Hypothermia and valproic acid activate prosurvival pathways after hemorrhage
Abstract Background Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may furth...
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| Veröffentlicht in: | The Journal of surgical research 2015-06, Vol.196 (1), p.159-165 |
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| creator | Bambakidis, Ted, MSc Dekker, Simone E., BSc Liu, Baoling, MD Maxwell, Jake Chtraklin, Kiril, DVM Linzel, Durk, MD Li, Yongqing, MD, PhD Alam, Hasan B., MD |
| description | Abstract Background Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. Materials and methods Male Sprague–Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C–37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA ( n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. Results Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia ( P |
| doi_str_mv | 10.1016/j.jss.2015.02.036 |
| format | Article |
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Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. Materials and methods Male Sprague–Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C–37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA ( n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. Results Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia ( P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups ( P < 0.005). The downstream prosurvival protein phospho-GSK-3β was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA ( P < 0.05). Levels of the prosurvival β-catenin were significantly higher in the combined treatment group relative to normothermia ( P < 0.01). Conclusions This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.</description><identifier>ISSN: 0022-4804</identifier><identifier>EISSN: 1095-8673</identifier><identifier>DOI: 10.1016/j.jss.2015.02.036</identifier><identifier>PMID: 25777823</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acetylation ; Animals ; Apoptosis ; Arterial Pressure ; Hemorrhagic shock ; Histone Deacetylase Inhibitors - pharmacology ; Histones - metabolism ; Hypothermia ; Hypothermia, Induced ; Male ; Rats ; Rats, Sprague-Dawley ; Resuscitation ; Shock, Hemorrhagic - mortality ; Shock, Hemorrhagic - physiopathology ; Shock, Hemorrhagic - therapy ; Surgery ; Valproic Acid - pharmacology</subject><ispartof>The Journal of surgical research, 2015-06, Vol.196 (1), p.159-165</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-27048d759a4401093193ad710aaaa76f3a6b18fadf739c0c88223269da8c42ce3</citedby><cites>FETCH-LOGICAL-c451t-27048d759a4401093193ad710aaaa76f3a6b18fadf739c0c88223269da8c42ce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jss.2015.02.036$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25777823$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bambakidis, Ted, MSc</creatorcontrib><creatorcontrib>Dekker, Simone E., BSc</creatorcontrib><creatorcontrib>Liu, Baoling, MD</creatorcontrib><creatorcontrib>Maxwell, Jake</creatorcontrib><creatorcontrib>Chtraklin, Kiril, DVM</creatorcontrib><creatorcontrib>Linzel, Durk, MD</creatorcontrib><creatorcontrib>Li, Yongqing, MD, PhD</creatorcontrib><creatorcontrib>Alam, Hasan B., MD</creatorcontrib><title>Hypothermia and valproic acid activate prosurvival pathways after hemorrhage</title><title>The Journal of surgical research</title><addtitle>J Surg Res</addtitle><description>Abstract Background Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. Materials and methods Male Sprague–Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C–37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA ( n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. Results Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia ( P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups ( P < 0.005). The downstream prosurvival protein phospho-GSK-3β was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA ( P < 0.05). Levels of the prosurvival β-catenin were significantly higher in the combined treatment group relative to normothermia ( P < 0.01). Conclusions This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.</description><subject>Acetylation</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Arterial Pressure</subject><subject>Hemorrhagic shock</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histones - metabolism</subject><subject>Hypothermia</subject><subject>Hypothermia, Induced</subject><subject>Male</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Resuscitation</subject><subject>Shock, Hemorrhagic - mortality</subject><subject>Shock, Hemorrhagic - physiopathology</subject><subject>Shock, Hemorrhagic - therapy</subject><subject>Surgery</subject><subject>Valproic Acid - pharmacology</subject><issn>0022-4804</issn><issn>1095-8673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhq2Kql0KP4ALypFLwvgjsSMkJFQBRVqpB-BsTe0J65CPxU622n-PV1s4cMAHW2O976uZZxh7xaHiwJu3fdWnVAngdQWiAtlcsA2Hti5No-UztgEQolQG1DV7nlIPuW61vGLXotZaGyE3bHt33M_LjuIYsMDJFwcc9nEOrkAXfL6WcMCFivyX1njIxVDscdk94jEV2C0Uix2Nc4w7_EEv2GWHQ6KXT-8N-_7p47fbu3J7__nL7Ydt6VTNl1JoUMbrukWlIPcreSvRaw6Yj246ic0DNx36TsvWgTNGCCma1qNxSjiSN-zNOTd39WultNgxJEfDgBPNa7K8MZlCXZs6S_lZ6vIAKVJn9zGMGI-Wgz1BtL3NEO0JogVhM8Tsef0Uvz6M5P86_lDLgndnAeUhD4GiTS7Q5MiHSG6xfg7_jX__j9sNYQoOh590pNTPa5wyPcttygb79bTF0xJ5DcCVUvI3Q-OXUg</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Bambakidis, Ted, MSc</creator><creator>Dekker, Simone E., BSc</creator><creator>Liu, Baoling, MD</creator><creator>Maxwell, Jake</creator><creator>Chtraklin, Kiril, DVM</creator><creator>Linzel, Durk, MD</creator><creator>Li, Yongqing, MD, PhD</creator><creator>Alam, Hasan B., MD</creator><general>Elsevier Inc</general><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>20150601</creationdate><title>Hypothermia and valproic acid activate prosurvival pathways after hemorrhage</title><author>Bambakidis, Ted, MSc ; Dekker, Simone E., BSc ; Liu, Baoling, MD ; Maxwell, Jake ; Chtraklin, Kiril, DVM ; Linzel, Durk, MD ; Li, Yongqing, MD, PhD ; Alam, Hasan B., MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-27048d759a4401093193ad710aaaa76f3a6b18fadf739c0c88223269da8c42ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acetylation</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Arterial Pressure</topic><topic>Hemorrhagic shock</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histones - metabolism</topic><topic>Hypothermia</topic><topic>Hypothermia, Induced</topic><topic>Male</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Resuscitation</topic><topic>Shock, Hemorrhagic - mortality</topic><topic>Shock, Hemorrhagic - physiopathology</topic><topic>Shock, Hemorrhagic - therapy</topic><topic>Surgery</topic><topic>Valproic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bambakidis, Ted, MSc</creatorcontrib><creatorcontrib>Dekker, Simone E., BSc</creatorcontrib><creatorcontrib>Liu, Baoling, MD</creatorcontrib><creatorcontrib>Maxwell, Jake</creatorcontrib><creatorcontrib>Chtraklin, Kiril, DVM</creatorcontrib><creatorcontrib>Linzel, Durk, MD</creatorcontrib><creatorcontrib>Li, Yongqing, MD, PhD</creatorcontrib><creatorcontrib>Alam, Hasan B., MD</creatorcontrib><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>The Journal of surgical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bambakidis, Ted, MSc</au><au>Dekker, Simone E., BSc</au><au>Liu, Baoling, MD</au><au>Maxwell, Jake</au><au>Chtraklin, Kiril, DVM</au><au>Linzel, Durk, MD</au><au>Li, Yongqing, MD, PhD</au><au>Alam, Hasan B., MD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypothermia and valproic acid activate prosurvival pathways after hemorrhage</atitle><jtitle>The Journal of surgical research</jtitle><addtitle>J Surg Res</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>196</volume><issue>1</issue><spage>159</spage><epage>165</epage><pages>159-165</pages><issn>0022-4804</issn><eissn>1095-8673</eissn><abstract>Abstract Background Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. Materials and methods Male Sprague–Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C–37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA ( n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. Results Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia ( P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups ( P < 0.005). The downstream prosurvival protein phospho-GSK-3β was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA ( P < 0.05). Levels of the prosurvival β-catenin were significantly higher in the combined treatment group relative to normothermia ( P < 0.01). Conclusions This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25777823</pmid><doi>10.1016/j.jss.2015.02.036</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation Animals Apoptosis Arterial Pressure Hemorrhagic shock Histone Deacetylase Inhibitors - pharmacology Histones - metabolism Hypothermia Hypothermia, Induced Male Rats Rats, Sprague-Dawley Resuscitation Shock, Hemorrhagic - mortality Shock, Hemorrhagic - physiopathology Shock, Hemorrhagic - therapy Surgery Valproic Acid - pharmacology |
| title | Hypothermia and valproic acid activate prosurvival pathways after hemorrhage |
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