Magnesium sulfate treatment reverses seizure susceptibility and decreases neuroinflammation in a rat model of severe preeclampsia
Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclamps...
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| Veröffentlicht in: | PloS one 2014-11, Vol.9 (11), p.e113670 |
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| description | Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP + HC ± MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼ 65% lower vs. control (12.4 ± 1.7 vs. 36.7 ± 3.9 mg/kg PTZ; p |
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Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP + HC ± MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼ 65% lower vs. control (12.4 ± 1.7 vs. 36.7 ± 3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7 ± 8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5-7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9 ± 1.0 vs. 12.2 ± 0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6 ± 1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35 ± 2% of microglia being active compared to 9 ± 2% in normal pregnancy (p<0.01; n = 3-8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6 ± 2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0113670</identifier><identifier>PMID: 25409522</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Brain - metabolism ; Brain Edema - etiology ; Brain Edema - prevention & control ; Cholesterol ; Convulsants - therapeutic use ; Diet, High-Fat ; Disease Models, Animal ; Disease Susceptibility ; Eclampsia ; Eclampsia - prevention & control ; Edema ; Etiology ; Female ; Fetuses ; Fluorescein ; High cholesterol diet ; Hypertension ; Inflammation ; Inflammation - prevention & control ; Ischemia ; Laboratory animals ; Magnesium ; Magnesium sulfate ; Magnesium Sulfate - pharmacology ; Magnesium Sulfate - therapeutic use ; Medicine ; Medicine and Health Sciences ; Membrane permeability ; Metabolism ; Microglia ; Microglia - drug effects ; Microglia - physiology ; Oxidative stress ; Oxidative Stress - drug effects ; Pentylenetetrazole ; Pentylenetetrazole - therapeutic use ; Perfusion ; Permeability ; Permeability - drug effects ; Pharmacology ; Physical Sciences ; Physiology ; Placenta ; Pre-eclampsia ; Pre-Eclampsia - pathology ; Preeclampsia ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Rodents ; Seizing ; Seizures - complications ; Seizures - drug therapy ; Seizures - physiopathology ; Severity of Illness Index ; Sodium ; Sulfates</subject><ispartof>PloS one, 2014-11, Vol.9 (11), p.e113670</ispartof><rights>2014 Johnson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Johnson et al 2014 Johnson et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-2285401e2dcfa067ba3ad284d74d223961099128b807ad48596bb2bf410b44d3</citedby><cites>FETCH-LOGICAL-c526t-2285401e2dcfa067ba3ad284d74d223961099128b807ad48596bb2bf410b44d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237502/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237502/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25409522$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johnson, Abbie Chapman</creatorcontrib><creatorcontrib>Tremble, Sarah M</creatorcontrib><creatorcontrib>Chan, Siu-Lung</creatorcontrib><creatorcontrib>Moseley, Janae</creatorcontrib><creatorcontrib>LaMarca, Babbette</creatorcontrib><creatorcontrib>Nagle, Keith J</creatorcontrib><creatorcontrib>Cipolla, Marilyn J</creatorcontrib><title>Magnesium sulfate treatment reverses seizure susceptibility and decreases neuroinflammation in a rat model of severe preeclampsia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description><![CDATA[Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP + HC ± MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼ 65% lower vs. control (12.4 ± 1.7 vs. 36.7 ± 3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7 ± 8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5-7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9 ± 1.0 vs. 12.2 ± 0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6 ± 1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35 ± 2% of microglia being active compared to 9 ± 2% in normal pregnancy (p<0.01; n = 3-8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6 ± 2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.]]></description><subject>Animals</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain - metabolism</subject><subject>Brain Edema - etiology</subject><subject>Brain Edema - prevention & control</subject><subject>Cholesterol</subject><subject>Convulsants - therapeutic use</subject><subject>Diet, High-Fat</subject><subject>Disease Models, Animal</subject><subject>Disease Susceptibility</subject><subject>Eclampsia</subject><subject>Eclampsia - prevention & control</subject><subject>Edema</subject><subject>Etiology</subject><subject>Female</subject><subject>Fetuses</subject><subject>Fluorescein</subject><subject>High cholesterol diet</subject><subject>Hypertension</subject><subject>Inflammation</subject><subject>Inflammation - prevention & control</subject><subject>Ischemia</subject><subject>Laboratory animals</subject><subject>Magnesium</subject><subject>Magnesium sulfate</subject><subject>Magnesium Sulfate - pharmacology</subject><subject>Magnesium Sulfate - therapeutic use</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Membrane permeability</subject><subject>Metabolism</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - physiology</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Pentylenetetrazole</subject><subject>Pentylenetetrazole - therapeutic use</subject><subject>Perfusion</subject><subject>Permeability</subject><subject>Permeability - drug effects</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Physiology</subject><subject>Placenta</subject><subject>Pre-eclampsia</subject><subject>Pre-Eclampsia - pathology</subject><subject>Preeclampsia</subject><subject>Pregnancy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Seizing</subject><subject>Seizures - 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Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP + HC ± MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼ 65% lower vs. control (12.4 ± 1.7 vs. 36.7 ± 3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7 ± 8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5-7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9 ± 1.0 vs. 12.2 ± 0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6 ± 1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35 ± 2% of microglia being active compared to 9 ± 2% in normal pregnancy (p<0.01; n = 3-8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6 ± 2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.]]></abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25409522</pmid><doi>10.1371/journal.pone.0113670</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-11, Vol.9 (11), p.e113670 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1626170848 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Blood-brain barrier Blood-Brain Barrier - metabolism Brain - metabolism Brain Edema - etiology Brain Edema - prevention & control Cholesterol Convulsants - therapeutic use Diet, High-Fat Disease Models, Animal Disease Susceptibility Eclampsia Eclampsia - prevention & control Edema Etiology Female Fetuses Fluorescein High cholesterol diet Hypertension Inflammation Inflammation - prevention & control Ischemia Laboratory animals Magnesium Magnesium sulfate Magnesium Sulfate - pharmacology Magnesium Sulfate - therapeutic use Medicine Medicine and Health Sciences Membrane permeability Metabolism Microglia Microglia - drug effects Microglia - physiology Oxidative stress Oxidative Stress - drug effects Pentylenetetrazole Pentylenetetrazole - therapeutic use Perfusion Permeability Permeability - drug effects Pharmacology Physical Sciences Physiology Placenta Pre-eclampsia Pre-Eclampsia - pathology Preeclampsia Pregnancy Rats Rats, Sprague-Dawley Rodents Seizing Seizures - complications Seizures - drug therapy Seizures - physiopathology Severity of Illness Index Sodium Sulfates |
| title | Magnesium sulfate treatment reverses seizure susceptibility and decreases neuroinflammation in a rat model of severe preeclampsia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T22%3A00%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Magnesium%20sulfate%20treatment%20reverses%20seizure%20susceptibility%20and%20decreases%20neuroinflammation%20in%20a%20rat%20model%20of%20severe%20preeclampsia&rft.jtitle=PloS%20one&rft.au=Johnson,%20Abbie%20Chapman&rft.date=2014-11-19&rft.volume=9&rft.issue=11&rft.spage=e113670&rft.pages=e113670-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0113670&rft_dat=%3Cproquest_plos_%3E3501855971%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1626170848&rft_id=info:pmid/25409522&rft_doaj_id=oai_doaj_org_article_44856711cfa44107a8ebbedbd4c79847&rfr_iscdi=true |