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Front. Neurosci. | doi: 10.3389/fnins.2018.00977

Simvastatin Diminishing Neutrophils Infiltration into Brain after Intracerebral Hemorrhage via Accelerating Peripheral Neutrophils Apoptosis

Jianbo Zhang1,  Shi Xia1, Na Hao2, Zhi Chen1, Linjie Wei1, Liang Tan1,  Yujie Chen1, Hua Feng1, Gang Zhu1* and  Qianwei Chen1, 3*
  • 1Southwest Hospital, Third Military Medical University, China
  • 2Chongqing Hospital of Traditional Chinese Medicine, China
  • 3The 452 Hospital of Western Air Force, China

Statins, known for their lipid-lowering effects, also have immunomodulatory properties. This study aims to examine whether systematic simvastatin administration could decrease polymorphonuclear neutrophils (PMNs) infiltration into brain tissue, as well as alleviate neuroinflammation in a rat model of intracerebral hemorrhage (ICH). The ICH model was induced in adult male Sprague–Dawley rats by an injection of autologous blood. Animals randomly received simvastatin (i.p. 2 mg/kg) or vehicle daily from 5 days before ICH until sacrificed. Routine blood counts, brain water content, neurological scoring, immunofluorescence and RT-PCR were conducted to evaluate the anti-inflammatory effect of simvastatin following ICH. Furthermore, flow cytometric and western blotting analysis were implemented for elucidating the mechanisms involved in simvastatin-induced reduction of neutrophil brain-invading. Elevated PMNs count and neutrophil-to-lymphocyte ratio in circulation were detected in rat model of ICH, which was reversed by using simvastatin. Simvastatin effectively alleviated PMNs infiltration and proinflammatory factors release in perihematomal area, as well as attenuated ICH-induced brain edema and neurological deficits. Simvastatin significantly downregulated the expression of antiapoptotic protein-Mcl-1 while increased the level of proapoptotic protein-Bax and cleaved caspase 3 in PMNs. Simvastatin treatment significantly alleviated PMNs brain-infiltrating and subsequent neuroinflammatory reaction after ICH, in part by accelerating peripheral PMNs apoptosis through disorganized the expression of apoptotic related proteins. Our data provided new evidence for simvastatin application on patients with ICH.

Keywords: intracerebral hemorrhage, Statins, polymorphonuclear neutrophils, Apoptosis, Inflammation

Received: 17 Aug 2018; Accepted: 06 Dec 2018.

Edited by:

Pietro Giusti, Università degli Studi di Padova, Italy

Reviewed by:

Andrea Baragetti, University of Milan, Italy
Massimiliano Ruscica, University of Milan, Italy  

Copyright: © 2018 Zhang, Xia, Hao, Chen, Wei, Tan, Chen, Feng, Zhu and Chen. 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:
Dr. Gang Zhu, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China, gangzhu6666@yeah.net
Dr. Qianwei Chen, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China, qianweichen88@yeah.net