19 October 2017
Int J Med Sci 2017; 14(10):927-936. doi:10.7150/ijms.18812
Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice
1. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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.
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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