International Journal of Medical Sciences

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19 October 2017

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Int J Med Sci 2017; 14(10):927-936. doi:10.7150/ijms.18812

Research Paper

Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice

Chongjie Cheng1, 2*, Zhanyang Yu2*, Song Zhao3, Zhengbu Liao1, 2, Changhong Xing2, Yinghua Jiang1, 2, Yong-Guang Yang4, Michael J. Whalen5, Eng H. Lo2, Xiaochuan Sun1✉, Xiaoying Wang2✉

1. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2. Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA;
3. Departments of Orthopedic and Neurosurgery, The First Bethune Hospital of Jilin University, Changchun, Jilin, China;
4. Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA;
5. Department of Pediatrics, Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
* These authors contributed equally to this work

Abstract

Background: Thrombospondin-1 (TSP-1) is an extracellular matrix protein that plays multiple physiological and pathophysiological roles in the brain. Experimental reports suggest that TSP-1 may have an adverse role in neuronal function recovery under certain injury conditions. However, the roles of TSP-1 in traumatic brain injury (TBI) have not been elucidated. In this study we for the first time investigated the roles of TSP-1 in a controlled cortical impact (CCI) model of TBI in TSP-1 knockout (TSP-1 KO) and wild type (WT) mice.

Methods: We examined blood brain-barrier (BBB) damage using at 1 day post-TBI by measuring Evans Blue leakage, and neurological functional recovery at 3 weeks post-TBI by measuring neurological severity score (NSS), wire gripping, corner test and Morris Water Maze (MWM). Mechanistically, we quantified pro-angiogenic biomarkers including cerebral vessel density, vascular endothelial growth factors (VEGF) and angiopoietin-1 (Ang-1) protein expression, synaptic biomarker synaptophysin, and synaptogenesis marker brain-derived neurotrophic factor (BDNF) protein expression in contralateral and ipsilateral (peri-lesion) cortex at 21 days after TBI using immunohistochemistry and Western Blot.

Results: TSP-1 is upregulated at early phase of TBI in WT mice. Compared to WT mice, TSP-1 KO (1) significantly worsened TBI-induced BBB leakage at 1 day after TBI; (2) had similar lesion size as WT mice at 3 weeks after TBI; (3) exhibited a significantly worse neurological deficits in motor and cognitive functions; (4) had no significant difference in cerebral vessel density, but significant increase of VEGF and Ang-1 protein expressions in peri-lesion cortex; (5) significantly increased BDNF but not synaptophysin protein level in peri-lesion cortex compared to sham, but both synaptophysin and BDNF expressions were significantly decreased in contralateral cortex compared to WT.

Conclusion: Our results suggest that TSP-1 may be beneficial for maintaining BBB integrity in the early phase and functional recovery in late phase after TBI. The molecular mechanisms of TSP-1 in early BBB pathophysiology, and long-term neurological function recovery after TBI need to be further investigated.

Keywords: traumatic brain injury, Thromspondin-1 (TSP-1), neurological severity score (NSS), blood-brain-barrier, morris water maze (MWM), angiogenesis, synaptogenesis.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Cheng C, Yu Z, Zhao S, Liao Z, Xing C, Jiang Y, Yang YG, Whalen MJ, Lo EH, Sun X, Wang X. Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice. Int J Med Sci 2017; 14(10):927-936. doi:10.7150/ijms.18812. Available from http://www.medsci.org/v14p0927.htm