Allopregnanolone, a Progesterone Metabolite, Is More Effective Than Progesterone in Reducing Cortical Infarct Volume After Transient Middle Cerebral Artery Occlusion
We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion. Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filam...
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| Veröffentlicht in: | Annals of emergency medicine 2006-04, Vol.47 (4), p.381-389 |
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| creator | Sayeed, Iqbal Guo, Qingmin Hoffman, Stuart W. Stein, Donald G. |
| description | We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion.
Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-β-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post–middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC.
After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%±10.57% (vehicle), 25.49%±7.38% (progesterone;
P |
| doi_str_mv | 10.1016/j.annemergmed.2005.12.011 |
| format | Article |
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Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-β-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post–middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC.
After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%±10.57% (vehicle), 25.49%±7.38% (progesterone;
P<.05 from vehicle), and 11.40%±7.09% (allopregnanolone;
P<.05 from vehicle;
P<.05 from progesterone). Caudate-putamen infarction (percentage of contralateral caudate-putamen) was 78.02%±22.81% (vehicle), 48.41%±22.44% (progesterone;
P<.05 from vehicle), and 50.44%±10.90% (allopregnanolone;
P<.05 from vehicle). Total hemispheric infarction (percentage of contralateral hemisphere) was 24.37%±6.69% (vehicle), 15.95%±3.59% (progesterone;
P<.05 from vehicle), and 11.54%±3.71% (allopregnanolone;
P<.05 from vehicle). No significant differences in cerebral blood flow between groups and time points during ischemia and early reperfusion were observed, suggesting that the relative ischemic insult was equivalent among all groups.
Although progesterone and allopregnanolone are effective in reducing infarct pathology, allopregnanolone is more potent than progesterone in attenuating cortical damage. Our results suggest that both neurosteroids should be examined for safety and efficacy in a clinical trial for ischemic stroke.]]></description><identifier>ISSN: 0196-0644</identifier><identifier>EISSN: 1097-6760</identifier><identifier>DOI: 10.1016/j.annemergmed.2005.12.011</identifier><identifier>PMID: 16546625</identifier><identifier>CODEN: AEMED3</identifier><language>eng</language><publisher>New York, NY: Mosby, Inc</publisher><subject>Analysis of Variance ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Autopsy ; Biological and medical sciences ; Brain - pathology ; Cerebrovascular Circulation ; Data Interpretation, Statistical ; Disease Models, Animal ; Emergency and intensive respiratory care ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - pathology ; Infarction, Middle Cerebral Artery - physiopathology ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Intensive care medicine ; Laser-Doppler Flowmetry ; Male ; Medical sciences ; Neurology ; Pregnanolone - administration & dosage ; Pregnanolone - therapeutic use ; Progesterone - administration & dosage ; Progesterone - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; Time Factors ; Vascular diseases and vascular malformations of the nervous system</subject><ispartof>Annals of emergency medicine, 2006-04, Vol.47 (4), p.381-389</ispartof><rights>2006 American College of Emergency Physicians</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-254908cdfe16cb86cd43b7edb5c3f7efd270e8265a789c24e49379936e45cae93</citedby><cites>FETCH-LOGICAL-c471t-254908cdfe16cb86cd43b7edb5c3f7efd270e8265a789c24e49379936e45cae93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.annemergmed.2005.12.011$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17664769$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16546625$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sayeed, Iqbal</creatorcontrib><creatorcontrib>Guo, Qingmin</creatorcontrib><creatorcontrib>Hoffman, Stuart W.</creatorcontrib><creatorcontrib>Stein, Donald G.</creatorcontrib><title>Allopregnanolone, a Progesterone Metabolite, Is More Effective Than Progesterone in Reducing Cortical Infarct Volume After Transient Middle Cerebral Artery Occlusion</title><title>Annals of emergency medicine</title><addtitle>Ann Emerg Med</addtitle><description><![CDATA[We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion.
Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-β-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post–middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC.
After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%±10.57% (vehicle), 25.49%±7.38% (progesterone;
P<.05 from vehicle), and 11.40%±7.09% (allopregnanolone;
P<.05 from vehicle;
P<.05 from progesterone). Caudate-putamen infarction (percentage of contralateral caudate-putamen) was 78.02%±22.81% (vehicle), 48.41%±22.44% (progesterone;
P<.05 from vehicle), and 50.44%±10.90% (allopregnanolone;
P<.05 from vehicle). Total hemispheric infarction (percentage of contralateral hemisphere) was 24.37%±6.69% (vehicle), 15.95%±3.59% (progesterone;
P<.05 from vehicle), and 11.54%±3.71% (allopregnanolone;
P<.05 from vehicle). No significant differences in cerebral blood flow between groups and time points during ischemia and early reperfusion were observed, suggesting that the relative ischemic insult was equivalent among all groups.
Although progesterone and allopregnanolone are effective in reducing infarct pathology, allopregnanolone is more potent than progesterone in attenuating cortical damage. Our results suggest that both neurosteroids should be examined for safety and efficacy in a clinical trial for ischemic stroke.]]></description><subject>Analysis of Variance</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Autopsy</subject><subject>Biological and medical sciences</subject><subject>Brain - pathology</subject><subject>Cerebrovascular Circulation</subject><subject>Data Interpretation, Statistical</subject><subject>Disease Models, Animal</subject><subject>Emergency and intensive respiratory care</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Infarction, Middle Cerebral Artery - physiopathology</subject><subject>Injections, Intraperitoneal</subject><subject>Injections, Subcutaneous</subject><subject>Intensive care medicine</subject><subject>Laser-Doppler Flowmetry</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neurology</subject><subject>Pregnanolone - administration & dosage</subject><subject>Pregnanolone - therapeutic use</subject><subject>Progesterone - administration & dosage</subject><subject>Progesterone - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion Injury</subject><subject>Time Factors</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0196-0644</issn><issn>1097-6760</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc-O0zAQhyMEYsvCKyBzYE8k2I5jJ8cqWqDSVotQ4Wo59qS4cuxiJyvtA_GeuGrFnxsny5pv7JnfVxRvCK4IJvz9oVLewwRxP4GpKMZNRWiFCXlSrAjuRMkFx0-LFSYdLzFn7Kp4kdIBY9wxSp4XV4Q3jHParIqfa-fCMcLeKx9c8PAOKfQ5hj2kGWK-oy3MagjOzrm0SWgbIqDbcQQ92wdAu-_K_8tbj76AWbT1e9SHOFutHNr4UUU9o2_BLROg9ZhhtIvKJwt-RltrjAPUQ4QhZnwdc_0R3WvtlmSDf1k8G5VL8OpyXhdfP9zu-k_l3f3HTb--KzUTZC5pwzrcajMC4XpouTasHgSYodH1KGA0VGBoKW-UaDtNGbCuFl1Xc2CNVtDV18XN-d1jDD-WvJKcbNLgnPIQliS5EJyyVmSwO4M6hpQijPIY7aTioyRYnhzJg_zLkTw5koTK7Cj3vr58sgyn2u_Oi5QMvL0AKuXwxhyTtukPJzhngp-m7c8c5EgeLESZdI5Tg7Ex65Em2P8Y5xdAeLke</recordid><startdate>20060401</startdate><enddate>20060401</enddate><creator>Sayeed, Iqbal</creator><creator>Guo, Qingmin</creator><creator>Hoffman, Stuart W.</creator><creator>Stein, Donald G.</creator><general>Mosby, Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20060401</creationdate><title>Allopregnanolone, a Progesterone Metabolite, Is More Effective Than Progesterone in Reducing Cortical Infarct Volume After Transient Middle Cerebral Artery Occlusion</title><author>Sayeed, Iqbal ; Guo, Qingmin ; Hoffman, Stuart W. ; Stein, Donald G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-254908cdfe16cb86cd43b7edb5c3f7efd270e8265a789c24e49379936e45cae93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Analysis of Variance</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Autopsy</topic><topic>Biological and medical sciences</topic><topic>Brain - pathology</topic><topic>Cerebrovascular Circulation</topic><topic>Data Interpretation, Statistical</topic><topic>Disease Models, Animal</topic><topic>Emergency and intensive respiratory care</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Infarction, Middle Cerebral Artery - physiopathology</topic><topic>Injections, Intraperitoneal</topic><topic>Injections, Subcutaneous</topic><topic>Intensive care medicine</topic><topic>Laser-Doppler Flowmetry</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Neurology</topic><topic>Pregnanolone - administration & dosage</topic><topic>Pregnanolone - therapeutic use</topic><topic>Progesterone - administration & dosage</topic><topic>Progesterone - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion Injury</topic><topic>Time Factors</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sayeed, Iqbal</creatorcontrib><creatorcontrib>Guo, Qingmin</creatorcontrib><creatorcontrib>Hoffman, Stuart W.</creatorcontrib><creatorcontrib>Stein, Donald G.</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>MEDLINE - Academic</collection><jtitle>Annals of emergency medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sayeed, Iqbal</au><au>Guo, Qingmin</au><au>Hoffman, Stuart W.</au><au>Stein, Donald G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Allopregnanolone, a Progesterone Metabolite, Is More Effective Than Progesterone in Reducing Cortical Infarct Volume After Transient Middle Cerebral Artery Occlusion</atitle><jtitle>Annals of emergency medicine</jtitle><addtitle>Ann Emerg Med</addtitle><date>2006-04-01</date><risdate>2006</risdate><volume>47</volume><issue>4</issue><spage>381</spage><epage>389</epage><pages>381-389</pages><issn>0196-0644</issn><eissn>1097-6760</eissn><coden>AEMED3</coden><abstract><![CDATA[We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion.
Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-β-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post–middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC.
After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%±10.57% (vehicle), 25.49%±7.38% (progesterone;
P<.05 from vehicle), and 11.40%±7.09% (allopregnanolone;
P<.05 from vehicle;
P<.05 from progesterone). Caudate-putamen infarction (percentage of contralateral caudate-putamen) was 78.02%±22.81% (vehicle), 48.41%±22.44% (progesterone;
P<.05 from vehicle), and 50.44%±10.90% (allopregnanolone;
P<.05 from vehicle). Total hemispheric infarction (percentage of contralateral hemisphere) was 24.37%±6.69% (vehicle), 15.95%±3.59% (progesterone;
P<.05 from vehicle), and 11.54%±3.71% (allopregnanolone;
P<.05 from vehicle). No significant differences in cerebral blood flow between groups and time points during ischemia and early reperfusion were observed, suggesting that the relative ischemic insult was equivalent among all groups.
Although progesterone and allopregnanolone are effective in reducing infarct pathology, allopregnanolone is more potent than progesterone in attenuating cortical damage. Our results suggest that both neurosteroids should be examined for safety and efficacy in a clinical trial for ischemic stroke.]]></abstract><cop>New York, NY</cop><pub>Mosby, Inc</pub><pmid>16546625</pmid><doi>10.1016/j.annemergmed.2005.12.011</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Annals of emergency medicine, 2006-04, Vol.47 (4), p.381-389 |
| issn | 0196-0644 1097-6760 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Analysis of Variance Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Autopsy Biological and medical sciences Brain - pathology Cerebrovascular Circulation Data Interpretation, Statistical Disease Models, Animal Emergency and intensive respiratory care Infarction, Middle Cerebral Artery - drug therapy Infarction, Middle Cerebral Artery - pathology Infarction, Middle Cerebral Artery - physiopathology Injections, Intraperitoneal Injections, Subcutaneous Intensive care medicine Laser-Doppler Flowmetry Male Medical sciences Neurology Pregnanolone - administration & dosage Pregnanolone - therapeutic use Progesterone - administration & dosage Progesterone - therapeutic use Rats Rats, Sprague-Dawley Reperfusion Injury Time Factors Vascular diseases and vascular malformations of the nervous system |
| title | Allopregnanolone, a Progesterone Metabolite, Is More Effective Than Progesterone in Reducing Cortical Infarct Volume After Transient Middle Cerebral Artery Occlusion |
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