Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β
IntroductionLomerizine is a calcium channel blocker that crosses the blood–brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet.MethodsTo assess the potential of lomerizine for...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150940/full |
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| author | Jin-Hee Park Jin-Hee Park Jeong-Woo Hwang Hyun-ju Lee Geum Mi Jang Yoo Joo Jeong Yoo Joo Jeong Joonho Cho Jinsoo Seo Hyang-Sook Hoe Hyang-Sook Hoe |
| author_facet | Jin-Hee Park Jin-Hee Park Jeong-Woo Hwang Hyun-ju Lee Geum Mi Jang Yoo Joo Jeong Yoo Joo Jeong Joonho Cho Jinsoo Seo Hyang-Sook Hoe Hyang-Sook Hoe |
| author_sort | Jin-Hee Park |
| collection | DOAJ |
| description | IntroductionLomerizine is a calcium channel blocker that crosses the blood–brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet.MethodsTo assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer’s disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice.ResultsIn BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice.DiscussionThese data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T03:13:03Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-76e5beac28284a098b0df467cca477042023-06-26T10:10:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11509401150940Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/βJin-Hee Park0Jin-Hee Park1Jeong-Woo Hwang2Hyun-ju Lee3Geum Mi Jang4Yoo Joo Jeong5Yoo Joo Jeong6Joonho Cho7Jinsoo Seo8Hyang-Sook Hoe9Hyang-Sook Hoe10Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of KoreaDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of KoreaDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, Republic of KoreaIntroductionLomerizine is a calcium channel blocker that crosses the blood–brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet.MethodsTo assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer’s disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice.ResultsIn BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice.DiscussionThese data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150940/fulllomerizineneuroinflammationtauopathyAlzheimer’s diseaseDYRK1ANLRP3 |
| spellingShingle | Jin-Hee Park Jin-Hee Park Jeong-Woo Hwang Hyun-ju Lee Geum Mi Jang Yoo Joo Jeong Yoo Joo Jeong Joonho Cho Jinsoo Seo Hyang-Sook Hoe Hyang-Sook Hoe Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β Frontiers in Immunology lomerizine neuroinflammation tauopathy Alzheimer’s disease DYRK1A NLRP3 |
| title | Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β |
| title_full | Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β |
| title_fullStr | Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β |
| title_full_unstemmed | Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β |
| title_short | Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β |
| title_sort | lomerizine inhibits lps mediated neuroinflammation and tau hyperphosphorylation by modulating nlrp3 dyrk1a and gsk3α β |
| topic | lomerizine neuroinflammation tauopathy Alzheimer’s disease DYRK1A NLRP3 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150940/full |
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