Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons
Excessive stimulation of the N-methyl- d-aspartate (NMDA)-type glutamate receptor has been implicated in the neuronal death resulting from focal hypoxia–ischemia. Certain neurosteroids, steroids synthesized de novo in the central nervous system (CNS), have been shown to modulate the action of neurot...
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| Veröffentlicht in: | Brain research 1998-08, Vol.803 (1), p.129-136 |
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| creator | Weaver, Charles E Wu, Fong-Sen Gibbs, Terrell T Farb, David H |
| description | Excessive stimulation of the
N-methyl-
d-aspartate (NMDA)-type glutamate receptor has been implicated in the neuronal death resulting from focal hypoxia–ischemia. Certain neurosteroids, steroids synthesized de novo in the central nervous system (CNS), have been shown to modulate the action of neurotransmitters at their cellular receptors. Pregnenolone sulfate (PS) is an abundant neurosteroid that enhances the current evoked by NMDA. Using the Ca
2+-sensitive fluorescent dye, Fluo-3, AM, and a trypan blue exclusion assay, we evaluated the ability of PS to modulate NMDA-induced changes in intracellular free calcium concentration ([Ca
2+]
i) and neuronal death in primary cultures of rat hippocampal neurons. The results demonstrate that PS potentiates NMDA-induced increases in [Ca
2+]
i by 150%. Further, PS exacerbates the MK-801-sensitive neuronal death produced by acute (PS EC
50=37 μM) or chronic NMDA exposure, reducing the EC
50 of NMDA from 13 to 4 μM under chronic exposure conditions, whereas pregnenolone is ineffective. Our results show that PS, or related sulfated neurosteroids, may play a role in the onset of excitotoxic neuronal death in vivo. |
| doi_str_mv | 10.1016/S0006-8993(98)00640-4 |
| format | Article |
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N-methyl-
d-aspartate (NMDA)-type glutamate receptor has been implicated in the neuronal death resulting from focal hypoxia–ischemia. Certain neurosteroids, steroids synthesized de novo in the central nervous system (CNS), have been shown to modulate the action of neurotransmitters at their cellular receptors. Pregnenolone sulfate (PS) is an abundant neurosteroid that enhances the current evoked by NMDA. Using the Ca
2+-sensitive fluorescent dye, Fluo-3, AM, and a trypan blue exclusion assay, we evaluated the ability of PS to modulate NMDA-induced changes in intracellular free calcium concentration ([Ca
2+]
i) and neuronal death in primary cultures of rat hippocampal neurons. The results demonstrate that PS potentiates NMDA-induced increases in [Ca
2+]
i by 150%. Further, PS exacerbates the MK-801-sensitive neuronal death produced by acute (PS EC
50=37 μM) or chronic NMDA exposure, reducing the EC
50 of NMDA from 13 to 4 μM under chronic exposure conditions, whereas pregnenolone is ineffective. Our results show that PS, or related sulfated neurosteroids, may play a role in the onset of excitotoxic neuronal death in vivo.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/S0006-8993(98)00640-4</identifier><identifier>PMID: 9729331</identifier><identifier>CODEN: BRREAP</identifier><language>eng</language><publisher>London: Elsevier B.V</publisher><subject>Aniline Compounds - analysis ; Aniline Compounds - metabolism ; Animals ; Biological and medical sciences ; Calcimycin - pharmacology ; Calcium - metabolism ; Cell Death - drug effects ; Cells, Cultured ; Central nervous system ; Central neurotransmission. Neuromudulation. Pathways and receptors ; Dose-Response Relationship, Drug ; Drug Synergism ; Excitotoxicity ; Fetus ; Fundamental and applied biological sciences. Psychology ; Hippocampus - drug effects ; Hippocampus - pathology ; N-Methylaspartate - pharmacology ; Neurons - drug effects ; Neurons - pathology ; NMDA receptor ; Potassium - pharmacology ; Pregnenolone - pharmacology ; Pregnenolone sulfate ; Rats ; Receptors, N-Methyl-D-Aspartate - drug effects ; Receptors, N-Methyl-D-Aspartate - metabolism ; Steroids ; Vertebrates: nervous system and sense organs ; Xanthenes - analysis ; Xanthenes - metabolism</subject><ispartof>Brain research, 1998-08, Vol.803 (1), p.129-136</ispartof><rights>1998 Elsevier Science B.V.</rights><rights>1998 INIST-CNRS</rights><rights>Copyright 1998 Elsevier Science B.V.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-33d3f5c5b0d2601901a2a3043d0740aade5bb3b9e2374d5f20555c30183f1d213</citedby><cites>FETCH-LOGICAL-c467t-33d3f5c5b0d2601901a2a3043d0740aade5bb3b9e2374d5f20555c30183f1d213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-8993(98)00640-4$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2378280$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9729331$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weaver, Charles E</creatorcontrib><creatorcontrib>Wu, Fong-Sen</creatorcontrib><creatorcontrib>Gibbs, Terrell T</creatorcontrib><creatorcontrib>Farb, David H</creatorcontrib><title>Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>Excessive stimulation of the
N-methyl-
d-aspartate (NMDA)-type glutamate receptor has been implicated in the neuronal death resulting from focal hypoxia–ischemia. Certain neurosteroids, steroids synthesized de novo in the central nervous system (CNS), have been shown to modulate the action of neurotransmitters at their cellular receptors. Pregnenolone sulfate (PS) is an abundant neurosteroid that enhances the current evoked by NMDA. Using the Ca
2+-sensitive fluorescent dye, Fluo-3, AM, and a trypan blue exclusion assay, we evaluated the ability of PS to modulate NMDA-induced changes in intracellular free calcium concentration ([Ca
2+]
i) and neuronal death in primary cultures of rat hippocampal neurons. The results demonstrate that PS potentiates NMDA-induced increases in [Ca
2+]
i by 150%. Further, PS exacerbates the MK-801-sensitive neuronal death produced by acute (PS EC
50=37 μM) or chronic NMDA exposure, reducing the EC
50 of NMDA from 13 to 4 μM under chronic exposure conditions, whereas pregnenolone is ineffective. Our results show that PS, or related sulfated neurosteroids, may play a role in the onset of excitotoxic neuronal death in vivo.</description><subject>Aniline Compounds - analysis</subject><subject>Aniline Compounds - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Calcimycin - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Cell Death - drug effects</subject><subject>Cells, Cultured</subject><subject>Central nervous system</subject><subject>Central neurotransmission. Neuromudulation. Pathways and receptors</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Excitotoxicity</subject><subject>Fetus</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - pathology</subject><subject>N-Methylaspartate - pharmacology</subject><subject>Neurons - drug effects</subject><subject>Neurons - pathology</subject><subject>NMDA receptor</subject><subject>Potassium - pharmacology</subject><subject>Pregnenolone - pharmacology</subject><subject>Pregnenolone sulfate</subject><subject>Rats</subject><subject>Receptors, N-Methyl-D-Aspartate - drug effects</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Steroids</subject><subject>Vertebrates: nervous system and sense organs</subject><subject>Xanthenes - analysis</subject><subject>Xanthenes - metabolism</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtv1DAQgK0KVJbSn1AphwrBIXT8SGKfUNWWR9UCEu3ZcuwJdZW1g51U8O_xdld75TQzmm8e-gg5ofCBAm3PfgJAW0ul-Dsl35dcQC0OyIrKjtUtE_CCrPbIK_I658dScq7gkByqjinO6Ypc_0j4K2CIYwxY5WUczIwV_jEWU1_SXH27vTyvfXCLRVc5NPNDFYfqwU9TtGY9mbEKuKQY8hvycjBjxuNdPCL3n67uLr7UN98_f704v6mtaLu55tzxobFND461QBVQwwwHwR10Aoxx2PQ97xUy3gnXDAyaprEcqOQDdYzyI_J2u3dK8feCedZrny2OowkYl6xpKxSXcgM2W9CmmHPCQU_Jr036qynojUP97FBvBGkl9bNDLcrcye7A0q_R7ad20kr_dNc32ZpxSCZYn_dY-VsyCQX7uMWwyHjymHS2HkPR6BPaWbvo__PIP1yfjL0</recordid><startdate>19980824</startdate><enddate>19980824</enddate><creator>Weaver, Charles E</creator><creator>Wu, Fong-Sen</creator><creator>Gibbs, Terrell T</creator><creator>Farb, David H</creator><general>Elsevier B.V</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>7TK</scope></search><sort><creationdate>19980824</creationdate><title>Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons</title><author>Weaver, Charles E ; Wu, Fong-Sen ; Gibbs, Terrell T ; Farb, David H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c467t-33d3f5c5b0d2601901a2a3043d0740aade5bb3b9e2374d5f20555c30183f1d213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Aniline Compounds - analysis</topic><topic>Aniline Compounds - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Calcimycin - pharmacology</topic><topic>Calcium - metabolism</topic><topic>Cell Death - drug effects</topic><topic>Cells, Cultured</topic><topic>Central nervous system</topic><topic>Central neurotransmission. Neuromudulation. Pathways and receptors</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Excitotoxicity</topic><topic>Fetus</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - pathology</topic><topic>N-Methylaspartate - pharmacology</topic><topic>Neurons - drug effects</topic><topic>Neurons - pathology</topic><topic>NMDA receptor</topic><topic>Potassium - pharmacology</topic><topic>Pregnenolone - pharmacology</topic><topic>Pregnenolone sulfate</topic><topic>Rats</topic><topic>Receptors, N-Methyl-D-Aspartate - drug effects</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Steroids</topic><topic>Vertebrates: nervous system and sense organs</topic><topic>Xanthenes - analysis</topic><topic>Xanthenes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weaver, Charles E</creatorcontrib><creatorcontrib>Wu, Fong-Sen</creatorcontrib><creatorcontrib>Gibbs, Terrell T</creatorcontrib><creatorcontrib>Farb, David H</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>Neurosciences Abstracts</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weaver, Charles E</au><au>Wu, Fong-Sen</au><au>Gibbs, Terrell T</au><au>Farb, David H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>1998-08-24</date><risdate>1998</risdate><volume>803</volume><issue>1</issue><spage>129</spage><epage>136</epage><pages>129-136</pages><issn>0006-8993</issn><eissn>1872-6240</eissn><coden>BRREAP</coden><abstract>Excessive stimulation of the
N-methyl-
d-aspartate (NMDA)-type glutamate receptor has been implicated in the neuronal death resulting from focal hypoxia–ischemia. Certain neurosteroids, steroids synthesized de novo in the central nervous system (CNS), have been shown to modulate the action of neurotransmitters at their cellular receptors. Pregnenolone sulfate (PS) is an abundant neurosteroid that enhances the current evoked by NMDA. Using the Ca
2+-sensitive fluorescent dye, Fluo-3, AM, and a trypan blue exclusion assay, we evaluated the ability of PS to modulate NMDA-induced changes in intracellular free calcium concentration ([Ca
2+]
i) and neuronal death in primary cultures of rat hippocampal neurons. The results demonstrate that PS potentiates NMDA-induced increases in [Ca
2+]
i by 150%. Further, PS exacerbates the MK-801-sensitive neuronal death produced by acute (PS EC
50=37 μM) or chronic NMDA exposure, reducing the EC
50 of NMDA from 13 to 4 μM under chronic exposure conditions, whereas pregnenolone is ineffective. Our results show that PS, or related sulfated neurosteroids, may play a role in the onset of excitotoxic neuronal death in vivo.</abstract><cop>London</cop><cop>Amsterdam</cop><cop>New York, NY</cop><pub>Elsevier B.V</pub><pmid>9729331</pmid><doi>10.1016/S0006-8993(98)00640-4</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aniline Compounds - analysis Aniline Compounds - metabolism Animals Biological and medical sciences Calcimycin - pharmacology Calcium - metabolism Cell Death - drug effects Cells, Cultured Central nervous system Central neurotransmission. Neuromudulation. Pathways and receptors Dose-Response Relationship, Drug Drug Synergism Excitotoxicity Fetus Fundamental and applied biological sciences. Psychology Hippocampus - drug effects Hippocampus - pathology N-Methylaspartate - pharmacology Neurons - drug effects Neurons - pathology NMDA receptor Potassium - pharmacology Pregnenolone - pharmacology Pregnenolone sulfate Rats Receptors, N-Methyl-D-Aspartate - drug effects Receptors, N-Methyl-D-Aspartate - metabolism Steroids Vertebrates: nervous system and sense organs Xanthenes - analysis Xanthenes - metabolism |
| title | Pregnenolone sulfate exacerbates NMDA-induced death of hippocampal neurons |
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