgNnm3yavROBysnvDjll_1kAqYv2M_vP7R1NgW_H43zE5YpGbfIZCJONsbFYC1neWmwdBrbeR_8t9z6W3H0s_ExyWgjHvw0-SvrLnEK0kVrXMpvKlPKBNOHXNioRjNb-Qg9GOQUzePjfYa-vH1zsX1fnH9-92H7-rxQrIO24AOratIwTYEraAgnRipZSaUUwNDTnnLZV33ftQ10imhJO13RfmjoIGstdXWGnh90s_mvi4lJzNmCmSbpjF-i4G3d0g54Bp_-A-78Elz2JvLfNWuAkQy1B0gFH2Mwg9gHO8twIwiINT2xE2tIYg1JrOmJ3-mJ6zz65Ki_9LPRd4PHuDLw7AjImFc25A0qG--4BjjlZPXw6sBd2cnc_LcB8fHTdq2qX-rzutY</recordid><startdate>200509</startdate><enddate>200509</enddate><creator>Korde, Amit S.</creator><creator>Pettigrew, L. 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Creed ; Craddock, Susan D. ; Maragos, William F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4908-6f435174d206c07161eaca3accc00fb2b26ab3bb98709c1da29d32bf72fa5dad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>2,4-Dinitrophenol - pharmacology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Brain</topic><topic>calcium</topic><topic>Calcium Signaling - drug effects</topic><topic>Calcium Signaling - physiology</topic><topic>Cerebral Infarction - drug therapy</topic><topic>Cerebral Infarction - physiopathology</topic><topic>Cerebral Infarction - prevention & control</topic><topic>Cytochromes c - metabolism</topic><topic>cytochrome c</topic><topic>Cytoprotection - drug effects</topic><topic>Cytoprotection - physiology</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Disease Models, Animal</topic><topic>Homeostasis - drug effects</topic><topic>Homeostasis - physiology</topic><topic>Ischemic Attack, Transient - drug therapy</topic><topic>Ischemic Attack, Transient - metabolism</topic><topic>Ischemic Attack, Transient - physiopathology</topic><topic>laser Doppler flowmetry</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>mitochondrial membrane potential</topic><topic>Nerve Degeneration - drug therapy</topic><topic>Nerve Degeneration - physiopathology</topic><topic>Nerve Degeneration - prevention & control</topic><topic>Neurology</topic><topic>Neurons</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - physiology</topic><topic>oximetry</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Rodents</topic><topic>Stroke</topic><topic>Tissues</topic><topic>Uncoupling Agents - pharmacology</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Korde, Amit S.</creatorcontrib><creatorcontrib>Pettigrew, L. Creed</creatorcontrib><creatorcontrib>Craddock, Susan D.</creatorcontrib><creatorcontrib>Maragos, William F.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Korde, Amit S.</au><au>Pettigrew, L. Creed</au><au>Craddock, Susan D.</au><au>Maragos, William F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The mitochondrial uncoupler 2,4‐dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2005-09</date><risdate>2005</risdate><volume>94</volume><issue>6</issue><spage>1676</spage><epage>1684</epage><pages>1676-1684</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ‘upstream’ targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia–reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>16045446</pmid><doi>10.1111/j.1471-4159.2005.03328.x</doi><tpages>9</tpages></addata></record> |
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| subjects | 2,4-Dinitrophenol - pharmacology Animals Biological and medical sciences Brain calcium Calcium Signaling - drug effects Calcium Signaling - physiology Cerebral Infarction - drug therapy Cerebral Infarction - physiopathology Cerebral Infarction - prevention & control Cytochromes c - metabolism cytochrome c Cytoprotection - drug effects Cytoprotection - physiology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Homeostasis - drug effects Homeostasis - physiology Ischemic Attack, Transient - drug therapy Ischemic Attack, Transient - metabolism Ischemic Attack, Transient - physiopathology laser Doppler flowmetry Male Medical sciences Mitochondria - drug effects Mitochondria - metabolism mitochondrial membrane potential Nerve Degeneration - drug therapy Nerve Degeneration - physiopathology Nerve Degeneration - prevention & control Neurology Neurons Neurons - drug effects Neurons - metabolism Neuroprotective Agents - pharmacology Oxidative Stress - drug effects Oxidative Stress - physiology oximetry Rats Rats, Sprague-Dawley reactive oxygen species Reactive Oxygen Species - metabolism Rodents Stroke Tissues Uncoupling Agents - pharmacology Vascular diseases and vascular malformations of the nervous system |
| title | The mitochondrial uncoupler 2,4‐dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia |
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