Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor
Objective The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has...
Gespeichert in:
| Veröffentlicht in: | Epilepsia (Copenhagen) 2022-06, Vol.63 (6), p.1580-1590 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1590 |
|---|---|
| container_issue | 6 |
| container_start_page | 1580 |
| container_title | Epilepsia (Copenhagen) |
| container_volume | 63 |
| creator | Nishi, Toshiya Metcalf, Cameron S. Fujimoto, Shinji Hasegawa, Shigeo Miyamoto, Maki Sunahara, Eiji Watanabe, Sayuri Kondo, Shinichi White, H. Steve |
| description | Objective
The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has not been fully studied. Soticlestat is a novel small‐molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
Methods
The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6‐Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady‐state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
Results
Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6‐Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S‐hydroxycholesterol lowering in the brain, suggesting that 24S‐hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.
Significance
The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy. |
| doi_str_mv | 10.1111/epi.17232 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9311151</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2672595184</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4432-1f77e0b1ddede821fec582c12071e9c1519689a8cded8481c2a4a4de064cbfff3</originalsourceid><addsrcrecordid>eNp1kd9qFDEUh4NY7Fq98AVkoDcKnTYnf2YyN4Wl1LZQ0AsF70I2c6abkp2Myczq3vkIfcY-iWm3llowN4H8Pj7OyY-Qd0APIZ8jHNwh1IyzF2QGkqkSoKpfkhmlwMtGKrpLXqd0TSmtq5q_Irtccqgk5zPyfd6PzoZ-Pfnk1lgMMQwYR4epCF2RQg49ptGMB4Up-rBGX9hluHvCGHzBxO3vm-WmjeHXxpuEheuXbuHGEN-Qnc74hG8f7j3y7dPp15Pz8vLz2cXJ_LK0QnBWQlfXSBfQttiiYtChlYpZYLQGbCxIaCrVGGVzroQCy4wwokVaCbvouo7vkeOtd5gWK2wt9mM0Xg_RrUzc6GCc_jfp3VJfhbVueP46CVnw4UEQw48pL6ZXLln03vQYpqRZJRgH1SiR0f1n6HWYYp_Xy1TNZCPhnvq4pWwMKUXsHocBqu_60rkvfd9XZt8_nf6R_FtQBo62wE_ncfN_kz79crFV_gESvKKb</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2672595184</pqid></control><display><type>article</type><title>Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor</title><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Nishi, Toshiya ; Metcalf, Cameron S. ; Fujimoto, Shinji ; Hasegawa, Shigeo ; Miyamoto, Maki ; Sunahara, Eiji ; Watanabe, Sayuri ; Kondo, Shinichi ; White, H. Steve</creator><creatorcontrib>Nishi, Toshiya ; Metcalf, Cameron S. ; Fujimoto, Shinji ; Hasegawa, Shigeo ; Miyamoto, Maki ; Sunahara, Eiji ; Watanabe, Sayuri ; Kondo, Shinichi ; White, H. Steve</creatorcontrib><description>Objective
The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has not been fully studied. Soticlestat is a novel small‐molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
Methods
The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6‐Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady‐state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
Results
Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6‐Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S‐hydroxycholesterol lowering in the brain, suggesting that 24S‐hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.
Significance
The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.17232</identifier><identifier>PMID: 35316533</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Amygdala ; Animal models ; anticonvulsants ; Auditory stimuli ; Cholesterol ; cholesterol 24‐hydroxylase ; Convulsions & seizures ; Cornea ; CYP46A1 ; Electroconvulsive therapy ; Encephalopathy ; Epilepsy ; Hydroxylase ; Kindling ; Pharmacodynamics ; Pharmacokinetics ; Phenotypes ; Seizures ; soticlestat</subject><ispartof>Epilepsia (Copenhagen), 2022-06, Vol.63 (6), p.1580-1590</ispartof><rights>2022 Takeda Pharmaceutical Company Limited. published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2022 Takeda Pharmaceutical Company Limited. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4432-1f77e0b1ddede821fec582c12071e9c1519689a8cded8481c2a4a4de064cbfff3</citedby><cites>FETCH-LOGICAL-c4432-1f77e0b1ddede821fec582c12071e9c1519689a8cded8481c2a4a4de064cbfff3</cites><orcidid>0000-0002-1510-0405 ; 0000-0002-9451-2423</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fepi.17232$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fepi.17232$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35316533$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nishi, Toshiya</creatorcontrib><creatorcontrib>Metcalf, Cameron S.</creatorcontrib><creatorcontrib>Fujimoto, Shinji</creatorcontrib><creatorcontrib>Hasegawa, Shigeo</creatorcontrib><creatorcontrib>Miyamoto, Maki</creatorcontrib><creatorcontrib>Sunahara, Eiji</creatorcontrib><creatorcontrib>Watanabe, Sayuri</creatorcontrib><creatorcontrib>Kondo, Shinichi</creatorcontrib><creatorcontrib>White, H. Steve</creatorcontrib><title>Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Objective
The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has not been fully studied. Soticlestat is a novel small‐molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
Methods
The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6‐Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady‐state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
Results
Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6‐Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S‐hydroxycholesterol lowering in the brain, suggesting that 24S‐hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.
Significance
The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.</description><subject>Amygdala</subject><subject>Animal models</subject><subject>anticonvulsants</subject><subject>Auditory stimuli</subject><subject>Cholesterol</subject><subject>cholesterol 24‐hydroxylase</subject><subject>Convulsions & seizures</subject><subject>Cornea</subject><subject>CYP46A1</subject><subject>Electroconvulsive therapy</subject><subject>Encephalopathy</subject><subject>Epilepsy</subject><subject>Hydroxylase</subject><subject>Kindling</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Phenotypes</subject><subject>Seizures</subject><subject>soticlestat</subject><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kd9qFDEUh4NY7Fq98AVkoDcKnTYnf2YyN4Wl1LZQ0AsF70I2c6abkp2Myczq3vkIfcY-iWm3llowN4H8Pj7OyY-Qd0APIZ8jHNwh1IyzF2QGkqkSoKpfkhmlwMtGKrpLXqd0TSmtq5q_Irtccqgk5zPyfd6PzoZ-Pfnk1lgMMQwYR4epCF2RQg49ptGMB4Up-rBGX9hluHvCGHzBxO3vm-WmjeHXxpuEheuXbuHGEN-Qnc74hG8f7j3y7dPp15Pz8vLz2cXJ_LK0QnBWQlfXSBfQttiiYtChlYpZYLQGbCxIaCrVGGVzroQCy4wwokVaCbvouo7vkeOtd5gWK2wt9mM0Xg_RrUzc6GCc_jfp3VJfhbVueP46CVnw4UEQw48pL6ZXLln03vQYpqRZJRgH1SiR0f1n6HWYYp_Xy1TNZCPhnvq4pWwMKUXsHocBqu_60rkvfd9XZt8_nf6R_FtQBo62wE_ncfN_kz79crFV_gESvKKb</recordid><startdate>202206</startdate><enddate>202206</enddate><creator>Nishi, Toshiya</creator><creator>Metcalf, Cameron S.</creator><creator>Fujimoto, Shinji</creator><creator>Hasegawa, Shigeo</creator><creator>Miyamoto, Maki</creator><creator>Sunahara, Eiji</creator><creator>Watanabe, Sayuri</creator><creator>Kondo, Shinichi</creator><creator>White, H. Steve</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1510-0405</orcidid><orcidid>https://orcid.org/0000-0002-9451-2423</orcidid></search><sort><creationdate>202206</creationdate><title>Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor</title><author>Nishi, Toshiya ; Metcalf, Cameron S. ; Fujimoto, Shinji ; Hasegawa, Shigeo ; Miyamoto, Maki ; Sunahara, Eiji ; Watanabe, Sayuri ; Kondo, Shinichi ; White, H. Steve</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4432-1f77e0b1ddede821fec582c12071e9c1519689a8cded8481c2a4a4de064cbfff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amygdala</topic><topic>Animal models</topic><topic>anticonvulsants</topic><topic>Auditory stimuli</topic><topic>Cholesterol</topic><topic>cholesterol 24‐hydroxylase</topic><topic>Convulsions & seizures</topic><topic>Cornea</topic><topic>CYP46A1</topic><topic>Electroconvulsive therapy</topic><topic>Encephalopathy</topic><topic>Epilepsy</topic><topic>Hydroxylase</topic><topic>Kindling</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Phenotypes</topic><topic>Seizures</topic><topic>soticlestat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nishi, Toshiya</creatorcontrib><creatorcontrib>Metcalf, Cameron S.</creatorcontrib><creatorcontrib>Fujimoto, Shinji</creatorcontrib><creatorcontrib>Hasegawa, Shigeo</creatorcontrib><creatorcontrib>Miyamoto, Maki</creatorcontrib><creatorcontrib>Sunahara, Eiji</creatorcontrib><creatorcontrib>Watanabe, Sayuri</creatorcontrib><creatorcontrib>Kondo, Shinichi</creatorcontrib><creatorcontrib>White, H. Steve</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nishi, Toshiya</au><au>Metcalf, Cameron S.</au><au>Fujimoto, Shinji</au><au>Hasegawa, Shigeo</au><au>Miyamoto, Maki</au><au>Sunahara, Eiji</au><au>Watanabe, Sayuri</au><au>Kondo, Shinichi</au><au>White, H. Steve</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2022-06</date><risdate>2022</risdate><volume>63</volume><issue>6</issue><spage>1580</spage><epage>1590</epage><pages>1580-1590</pages><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Objective
The formation of 24S‐hydroxycholesterol is a brain‐specific mechanism of cholesterol catabolism catalyzed by cholesterol 24‐hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S‐hydroxycholesterol has not been fully studied. Soticlestat is a novel small‐molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.
Methods
The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6‐Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady‐state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.
Results
Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6‐Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S‐hydroxycholesterol lowering in the brain, suggesting that 24S‐hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.
Significance
The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>35316533</pmid><doi>10.1111/epi.17232</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-1510-0405</orcidid><orcidid>https://orcid.org/0000-0002-9451-2423</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0013-9580 |
| ispartof | Epilepsia (Copenhagen), 2022-06, Vol.63 (6), p.1580-1590 |
| issn | 0013-9580 1528-1167 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9311151 |
| source | Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Amygdala Animal models anticonvulsants Auditory stimuli Cholesterol cholesterol 24‐hydroxylase Convulsions & seizures Cornea CYP46A1 Electroconvulsive therapy Encephalopathy Epilepsy Hydroxylase Kindling Pharmacodynamics Pharmacokinetics Phenotypes Seizures soticlestat |
| title | Anticonvulsive properties of soticlestat, a novel cholesterol 24‐hydroxylase inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T11%3A11%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Anticonvulsive%20properties%20of%20soticlestat,%20a%20novel%20cholesterol%2024%E2%80%90hydroxylase%20inhibitor&rft.jtitle=Epilepsia%20(Copenhagen)&rft.au=Nishi,%20Toshiya&rft.date=2022-06&rft.volume=63&rft.issue=6&rft.spage=1580&rft.epage=1590&rft.pages=1580-1590&rft.issn=0013-9580&rft.eissn=1528-1167&rft_id=info:doi/10.1111/epi.17232&rft_dat=%3Cproquest_pubme%3E2672595184%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2672595184&rft_id=info:pmid/35316533&rfr_iscdi=true |