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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02707

Intranasal MMI-0100 attenuates Aβ1-42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway

Jinhong Jiang1, Zhe Wang2, Xueya Liang1, Yaoyan Nie1, Xin Chang1, Hongxiang Xue1, Shu Li1 and  Min Chang1*
  • 1School of Life Sciences, Lanzhou University, China
  • 2School of Basic Medical College, Xi'an Jiaotong University, China

Accumulating evidence suggests that 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.
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.
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 failure of macromolecular protein or peptide drugs in the treatment of AD can not across 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 experiments results showed that a strong fluorescent signal, coming from mice 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.
MMI-0100 attenuates Aβ1-42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that MMI-0100/MK2 system may provide a new potential target for treatment of AD.

Keywords: MMI-0100, Neuroinflammation, MAPK-activated protein kinase II (MK2), intranasal, near-infrared fluorescent

Received: 01 May 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 Jiang, Wang, Liang, Nie, Chang, Xue, Li and Chang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Min Chang, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu Province, China,