Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models
Background The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. Objective The objective of this study was...
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| Veröffentlicht in: | Movement disorders 2021-07, Vol.36 (7), p.1554-1564 |
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| creator | Ueda, Jun Uemura, Norihito Sawamura, Masanori Taguchi, Tomoyuki Ikuno, Masashi Kaji, Seiji Taruno, Yosuke Matsuzawa, Shuichi Yamakado, Hodaka Takahashi, Ryosuke |
| description | Background
The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.
Objective
The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.
Methods
Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo.
Results
Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.
Conclusion
Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society |
| doi_str_mv | 10.1002/mds.28558 |
| format | Article |
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The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.
Objective
The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.
Methods
Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo.
Results
Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.
Conclusion
Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society</description><identifier>ISSN: 0885-3185</identifier><identifier>EISSN: 1531-8257</identifier><identifier>DOI: 10.1002/mds.28558</identifier><identifier>PMID: 33813737</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>alpha-Synuclein - genetics ; Animal models ; Animals ; Antiepileptic agents ; Cell culture ; Disease transmission ; Fibrils ; Hippocampus ; macropinocytosis ; Mice ; Movement disorders ; Neurodegenerative diseases ; Neuromodulation ; neuronal activity ; Nitriles ; Oral administration ; Parkinson Disease - drug therapy ; Parkinson's disease ; Pathology ; perampanel ; Pyridones - pharmacology ; Synuclein ; Synucleinopathies ; α‐synuclein</subject><ispartof>Movement disorders, 2021-07, Vol.36 (7), p.1554-1564</ispartof><rights>2021 International Parkinson and Movement Disorder Society</rights><rights>2021 International Parkinson and Movement Disorder Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4988-f574773b739f9b71a0385c3dd366547db486c0f1ff565a0a87f32264e22223af3</citedby><cites>FETCH-LOGICAL-c4988-f574773b739f9b71a0385c3dd366547db486c0f1ff565a0a87f32264e22223af3</cites><orcidid>0000-0002-6251-0810 ; 0000-0002-6436-7923 ; 0000-0002-1407-9640</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmds.28558$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmds.28558$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33813737$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ueda, Jun</creatorcontrib><creatorcontrib>Uemura, Norihito</creatorcontrib><creatorcontrib>Sawamura, Masanori</creatorcontrib><creatorcontrib>Taguchi, Tomoyuki</creatorcontrib><creatorcontrib>Ikuno, Masashi</creatorcontrib><creatorcontrib>Kaji, Seiji</creatorcontrib><creatorcontrib>Taruno, Yosuke</creatorcontrib><creatorcontrib>Matsuzawa, Shuichi</creatorcontrib><creatorcontrib>Yamakado, Hodaka</creatorcontrib><creatorcontrib>Takahashi, Ryosuke</creatorcontrib><title>Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models</title><title>Movement disorders</title><addtitle>Mov Disord</addtitle><description>Background
The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.
Objective
The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.
Methods
Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo.
Results
Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.
Conclusion
Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society</description><subject>alpha-Synuclein - genetics</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antiepileptic agents</subject><subject>Cell culture</subject><subject>Disease transmission</subject><subject>Fibrils</subject><subject>Hippocampus</subject><subject>macropinocytosis</subject><subject>Mice</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Neuromodulation</subject><subject>neuronal activity</subject><subject>Nitriles</subject><subject>Oral administration</subject><subject>Parkinson Disease - drug therapy</subject><subject>Parkinson's disease</subject><subject>Pathology</subject><subject>perampanel</subject><subject>Pyridones - pharmacology</subject><subject>Synuclein</subject><subject>Synucleinopathies</subject><subject>α‐synuclein</subject><issn>0885-3185</issn><issn>1531-8257</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10E1KxDAUB_Agio6jCy8gBRfqopqPpkmX4vgxMIMD6rqkbYLRNh3zLDI7j-BVvIiH8CRGO7oQzOYR-PHnvT9COwQfEYzpcVPBEZWcyxU0IJyRWFIuVtEAS8ljRiTfQJsA9xgTwkm6jjYYk4QJJgZoOtNeNXPldB2N3Z0t7BNE728fL6_XC9eVtbYuuvHKQWMBbOui8J8p_2AdtG4fopEFrUBH07bSNWyhNaNq0NvLOUS352c3p5fx5OpifHoyicskkzI2XCRCsEKwzGSFIAozyUtWVSxNeSKqIpFpiQ0xhqdcYSWFYZSmiabhMWXYEB30uXPfPnYanvKwXqnrOtzRdpBTHk7PqKQy0L0_9L7tvAvbBcUTLlIuRVCHvSp9C-C1yefeNsovcoLzr47z0HH-3XGwu8vErmh09St_Sg3guAfPttaL_5Py6ei6j_wEtVWF1Q</recordid><startdate>202107</startdate><enddate>202107</enddate><creator>Ueda, Jun</creator><creator>Uemura, Norihito</creator><creator>Sawamura, Masanori</creator><creator>Taguchi, Tomoyuki</creator><creator>Ikuno, Masashi</creator><creator>Kaji, Seiji</creator><creator>Taruno, Yosuke</creator><creator>Matsuzawa, Shuichi</creator><creator>Yamakado, Hodaka</creator><creator>Takahashi, Ryosuke</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, 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>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6251-0810</orcidid><orcidid>https://orcid.org/0000-0002-6436-7923</orcidid><orcidid>https://orcid.org/0000-0002-1407-9640</orcidid></search><sort><creationdate>202107</creationdate><title>Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models</title><author>Ueda, Jun ; Uemura, Norihito ; Sawamura, Masanori ; Taguchi, Tomoyuki ; Ikuno, Masashi ; Kaji, Seiji ; Taruno, Yosuke ; Matsuzawa, Shuichi ; Yamakado, Hodaka ; Takahashi, Ryosuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4988-f574773b739f9b71a0385c3dd366547db486c0f1ff565a0a87f32264e22223af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>alpha-Synuclein - genetics</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antiepileptic agents</topic><topic>Cell culture</topic><topic>Disease transmission</topic><topic>Fibrils</topic><topic>Hippocampus</topic><topic>macropinocytosis</topic><topic>Mice</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Neuromodulation</topic><topic>neuronal activity</topic><topic>Nitriles</topic><topic>Oral administration</topic><topic>Parkinson Disease - drug therapy</topic><topic>Parkinson's disease</topic><topic>Pathology</topic><topic>perampanel</topic><topic>Pyridones - pharmacology</topic><topic>Synuclein</topic><topic>Synucleinopathies</topic><topic>α‐synuclein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ueda, Jun</creatorcontrib><creatorcontrib>Uemura, Norihito</creatorcontrib><creatorcontrib>Sawamura, Masanori</creatorcontrib><creatorcontrib>Taguchi, Tomoyuki</creatorcontrib><creatorcontrib>Ikuno, Masashi</creatorcontrib><creatorcontrib>Kaji, Seiji</creatorcontrib><creatorcontrib>Taruno, Yosuke</creatorcontrib><creatorcontrib>Matsuzawa, Shuichi</creatorcontrib><creatorcontrib>Yamakado, Hodaka</creatorcontrib><creatorcontrib>Takahashi, Ryosuke</creatorcontrib><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><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Movement disorders</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ueda, Jun</au><au>Uemura, Norihito</au><au>Sawamura, Masanori</au><au>Taguchi, Tomoyuki</au><au>Ikuno, Masashi</au><au>Kaji, Seiji</au><au>Taruno, Yosuke</au><au>Matsuzawa, Shuichi</au><au>Yamakado, Hodaka</au><au>Takahashi, Ryosuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models</atitle><jtitle>Movement disorders</jtitle><addtitle>Mov Disord</addtitle><date>2021-07</date><risdate>2021</risdate><volume>36</volume><issue>7</issue><spage>1554</spage><epage>1564</epage><pages>1554-1564</pages><issn>0885-3185</issn><eissn>1531-8257</eissn><abstract>Background
The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.
Objective
The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.
Methods
Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo.
Results
Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.
Conclusion
Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>33813737</pmid><doi>10.1002/mds.28558</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-6251-0810</orcidid><orcidid>https://orcid.org/0000-0002-6436-7923</orcidid><orcidid>https://orcid.org/0000-0002-1407-9640</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Access via Wiley Online Library |
| subjects | alpha-Synuclein - genetics Animal models Animals Antiepileptic agents Cell culture Disease transmission Fibrils Hippocampus macropinocytosis Mice Movement disorders Neurodegenerative diseases Neuromodulation neuronal activity Nitriles Oral administration Parkinson Disease - drug therapy Parkinson's disease Pathology perampanel Pyridones - pharmacology Synuclein Synucleinopathies α‐synuclein |
| title | Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models |
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