A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat
Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling mod...
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| description | Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6) TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis. |
| doi_str_mv | 10.1371/journal.pone.0066885 |
| format | Article |
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The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6) TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0066885</identifier><identifier>PMID: 23825580</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amygdala ; Amygdala - physiopathology ; Animals ; Biology ; Brain ; Convulsions & seizures ; Dentate gyrus ; Dentate Gyrus - enzymology ; Dentate Gyrus - physiopathology ; Electrical stimuli ; Enzymes ; Epilepsy ; Epilepsy - enzymology ; Epilepsy - physiopathology ; Glutamate-ammonia ligase ; Glutamate-Ammonia Ligase - metabolism ; Glutamine ; Health aspects ; Hospitals ; Kindling ; Kindling, Neurologic ; Laboratory animals ; Ligases ; Male ; Medicine ; Methionine ; miRNA ; Neurobiology ; Neurosciences ; Pentylenetetrazole ; Pharmaceutical sciences ; Pharmacology ; Rats ; Rats, Sprague-Dawley ; Ribonucleic acid ; RNA ; Rodents ; Seizing ; Seizures ; Seizures (Medicine) ; Up-Regulation</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e66885-e66885</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2013 Sun et al 2013 Sun et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-95aaa925175a2de8a1ec315711dae774630dd86394c9500d8007afc57bcc3e053</citedby><cites>FETCH-LOGICAL-c692t-95aaa925175a2de8a1ec315711dae774630dd86394c9500d8007afc57bcc3e053</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/PMC3688959/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688959/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23825580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Amédée, Thierry</contributor><creatorcontrib>Sun, Hong-Liu</creatorcontrib><creatorcontrib>Zhang, Shi-Hong</creatorcontrib><creatorcontrib>Zhong, Kai</creatorcontrib><creatorcontrib>Xu, Zheng-Hao</creatorcontrib><creatorcontrib>Feng, Bo</creatorcontrib><creatorcontrib>Yu, Jie</creatorcontrib><creatorcontrib>Fang, Qi</creatorcontrib><creatorcontrib>Wang, Shuang</creatorcontrib><creatorcontrib>Wu, Deng-Chang</creatorcontrib><creatorcontrib>Zhang, Jian-Min</creatorcontrib><creatorcontrib>Chen, Zhong</creatorcontrib><title>A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6) TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.</description><subject>Amygdala</subject><subject>Amygdala - physiopathology</subject><subject>Animals</subject><subject>Biology</subject><subject>Brain</subject><subject>Convulsions & seizures</subject><subject>Dentate gyrus</subject><subject>Dentate Gyrus - enzymology</subject><subject>Dentate Gyrus - physiopathology</subject><subject>Electrical stimuli</subject><subject>Enzymes</subject><subject>Epilepsy</subject><subject>Epilepsy - enzymology</subject><subject>Epilepsy - physiopathology</subject><subject>Glutamate-ammonia ligase</subject><subject>Glutamate-Ammonia Ligase - metabolism</subject><subject>Glutamine</subject><subject>Health aspects</subject><subject>Hospitals</subject><subject>Kindling</subject><subject>Kindling, Neurologic</subject><subject>Laboratory animals</subject><subject>Ligases</subject><subject>Male</subject><subject>Medicine</subject><subject>Methionine</subject><subject>miRNA</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><subject>Pentylenetetrazole</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Rodents</subject><subject>Seizing</subject><subject>Seizures</subject><subject>Seizures 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Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat</title><author>Sun, Hong-Liu ; Zhang, Shi-Hong ; Zhong, Kai ; Xu, Zheng-Hao ; Feng, Bo ; Yu, Jie ; Fang, Qi ; Wang, Shuang ; Wu, Deng-Chang ; Zhang, Jian-Min ; Chen, Zhong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-95aaa925175a2de8a1ec315711dae774630dd86394c9500d8007afc57bcc3e053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amygdala</topic><topic>Amygdala - physiopathology</topic><topic>Animals</topic><topic>Biology</topic><topic>Brain</topic><topic>Convulsions & seizures</topic><topic>Dentate gyrus</topic><topic>Dentate Gyrus - enzymology</topic><topic>Dentate Gyrus - physiopathology</topic><topic>Electrical stimuli</topic><topic>Enzymes</topic><topic>Epilepsy</topic><topic>Epilepsy - enzymology</topic><topic>Epilepsy - 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titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Hong-Liu</au><au>Zhang, Shi-Hong</au><au>Zhong, Kai</au><au>Xu, Zheng-Hao</au><au>Feng, Bo</au><au>Yu, Jie</au><au>Fang, Qi</au><au>Wang, Shuang</au><au>Wu, Deng-Chang</au><au>Zhang, Jian-Min</au><au>Chen, Zhong</au><au>Amédée, Thierry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-06-18</date><risdate>2013</risdate><volume>8</volume><issue>6</issue><spage>e66885</spage><epage>e66885</epage><pages>e66885-e66885</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6) TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23825580</pmid><doi>10.1371/journal.pone.0066885</doi><tpages>e66885</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1369310511 |
| source | PLoS (Open access); MEDLINE; Full-Text Journals in Chemistry (Open access); PubMed Central; Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Amygdala Amygdala - physiopathology Animals Biology Brain Convulsions & seizures Dentate gyrus Dentate Gyrus - enzymology Dentate Gyrus - physiopathology Electrical stimuli Enzymes Epilepsy Epilepsy - enzymology Epilepsy - physiopathology Glutamate-ammonia ligase Glutamate-Ammonia Ligase - metabolism Glutamine Health aspects Hospitals Kindling Kindling, Neurologic Laboratory animals Ligases Male Medicine Methionine miRNA Neurobiology Neurosciences Pentylenetetrazole Pharmaceutical sciences Pharmacology Rats Rats, Sprague-Dawley Ribonucleic acid RNA Rodents Seizing Seizures Seizures (Medicine) Up-Regulation |
| title | A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T16%3A24%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Transient%20Upregulation%20of%20Glutamine%20Synthetase%20in%20the%20Dentate%20Gyrus%20Is%20Involved%20in%20Epileptogenesis%20Induced%20by%20Amygdala%20Kindling%20in%20the%20Rat&rft.jtitle=PloS%20one&rft.au=Sun,%20Hong-Liu&rft.date=2013-06-18&rft.volume=8&rft.issue=6&rft.spage=e66885&rft.epage=e66885&rft.pages=e66885-e66885&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0066885&rft_dat=%3Cgale_plos_%3EA478225229%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1369310511&rft_id=info:pmid/23825580&rft_galeid=A478225229&rft_doaj_id=oai_doaj_org_article_5a0f2f95fdfe40fd9aee896cffb32034&rfr_iscdi=true |