Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood-brain barrier.

Abstract

Intracranial hemorrhage remains a devastating disease. Among antiplatelet drugs, cilostazol, a phosphodiesterase 3 inhibitor, was recently reported to prevent secondary hemorrhagic stroke in patients in a clinical trial. The aim of this study was to evaluate whether pre-treatment with cilostazol could decrease the intracranial hemorrhage volume and examine the protective mechanisms of cilostazol. We evaluated the pre-treatment effects of the antiplatelet drug cilostazol on the collagenase-induced intracranial hemorrhage volume and neurological outcomes in mice. To estimate the mechanism of collagenase injury, we evaluated various vascular components in vitro, including endothelial cells, vascular smooth muscle cells, pericytes, and a blood-brain barrier model. Cilostazol pre-treatment reduced the intracranial hemorrhage volume with sufficient inhibition of platelet aggregation, and motor function was improved by cilostazol treatment. Blood-brain barrier permeability was increased by collagenase-induced intracranial hemorrhage, and cilostazol attenuated blood-brain barrier leakage. Terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot analysis showed that cilostazol prevented pericyte cell death by inducing cyclic adenosine monophosphate-responsive element-binding protein phosphorylation. Cilostazol also prevented endothelial cell death and protected collagen type 4, laminin, and vascular endothelial- and N-cadherins from collagenase injury. In conclusion, cilostazol reduced collagenase-induced intracranial hemorrhage volume by protecting the blood-brain barrier.

• Authors: Toshinori Takagi, Takahiko Imai, Keisuke Mishiro, Mitsue Ishisaka, Masanori Tsujimoto, Hideki Ito, Kazunori Nagashima, Haruka Matsukawa, Kazuhiro Tsuruma, Masamitsu Shimazawa, Shinichi Yoshimura, Osamu Kozawa, Toru Iwama, Hideaki Hara
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 37 Issue 1 Pg. 123-139 (01 2017) ISSN: 1559-7016 [Electronic] United States
• PMID: 26661252 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2015.

Chemical References

• Protective Agents
• Tetrazoles
• Collagenases
• Cilostazol

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Cell Death (drug effects)
• Cerebral Hemorrhage (chemically induced, drug therapy, prevention & control)
• Cilostazol
• Collagenases
• Endothelial Cells (drug effects)
• Mice
• Pericytes (cytology)
• Premedication (methods)
• Protective Agents
• Tetrazoles (pharmacology)