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
1  Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
3  Department of Pharmacy, Fukuoka University Hospital, Jonan, Fukuoka, Japan
,
Yoshihiko Nakamura
4  Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan
,
Kiyoshi Matsuyama
5  Department of Biochemistry and Applied Chemistry, Kurume National College of Technology, Kurume, Japan
,
Keiichi Irie
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Mako Yasumura
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Yurie Hirata
5  Department of Biochemistry and Applied Chemistry, Kurume National College of Technology, Kurume, Japan
,
Motoki Yamasaki
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Kanae Misumi
4  Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan
,
Yuta Yamashita
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Takayuki Myose
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Koichi Matsuo
1  Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Kazunori Sano
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Hidetoshi Kamimura
1  Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
3  Department of Pharmacy, Fukuoka University Hospital, Jonan, Fukuoka, Japan
,
Hiroyasu Ishikura
4  Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Jonan, Fukuoka, Japan
,
Takashi Egawa
1  Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
,
Kenichi Mishima
2  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Jyonan, Fukuoka, Japan
› Author Affiliations
Funding None.
Further Information

Publication History

23 July 2018

09 December 2018

Publication Date:
21 January 2019 (eFirst)

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.

Authors' Contributions

T.N. performed the in vivo experiments, analysed the data and described the manuscript. Y.N., Mako Y., Motoki Y., Kanae M., Y.Y. and T.M. performed the in vivo experiments and analysed the data. Kioshi M. and Y.H. performed the in vitro experiments and analysed the data. K.I. interpreted the data and contributed most to the writing of the manuscript. Koichi M., K.S., H.K., H.I., T.E. and Kenichi M. interpreted the data and contributed to the writing of the manuscript. All authors read and approved the final manuscript.


Supplementary Material