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アイテム
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In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes neurons to synaptodendritic injury. Drugs targeting the degradative enzymes of endogenous cannabinoids have shown promise in reducing inflammation with minimal side effects in rodent models. Considering that markers of neuroinflammation can predict the extent of neuronal injury in HAND patients, we evaluated the neurotoxic effect of HIV-1 Tat-exposed microglia following blockade of fatty acid amid hydrolyze (FAAH), a catabolic enzyme responsible for degradation of endocannabinoids, e.g. anandamide (AEA). In the present study, cultured murine microglia were incubated with Tat and/or a FAAH inhibitor (PF3845). After 24 h, cells were imaged for morphological analysis and microglial conditioned media (MCM) was collected. Frontal cortex neuron cultures (DIV 7–11) were then exposed to MCM, and neurotoxicity was assessed via live cell calcium imaging and staining of actin positive dendritic structures. 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GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration
https://oist.repo.nii.ac.jp/records/2254
https://oist.repo.nii.ac.jp/records/2254214332a0-469a-45a7-bd42-3b04581ea873
名前 / ファイル | ライセンス | アクション |
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Hermes-2021-Gpr-drives-faah-inhibition-induced (8.2 MB)
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CC BY-NC-ND 4.0
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International(https://creativecommons.org/licenses/by-nc-nd/4.0/) |
Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2021-09-09 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | GPR18 drives FAAH inhibition-induced neuroprotection against HIV-1 Tat-induced neurodegeneration | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Anandamide | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Endocannabinoid | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Fatty acid amide hydrolase | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | G protein coupled receptor | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | HIV-1 Tat | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Matrix metalloproteinase | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Microglia | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Monocyte chemoattractant protein 1 | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Neuroinflammation | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Neuroprotection | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者(英) |
Hermes, Douglas J.
× Hermes, Douglas J.× Yadav-Samudrala, Barkha J.× Xu, Changqing× Paniccia, Jacqueline E.× Meeker, Rick B.× Armstrong, Michael L.× Reisdorph, Nichole× Cravatt, Benjamin F.× Mackie, Ken× Lichtman, Aron H.× Ignatowska-Jankowska, Bogna M.× Lysle, Donald T.× Fitting, Sylvia |
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書誌情報 |
en : Experimental Neurology 巻 341, p. 113699, 発行日 2021-03-15 |
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抄録 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Human immunodeficiency virus type 1 (HIV-1) is known to provoke microglial immune responses which likely play a paramount role in the development of chronic neuroinflammatory conditions and neuronal damage related to HIV-1 associated neurocognitive disorders (HAND). In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes neurons to synaptodendritic injury. Drugs targeting the degradative enzymes of endogenous cannabinoids have shown promise in reducing inflammation with minimal side effects in rodent models. Considering that markers of neuroinflammation can predict the extent of neuronal injury in HAND patients, we evaluated the neurotoxic effect of HIV-1 Tat-exposed microglia following blockade of fatty acid amid hydrolyze (FAAH), a catabolic enzyme responsible for degradation of endocannabinoids, e.g. anandamide (AEA). In the present study, cultured murine microglia were incubated with Tat and/or a FAAH inhibitor (PF3845). After 24 h, cells were imaged for morphological analysis and microglial conditioned media (MCM) was collected. Frontal cortex neuron cultures (DIV 7–11) were then exposed to MCM, and neurotoxicity was assessed via live cell calcium imaging and staining of actin positive dendritic structures. Results demonstrate a strong attenuation of microglial responses to Tat by PF3845 pretreatment, which is indicated by 1) microglial changes in morphology to a less proinflammatory phenotype using fractal analysis, 2) a decrease in release of neurotoxic cytokines/chemokines (MCP-1/CCL2) and matrix metalloproteinases (MMPs; MMP-9) using ELISA/multiplex assays, and 3) enhanced production of endocannabinoids (AEA) using LC/MS/MS. Additionally, PF3845's effects on Tat-induced microglial-mediated neurotoxicity, decreased dysregulation of neuronal intracellular calcium and prevented the loss of actin-positive staining and punctate structure in frontal cortex neuron cultures. Interestingly, these observed neuroprotective effects appeared to be independent of cannabinoid receptor activity (CB1R & CB2R). We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all experiments. Collectively, these experiments increase understanding of the role of FAAH inhibition and Tat in mediating microglial neurotoxicity in the HAND condition. | |||||
出版者 | ||||||
出版者 | Elsevier Inc. | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0014-4886 | |||||
PubMed番号 | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | PMID | |||||
関連識別子 | info:pmid/33736974 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1016/j.expneurol.2021.113699 | |||||
権利 | ||||||
権利情報 | © 2021 Elsevier Inc. | |||||
関連サイト | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://www.sciencedirect.com/science/article/pii/S0014488621001047 | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 |