Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway
Background: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02707/full |
| _version_ | 1818608855440949248 |
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| author | JinHong Jiang JinHong Jiang Zhe Wang Zhe Wang XueYa Liang YaoYan Nie Xin Chang HongXiang Xue Shu Li Chang Min |
| author_facet | JinHong Jiang JinHong Jiang Zhe Wang Zhe Wang XueYa Liang YaoYan Nie Xin Chang HongXiang Xue Shu Li Chang Min |
| author_sort | JinHong Jiang |
| collection | DOAJ |
| description | Background: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as a promising option for the treatment of AD. Increasing evidence points at MK2 as involved in neuroinflammatory responses. MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. Therefore, it is important to understand the actions of MMI-0100 in neuroinflammation.Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, Western blotting, and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution after intranasal MMI-0100 application.Results: Central MMI-0100 was able to ameliorate the memory deficit induced by Aβ1−42 or LPS in novel object and location memory tasks. MMI-0100 suppressed LPS-induced activation of astrocytes and microglia, and dramatically decreased a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, COX-2, and iNOS via inhibiting phosphorylation of MK2, but not ERK, JNK, and p38 in vivo and in vitro. Importantly, one of the reasons for the failure of macromolecular protein or peptide drugs in the treatment of AD is that they cannot cross the blood–brain barrier. Our data showed that intranasal administration of MMI-0100 significantly ameliorates the memory deficit induced by Aβ1−42 or LPS. Near-infrared fluorescent and confocal microscopy experiment results showed that a strong fluorescent signal, coming from mouse brains, was observed at 2 h after nasal applications of Cy7.5-MMI-0100. However, brains from control mice treated with saline or Cy7.5 alone displayed no significant signal.Conclusions: MMI-0100 attenuates Aβ1−42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that the MMI-0100/MK2 system may provide a new potential target for treatment of AD. |
| first_indexed | 2024-12-16T14:49:17Z |
| format | Article |
| id | doaj.art-90aabe5fb784479981483ce68c936cfa |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T14:49:17Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-90aabe5fb784479981483ce68c936cfa2022-12-21T22:27:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02707469485Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling PathwayJinHong Jiang0JinHong Jiang1Zhe Wang2Zhe Wang3XueYa Liang4YaoYan Nie5Xin Chang6HongXiang Xue7Shu Li8Chang Min9Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaJiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaInstitute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, ChinaBackground: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as a promising option for the treatment of AD. Increasing evidence points at MK2 as involved in neuroinflammatory responses. MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. Therefore, it is important to understand the actions of MMI-0100 in neuroinflammation.Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, Western blotting, and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution after intranasal MMI-0100 application.Results: Central MMI-0100 was able to ameliorate the memory deficit induced by Aβ1−42 or LPS in novel object and location memory tasks. MMI-0100 suppressed LPS-induced activation of astrocytes and microglia, and dramatically decreased a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, COX-2, and iNOS via inhibiting phosphorylation of MK2, but not ERK, JNK, and p38 in vivo and in vitro. Importantly, one of the reasons for the failure of macromolecular protein or peptide drugs in the treatment of AD is that they cannot cross the blood–brain barrier. Our data showed that intranasal administration of MMI-0100 significantly ameliorates the memory deficit induced by Aβ1−42 or LPS. Near-infrared fluorescent and confocal microscopy experiment results showed that a strong fluorescent signal, coming from mouse brains, was observed at 2 h after nasal applications of Cy7.5-MMI-0100. However, brains from control mice treated with saline or Cy7.5 alone displayed no significant signal.Conclusions: MMI-0100 attenuates Aβ1−42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that the MMI-0100/MK2 system may provide a new potential target for treatment of AD.https://www.frontiersin.org/article/10.3389/fimmu.2019.02707/fullMMI-0100neuroinflammationMAPK-activated protein kinase II (MK2)intranasalnear-infrared fluorescent |
| spellingShingle | JinHong Jiang JinHong Jiang Zhe Wang Zhe Wang XueYa Liang YaoYan Nie Xin Chang HongXiang Xue Shu Li Chang Min Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway Frontiers in Immunology MMI-0100 neuroinflammation MAPK-activated protein kinase II (MK2) intranasal near-infrared fluorescent |
| title | Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway |
| title_full | Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway |
| title_fullStr | Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway |
| title_full_unstemmed | Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway |
| title_short | Intranasal MMI-0100 Attenuates Aβ1−42- and LPS-Induced Neuroinflammation and Memory Impairments via the MK2 Signaling Pathway |
| title_sort | intranasal mmi 0100 attenuates aβ1 42 and lps induced neuroinflammation and memory impairments via the mk2 signaling pathway |
| topic | MMI-0100 neuroinflammation MAPK-activated protein kinase II (MK2) intranasal near-infrared fluorescent |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02707/full |
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