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Sci Rep. 2018 Dec 11;8(1):17770. doi: 10.1038/s41598-018-35898-z.

Development of a novel RANKL-based peptide, microglial healing peptide1-AcN (MHP1-AcN), for treatment of ischemic stroke.

Author information

1
Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. shimamuu@cgt.med.osaka-u.ac.jp.
2
Department of Neurology, Osaka University Graduate School of Medicine, Centre of Medical Innovation and Translational Research (6th floor, Room 0612B), Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. shimamuu@cgt.med.osaka-u.ac.jp.
3
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka, Japan.
4
Department of Internal Medicine, Osaka Dental University, Osaka, Japan.
5
Tsukuba Laboratories, Nemoto Science Co., Ltd, Ibaraki, Japan.
6
Contract Research Department, Drug Development Solutions Center, Drug Development Solutions Division, Sekisui Medical Co., Ltd, Ibaraki, Japan.
7
Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
8
Department of Neurology, Osaka University Graduate School of Medicine, Centre of Medical Innovation and Translational Research (6th floor, Room 0612B), Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
9
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka, Japan. morishit@cgt.med.osaka-u.ac.jp.

Abstract

Although the regulation of post-ischemic inflammation is an important strategy to treat ischemic stroke, all clinical trials have failed to show its efficacy. To solve the problem, we previously developed a novel partial peptide of RANKL, microglial healing peptide 1 (MHP1), which could reduce ischemic injury by inhibiting Toll-like receptor (TLR) induced inflammation. However, optimization of the peptide was necessary to increase the stability and efficacies for clinical use. According to information gathered through HPLC/MS in serum, we have newly designed a series of modified MHP1 peptides and have found that N-terminal acetylation and C-terminal amidation in MHP1 (MHP1-AcN), can strengthen its anti-inflammatory effects and increase its stability with anti-osteoclastogenic effects. Anti-TLR activity was reported to be reduced in MHP1 when incubated at 37 °C for 24 hrs, but MHP1-AcN could keep the activity under the same condition. The therapeutic effect of MHP1-AcN was observed in transient ischemic stroke model at lower dose than MHP1. Importantly, MHP1-AcN did not affect thrombolytic effects of tissue plasminogen activator (tPA) and inhibited tPA-induced hemorrhagic transformation. These findings indicated that MHP1-AcN was stable and effective anti-TLR signal peptide and could be a promising agent for treating stroke patients receiving tPA and endovascular therapy.

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