Chronic restraint stress exacerbates neurological deficits and disrupts the remodeling of the neurovascular unit in a mouse intracerebral hemorrhage model

Cheng Gao; Ying Meng; Guang Chen; Wei Chen; Xue-Shi Chen; Cheng-Liang Luo; Ming-Yang Zhang; Zu-Feng Wang; Tao Wang; Lu-Yang Tao

doi:10.1080/10253890.2019.1678023

Chronic restraint stress exacerbates neurological deficits and disrupts the remodeling of the neurovascular unit in a mouse intracerebral hemorrhage model

Stress. 2020 May;23(3):338-348. doi: 10.1080/10253890.2019.1678023. Epub 2019 Oct 18.

Authors

Cheng Gao^{1

2}, Ying Meng³, Guang Chen², Wei Chen², Xue-Shi Chen², Cheng-Liang Luo², Ming-Yang Zhang², Zu-Feng Wang², Tao Wang^{1

2

4}, Lu-Yang Tao²

Affiliations

¹ Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai, China.
² Department of Forensic Medicine, Medical School of Soochow University, Suzhou, China.
³ Community Health Center, Suzhou Western Eco-City, Suzhou, China.
⁴ School of Pharmacy, Soochow University, Suzhou, China.

PMID: 31591949
DOI: 10.1080/10253890.2019.1678023

Abstract

Growing evidences have shown that patients recovering from stroke experience high and unremitting stress. Chronic restraint stress (CRS) has been found to exacerbate neurological impairments in an experimental focal cortical ischemia model. However, there have been no studies reporting the effect and mechanism of CRS on intracerebral hemorrhage (ICH). This study aimed to evaluate the effect of CRS on a mouse ICH model. Adult male C57BL mice were subjected to infusion of collagenase IV (to induce ICH) or saline (for sham) into the left striatum. After ICH, animals were stressed with application of CRS protocol for 21 days. Our results showed that CRS significantly exacerbated neurological deficits (Garcia test, corner turn test, and wire grip test) and the ipsilateral brain atrophy and reduced body weight gain after ICH. Immunofluorescence staining indicated that CRS exerted significant suppressive effects on neuron, astrocyte, vascular endothelial cell and pericyte and excessively activated microglia post ICH. All of the key cellular components mentioned above are involved in the neurovascular unit (NVU) remodeling in the peri-hemorrhagic region after ICH. Western blot results showed that matrix metalloproteinase (MMP)-9 and tight junction (TJ) proteins including zonula occludens-1, occludin and claudin-5 were increased after ICH, but MMP-9 protein was further up-regulated and TJ-related proteins were down-regulated by CRS. In addition, ICH-induced activation of endoplasmic reticulum stress and apoptosis were further strengthened by CRS. Collectively, CRS exacerbates neurological deficits and disrupts the remodeling of the peri-hemorrhagic NVU after ICH, which may be associated with TJ proteins degradation and excessive activation of MMP-9 and endoplasmic reticulum stress-apoptosis.LAY SUMMARYCRS exacerbates neurological deficits and disrupts the remodeling of the NVU in the recovery stage after ICH, which suggest that monitoring chronic stress levels in patients recovering from ICH may merit consideration in the future.

Keywords: Intracerebral hemorrhage; apoptosis; chronic restraint stress; endoplasmic reticulum stress; neurovascular unit; tight junction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cerebral Hemorrhage*
Disease Models, Animal
Humans
Male
Mice
Mice, Inbred C57BL
Neurons
Stress, Psychological*