Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model
Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms unde...
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creator | Koshimizu, Hiroyuki Ohkawara, Bisei Nakashima, Hiroaki Ota, Kyotaro Kanbara, Shunsuke Inoue, Taro Tomita, Hiroyuki Sayo, Akira Kiryu-Seo, Sumiko Konishi, Hiroyuki Ito, Mikako Masuda, Akio Ishiguro, Naoki Imagama, Shiro Kiyama, Hiroshi Ohno, Kinji |
description | Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation. |
doi_str_mv | 10.1016/j.lfs.2020.118577 |
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Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/j.lfs.2020.118577</identifier><identifier>PMID: 33058918</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Allodynia ; Anesthetics ; Animals ; Anticonvulsants ; Anticonvulsants - pharmacology ; Antidepressants ; Chemical compounds ; Cytokines ; Cytokines - metabolism ; Diabetes mellitus ; Diabetic neuropathy ; Disease Models, Animal ; Dorsal horn ; Epilepsy ; Hyperalgesia - drug therapy ; Hyperalgesia - physiopathology ; Inflammation ; Inflammatory cytokines ; Injury prevention ; Lipopolysaccharides ; Male ; Mice ; Microglia ; Microglia - metabolism ; Microglial cells ; Movement disorders ; Nervous system ; Neuralgia - drug therapy ; Neuralgia - physiopathology ; Neurodegenerative diseases ; Neuropathic pain ; Pain ; Pain perception ; Parkinson's disease ; Pharmacology ; Signs and symptoms ; Spinal cord ; Spinal Cord - metabolism ; Spinal microglial activation ; Zonisamide ; Zonisamide - pharmacology</subject><ispartof>Life sciences (1973), 2020-12, Vol.263, p.118577-118577, Article 118577</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier BV Dec 15, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-61fde7cfd5e5d009a02ebf86bb54f667a24f8b12ea54c744ff1bf57aaf7a94a93</citedby><cites>FETCH-LOGICAL-c447t-61fde7cfd5e5d009a02ebf86bb54f667a24f8b12ea54c744ff1bf57aaf7a94a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0024320520313308$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33058918$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koshimizu, Hiroyuki</creatorcontrib><creatorcontrib>Ohkawara, Bisei</creatorcontrib><creatorcontrib>Nakashima, Hiroaki</creatorcontrib><creatorcontrib>Ota, Kyotaro</creatorcontrib><creatorcontrib>Kanbara, Shunsuke</creatorcontrib><creatorcontrib>Inoue, Taro</creatorcontrib><creatorcontrib>Tomita, Hiroyuki</creatorcontrib><creatorcontrib>Sayo, Akira</creatorcontrib><creatorcontrib>Kiryu-Seo, Sumiko</creatorcontrib><creatorcontrib>Konishi, Hiroyuki</creatorcontrib><creatorcontrib>Ito, Mikako</creatorcontrib><creatorcontrib>Masuda, Akio</creatorcontrib><creatorcontrib>Ishiguro, Naoki</creatorcontrib><creatorcontrib>Imagama, Shiro</creatorcontrib><creatorcontrib>Kiyama, Hiroshi</creatorcontrib><creatorcontrib>Ohno, Kinji</creatorcontrib><title>Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.</description><subject>Allodynia</subject><subject>Anesthetics</subject><subject>Animals</subject><subject>Anticonvulsants</subject><subject>Anticonvulsants - pharmacology</subject><subject>Antidepressants</subject><subject>Chemical compounds</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Diabetes mellitus</subject><subject>Diabetic neuropathy</subject><subject>Disease Models, Animal</subject><subject>Dorsal horn</subject><subject>Epilepsy</subject><subject>Hyperalgesia - drug therapy</subject><subject>Hyperalgesia - physiopathology</subject><subject>Inflammation</subject><subject>Inflammatory cytokines</subject><subject>Injury prevention</subject><subject>Lipopolysaccharides</subject><subject>Male</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - metabolism</subject><subject>Microglial cells</subject><subject>Movement disorders</subject><subject>Nervous system</subject><subject>Neuralgia - drug therapy</subject><subject>Neuralgia - physiopathology</subject><subject>Neurodegenerative diseases</subject><subject>Neuropathic pain</subject><subject>Pain</subject><subject>Pain perception</subject><subject>Parkinson's disease</subject><subject>Pharmacology</subject><subject>Signs and symptoms</subject><subject>Spinal cord</subject><subject>Spinal Cord - metabolism</subject><subject>Spinal microglial activation</subject><subject>Zonisamide</subject><subject>Zonisamide - pharmacology</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhAbggS1y4ZLEdO07ECVVAkSpxgQsXa-KMW6-cONhO0b49Xm3hwKGXGY39za-Z-Ql5zdmeM969P-yDy3vBRK15r7R-Qna810PDupY_JTvGhGxawdQFeZHzgTGmlG6fk4u2ZaofeL8jv3_GxWeY_YQUZgw-JiiY6YJbiiuUO2_pCn6pIZVwpOOR5m1dE-bsl1s6e5vibfAQKNji76H4uNCKlzukefVL_bAxTacnoHPcMtY4YXhJnjkIGV895Evy4_On71fXzc23L1-vPt40Vkpdmo67CbV1k0I1MTYAEzi6vhtHJV3XaRDS9SMXCEpaLaVzfHRKAzgNg4ShvSTvzrprir82zMXMPlsMARas0xghVb2ckK2q6Nv_0EPcUt2gUkoIKWTPToL8TNXFc07ozJr8DOloODMnV8zBVFfMyRVzdqX2vHlQ3sYZp38df22owIczgPUU9x6TydbjYnHyCW0xU_SPyP8BkKafgA</recordid><startdate>20201215</startdate><enddate>20201215</enddate><creator>Koshimizu, Hiroyuki</creator><creator>Ohkawara, Bisei</creator><creator>Nakashima, Hiroaki</creator><creator>Ota, Kyotaro</creator><creator>Kanbara, Shunsuke</creator><creator>Inoue, Taro</creator><creator>Tomita, Hiroyuki</creator><creator>Sayo, Akira</creator><creator>Kiryu-Seo, Sumiko</creator><creator>Konishi, Hiroyuki</creator><creator>Ito, Mikako</creator><creator>Masuda, Akio</creator><creator>Ishiguro, Naoki</creator><creator>Imagama, Shiro</creator><creator>Kiyama, Hiroshi</creator><creator>Ohno, Kinji</creator><general>Elsevier Inc</general><general>Elsevier BV</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20201215</creationdate><title>Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model</title><author>Koshimizu, Hiroyuki ; Ohkawara, Bisei ; Nakashima, Hiroaki ; Ota, Kyotaro ; Kanbara, Shunsuke ; Inoue, Taro ; Tomita, Hiroyuki ; Sayo, Akira ; Kiryu-Seo, Sumiko ; Konishi, Hiroyuki ; Ito, Mikako ; Masuda, Akio ; Ishiguro, Naoki ; Imagama, Shiro ; Kiyama, Hiroshi ; Ohno, Kinji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-61fde7cfd5e5d009a02ebf86bb54f667a24f8b12ea54c744ff1bf57aaf7a94a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Allodynia</topic><topic>Anesthetics</topic><topic>Animals</topic><topic>Anticonvulsants</topic><topic>Anticonvulsants - pharmacology</topic><topic>Antidepressants</topic><topic>Chemical compounds</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Diabetes mellitus</topic><topic>Diabetic neuropathy</topic><topic>Disease Models, Animal</topic><topic>Dorsal horn</topic><topic>Epilepsy</topic><topic>Hyperalgesia - drug therapy</topic><topic>Hyperalgesia - physiopathology</topic><topic>Inflammation</topic><topic>Inflammatory cytokines</topic><topic>Injury prevention</topic><topic>Lipopolysaccharides</topic><topic>Male</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - metabolism</topic><topic>Microglial cells</topic><topic>Movement disorders</topic><topic>Nervous system</topic><topic>Neuralgia - drug therapy</topic><topic>Neuralgia - physiopathology</topic><topic>Neurodegenerative diseases</topic><topic>Neuropathic pain</topic><topic>Pain</topic><topic>Pain perception</topic><topic>Parkinson's disease</topic><topic>Pharmacology</topic><topic>Signs and symptoms</topic><topic>Spinal cord</topic><topic>Spinal Cord - metabolism</topic><topic>Spinal microglial activation</topic><topic>Zonisamide</topic><topic>Zonisamide - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koshimizu, Hiroyuki</creatorcontrib><creatorcontrib>Ohkawara, Bisei</creatorcontrib><creatorcontrib>Nakashima, Hiroaki</creatorcontrib><creatorcontrib>Ota, Kyotaro</creatorcontrib><creatorcontrib>Kanbara, Shunsuke</creatorcontrib><creatorcontrib>Inoue, Taro</creatorcontrib><creatorcontrib>Tomita, Hiroyuki</creatorcontrib><creatorcontrib>Sayo, Akira</creatorcontrib><creatorcontrib>Kiryu-Seo, Sumiko</creatorcontrib><creatorcontrib>Konishi, Hiroyuki</creatorcontrib><creatorcontrib>Ito, Mikako</creatorcontrib><creatorcontrib>Masuda, Akio</creatorcontrib><creatorcontrib>Ishiguro, Naoki</creatorcontrib><creatorcontrib>Imagama, Shiro</creatorcontrib><creatorcontrib>Kiyama, Hiroshi</creatorcontrib><creatorcontrib>Ohno, Kinji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koshimizu, Hiroyuki</au><au>Ohkawara, Bisei</au><au>Nakashima, Hiroaki</au><au>Ota, Kyotaro</au><au>Kanbara, Shunsuke</au><au>Inoue, Taro</au><au>Tomita, Hiroyuki</au><au>Sayo, Akira</au><au>Kiryu-Seo, Sumiko</au><au>Konishi, Hiroyuki</au><au>Ito, Mikako</au><au>Masuda, Akio</au><au>Ishiguro, Naoki</au><au>Imagama, Shiro</au><au>Kiyama, Hiroshi</au><au>Ohno, Kinji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2020-12-15</date><risdate>2020</risdate><volume>263</volume><spage>118577</spage><epage>118577</epage><pages>118577-118577</pages><artnum>118577</artnum><issn>0024-3205</issn><eissn>1879-0631</eissn><abstract>Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>33058918</pmid><doi>10.1016/j.lfs.2020.118577</doi><tpages>1</tpages></addata></record> |
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subjects | Allodynia Anesthetics Animals Anticonvulsants Anticonvulsants - pharmacology Antidepressants Chemical compounds Cytokines Cytokines - metabolism Diabetes mellitus Diabetic neuropathy Disease Models, Animal Dorsal horn Epilepsy Hyperalgesia - drug therapy Hyperalgesia - physiopathology Inflammation Inflammatory cytokines Injury prevention Lipopolysaccharides Male Mice Microglia Microglia - metabolism Microglial cells Movement disorders Nervous system Neuralgia - drug therapy Neuralgia - physiopathology Neurodegenerative diseases Neuropathic pain Pain Pain perception Parkinson's disease Pharmacology Signs and symptoms Spinal cord Spinal Cord - metabolism Spinal microglial activation Zonisamide Zonisamide - pharmacology |
title | Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model |
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