Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model
No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson&...
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| Veröffentlicht in: | PloS one 2015-11, Vol.10 (11), p.e0142786-e0142786 |
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| creator | Yagi, Hideki Ohkawara, Bisei Nakashima, Hiroaki Ito, Kenyu Tsushima, Mikito Ishii, Hisao Noto, Kimitoshi Ohta, Kyotaro Masuda, Akio Imagama, Shiro Ishiguro, Naoki Ohno, Kinji |
| description | No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies. |
| doi_str_mv | 10.1371/journal.pone.0142786 |
| format | Article |
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To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0142786</identifier><identifier>PMID: 26571146</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activities of daily living ; Animals ; Anticonvulsants ; Apoptosis ; Autografts - drug effects ; Axons ; Bone surgery ; Brain-derived neurotrophic factor ; Cancer therapies ; Cell death ; Cell Line, Tumor ; Cells, Cultured ; Chemical compounds ; Cytoprotection - drug effects ; Degeneration ; Denervation ; Drug approval ; Elongation ; Epilepsy ; Etiology ; Gene expression ; Growth factors ; Hand surgery ; Ischemia ; Isoxazoles - pharmacology ; Kinases ; Male ; Medicine ; Mice, Inbred C57BL ; Models, Animal ; Motor neurons ; Motor Neurons - drug effects ; Motor Neurons - physiology ; Muscles ; Nerve growth factor ; Nerve Growth Factors - genetics ; Nerve Growth Factors - metabolism ; Nerve Regeneration - drug effects ; Neurites - drug effects ; Neurites - physiology ; Neuroblastoma ; Neurons ; Neuropathy ; Neurotrophin 4 ; Orthopedics ; Oxidative stress ; Oxidative Stress - drug effects ; Parkinson's disease ; Peripheral neuropathy ; Pharmacology ; Receptors ; Receptors, Nerve Growth Factor - genetics ; Receptors, Nerve Growth Factor - metabolism ; Regeneration ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Sciatic nerve ; Sciatic Nerve - drug effects ; Sciatic Nerve - physiology ; Skeletal muscle ; Spinal cord ; Surgery ; Time Factors ; Tropomyosin ; University graduates ; Up-Regulation - drug effects ; Up-Regulation - genetics ; Zonisamide</subject><ispartof>PloS one, 2015-11, Vol.10 (11), p.e0142786-e0142786</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Yagi 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>2015 Yagi et al 2015 Yagi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c802t-c105d8c972b0ae3018ae221e3bc5fcb6470d8ec73a51916d6ceef0c3e2680bae3</citedby><cites>FETCH-LOGICAL-c802t-c105d8c972b0ae3018ae221e3bc5fcb6470d8ec73a51916d6ceef0c3e2680bae3</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/PMC4646494/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646494/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26571146$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Nógrádi, Antal</contributor><creatorcontrib>Yagi, Hideki</creatorcontrib><creatorcontrib>Ohkawara, Bisei</creatorcontrib><creatorcontrib>Nakashima, Hiroaki</creatorcontrib><creatorcontrib>Ito, Kenyu</creatorcontrib><creatorcontrib>Tsushima, Mikito</creatorcontrib><creatorcontrib>Ishii, Hisao</creatorcontrib><creatorcontrib>Noto, Kimitoshi</creatorcontrib><creatorcontrib>Ohta, Kyotaro</creatorcontrib><creatorcontrib>Masuda, Akio</creatorcontrib><creatorcontrib>Imagama, Shiro</creatorcontrib><creatorcontrib>Ishiguro, Naoki</creatorcontrib><creatorcontrib>Ohno, Kinji</creatorcontrib><title>Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.</description><subject>Activities of daily living</subject><subject>Animals</subject><subject>Anticonvulsants</subject><subject>Apoptosis</subject><subject>Autografts - drug effects</subject><subject>Axons</subject><subject>Bone surgery</subject><subject>Brain-derived neurotrophic factor</subject><subject>Cancer therapies</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Chemical compounds</subject><subject>Cytoprotection - drug effects</subject><subject>Degeneration</subject><subject>Denervation</subject><subject>Drug approval</subject><subject>Elongation</subject><subject>Epilepsy</subject><subject>Etiology</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Hand surgery</subject><subject>Ischemia</subject><subject>Isoxazoles - pharmacology</subject><subject>Kinases</subject><subject>Male</subject><subject>Medicine</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Animal</subject><subject>Motor neurons</subject><subject>Motor Neurons - drug effects</subject><subject>Motor Neurons - physiology</subject><subject>Muscles</subject><subject>Nerve growth factor</subject><subject>Nerve Growth Factors - genetics</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Nerve Regeneration - drug effects</subject><subject>Neurites - drug effects</subject><subject>Neurites - physiology</subject><subject>Neuroblastoma</subject><subject>Neurons</subject><subject>Neuropathy</subject><subject>Neurotrophin 4</subject><subject>Orthopedics</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Parkinson's disease</subject><subject>Peripheral neuropathy</subject><subject>Pharmacology</subject><subject>Receptors</subject><subject>Receptors, Nerve Growth Factor - genetics</subject><subject>Receptors, Nerve Growth Factor - metabolism</subject><subject>Regeneration</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Sciatic nerve</subject><subject>Sciatic Nerve - drug effects</subject><subject>Sciatic Nerve - physiology</subject><subject>Skeletal muscle</subject><subject>Spinal cord</subject><subject>Surgery</subject><subject>Time Factors</subject><subject>Tropomyosin</subject><subject>University graduates</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - genetics</subject><subject>Zonisamide</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9Fu0zAUhiMEYmPwBggiISG4aLFjx3FuJk3TBpUGmwbsghvLtU9aV6ldbGeCZ-ClcdpsatAukKXEOfn-_9jHPln2EqMpJhX-sHKdt7KdbpyFKcK0qDh7lB3imhQTViDyeG9-kD0LYYVQSThjT7ODgpUVxpQdZn9-OGuCXBsN-ZldSqsg5F-g8yamQOvsQkbjbO6a_MqbtfS_888uOr9lnA25tDo_l8q0JsqYtFfgzWYJXrYJ8beQX8MCbPre2sxsfmOid1uZsblMbl2A9NTQPs-eNLIN8GJ4H2Xfz8--nX6aXFx-nJ2eXEwUR0WcKIxKzVVdFXMkgSDMJRQFBjJXZaPmjFZIc1AVkSWuMdNMATRIESgYR_OkOMpe73w3rQtiqGMQuCKE8rpmOBGzHaGdXInNbuPCSSO2AecXQvpoVAuibhDHmjYMtKasZpKTuqEE4xLSAmWdvI6HbN18DVqBjak4I9PxH2uWYuFuBWVp1DQZvBsMvPvZQYhibYKCtpUWUvH6dTOazh_zhL75B314dwO1kGkDxjYu5VW9qTihhFaUI96nnT5ApaFhbVS6dI1J8ZHg_UiQmAi_4kJ2IYjZ1-v_Zy9vxuzbPXYJso3L4Nquv1BhDNIdqLwLwUNzX2SMRN8zd9UQfc-IoWeS7NX-Ad2L7pqE_AUXVRLV</recordid><startdate>20151116</startdate><enddate>20151116</enddate><creator>Yagi, Hideki</creator><creator>Ohkawara, Bisei</creator><creator>Nakashima, Hiroaki</creator><creator>Ito, Kenyu</creator><creator>Tsushima, Mikito</creator><creator>Ishii, Hisao</creator><creator>Noto, Kimitoshi</creator><creator>Ohta, Kyotaro</creator><creator>Masuda, Akio</creator><creator>Imagama, Shiro</creator><creator>Ishiguro, Naoki</creator><creator>Ohno, Kinji</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20151116</creationdate><title>Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model</title><author>Yagi, Hideki ; Ohkawara, Bisei ; Nakashima, Hiroaki ; Ito, Kenyu ; Tsushima, Mikito ; Ishii, Hisao ; Noto, Kimitoshi ; Ohta, Kyotaro ; Masuda, Akio ; Imagama, Shiro ; Ishiguro, Naoki ; Ohno, Kinji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c802t-c105d8c972b0ae3018ae221e3bc5fcb6470d8ec73a51916d6ceef0c3e2680bae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activities of daily living</topic><topic>Animals</topic><topic>Anticonvulsants</topic><topic>Apoptosis</topic><topic>Autografts - drug effects</topic><topic>Axons</topic><topic>Bone surgery</topic><topic>Brain-derived neurotrophic factor</topic><topic>Cancer therapies</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>Chemical compounds</topic><topic>Cytoprotection - drug effects</topic><topic>Degeneration</topic><topic>Denervation</topic><topic>Drug approval</topic><topic>Elongation</topic><topic>Epilepsy</topic><topic>Etiology</topic><topic>Gene expression</topic><topic>Growth factors</topic><topic>Hand surgery</topic><topic>Ischemia</topic><topic>Isoxazoles - pharmacology</topic><topic>Kinases</topic><topic>Male</topic><topic>Medicine</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Animal</topic><topic>Motor neurons</topic><topic>Motor Neurons - drug effects</topic><topic>Motor Neurons - physiology</topic><topic>Muscles</topic><topic>Nerve growth factor</topic><topic>Nerve Growth Factors - genetics</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Nerve Regeneration - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yagi, Hideki</au><au>Ohkawara, Bisei</au><au>Nakashima, Hiroaki</au><au>Ito, Kenyu</au><au>Tsushima, Mikito</au><au>Ishii, Hisao</au><au>Noto, Kimitoshi</au><au>Ohta, Kyotaro</au><au>Masuda, Akio</au><au>Imagama, Shiro</au><au>Ishiguro, Naoki</au><au>Ohno, Kinji</au><au>Nógrádi, Antal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-11-16</date><risdate>2015</risdate><volume>10</volume><issue>11</issue><spage>e0142786</spage><epage>e0142786</epage><pages>e0142786-e0142786</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26571146</pmid><doi>10.1371/journal.pone.0142786</doi><tpages>e0142786</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-11, Vol.10 (11), p.e0142786-e0142786 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1733489961 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activities of daily living Animals Anticonvulsants Apoptosis Autografts - drug effects Axons Bone surgery Brain-derived neurotrophic factor Cancer therapies Cell death Cell Line, Tumor Cells, Cultured Chemical compounds Cytoprotection - drug effects Degeneration Denervation Drug approval Elongation Epilepsy Etiology Gene expression Growth factors Hand surgery Ischemia Isoxazoles - pharmacology Kinases Male Medicine Mice, Inbred C57BL Models, Animal Motor neurons Motor Neurons - drug effects Motor Neurons - physiology Muscles Nerve growth factor Nerve Growth Factors - genetics Nerve Growth Factors - metabolism Nerve Regeneration - drug effects Neurites - drug effects Neurites - physiology Neuroblastoma Neurons Neuropathy Neurotrophin 4 Orthopedics Oxidative stress Oxidative Stress - drug effects Parkinson's disease Peripheral neuropathy Pharmacology Receptors Receptors, Nerve Growth Factor - genetics Receptors, Nerve Growth Factor - metabolism Regeneration RNA RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Sciatic nerve Sciatic Nerve - drug effects Sciatic Nerve - physiology Skeletal muscle Spinal cord Surgery Time Factors Tropomyosin University graduates Up-Regulation - drug effects Up-Regulation - genetics Zonisamide |
| title | Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model |
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