Long-Term Treatment with Thrombomodulin Improves Functional Outcomes after Cerebral Ischemia Even if Administration is Delayed

Takafumi Nakano; Yoshihiko Nakamura; Kiyoshi Matsuyama; Keiichi Irie; Mako Yasumura; Yurie Hirata; Motoki Yamasaki; Kanae Misumi; Yuta Yamashita; Takayuki Myose; Koichi Matsuo; Kazunori Sano; Hidetoshi Kamimura; Hiroyasu Ishikura; Takashi Egawa; Kenichi Mishima

doi:10.1055/s-0038-1677532

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(03): 467-478
DOI: 10.1055/s-0038-1677532

Stroke, Systemic or Venous Thromboembolism

Georg Thieme Verlag KG Stuttgart · New York

Long-Term Treatment with Thrombomodulin Improves Functional Outcomes after Cerebral Ischemia Even if Administration is Delayed

Takafumi Nakano

¹Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

³Department of Pharmacy, Fukuoka University Hospital, Jonan, Fukuoka, Japan

,

Yoshihiko Nakamura

⁴Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan

,

Kiyoshi Matsuyama

⁵Department of Biochemistry and Applied Chemistry, Kurume National College of Technology, Kurume, Japan

,

Keiichi Irie

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Mako Yasumura

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Yurie Hirata

⁵Department of Biochemistry and Applied Chemistry, Kurume National College of Technology, Kurume, Japan

,

Motoki Yamasaki

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Kanae Misumi

⁴Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan

,

Yuta Yamashita

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Takayuki Myose

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Koichi Matsuo

¹Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Kazunori Sano

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Hidetoshi Kamimura

¹Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

³Department of Pharmacy, Fukuoka University Hospital, Jonan, Fukuoka, Japan

,

Hiroyasu Ishikura

⁴Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan

,

Takashi Egawa

¹Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

,

Kenichi Mishima

²Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan

› Author Affiliations

Abstract

Our previous study indicated that recombinant human soluble thrombomodulin (rhsTM) could attenuate brain damage when administered as a bolus in the cerebral ischaemic early phase. Then, we considered that treatment with rhsTM may show therapeutic effects even when administered in the ischaemic delayed phase, because rhsTM has an action of inhibiting high-mobility group box 1 (HMGB1) as a late mediator of lethal systemic inflammation. This study was performed to investigate the effects of delayed treatment with rhsTM on ischaemic brain damage induced by high HMGB1 level in mice subjected to 4-hour middle cerebral artery occlusion (MCAO). One day after MCAO, rhsTM was administered intraperitoneally at a dose of 1 or 5 mg/kg once a day for 7 days. Neurological score, motor coordination and HMGB1 levels were measured 1, 3 and 7 days after MCAO. The presence of activated microglia was evaluated 7 days after MCAO. Systemic HMGB1 levels increased 1 to 7 days after MCAO and were higher at 7 days compared with day 1. At the same time, survival rate decreased, and activated microglia increased in the infarct area. Treatment with rhsTM improved neurological score, motor coordination, survival and prevented brain damage. Moreover, rhsTM decreased both HMGB1 level and number of activated M1 microglia. The results of this study indicated that rhsTM improved functional outcomes via inhibition of HMGB1 up-regulation and M1 microglial activation in the cerebral ischaemic delayed phase. rhsTM may become a new therapeutic agent with a wide therapeutic time window in patients with cerebral ischaemia.

Keywords

recombinant human soluble thrombomodulin - ischaemic stroke - ischaemic delayed phase - microglial activation - high-mobility group box 1

Full Text

References

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Supplementary Material

Supplementary Material