Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 21, Issue 12, Pages 3322-3336Publisher
WILEY
DOI: 10.1111/jcmm.13235
Keywords
blood-spinal cord barrier; metformin; neutrophil; matrix metalloproteinases; inflammation; spinal cord injury
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Funding
- National Natural Science Foundation of China [81601963, 81401871, 81401162, 81572227, 81501907, 81371988]
- Zhejiang Provincial Natural Science Foundation of China [LY17H060010, LY15H060008, LY14H170002]
- Zhejiang Medical Science Foundation [2013KYA127, 2013KYB177]
- Wenzhou Science and Technology Bereau Foundation [S20100048, Y20100357]
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Blood-spinal cord barrier (BSCB) disruption is a major process for the secondary injury of spinal cord injury (SCI) and is considered to be a therapeutic target for SCI. Previously, we demonstrated that metformin could improve functional recovery after SCI; however, the effect of metformin on BSCB is still unknown. In this study, we found that metformin could prevent the loss of tight junction (TJ) proteins at day 3 after SCI in vivo, but in vitro there was no significant difference of these proteins between control and metformin treatment in endothelial cells. This indicated that metformin-induced BSCB protection might not be mediated by up-regulating TJ proteins directly, but by inhibiting TJ proteins degradation. Thus, we investigated the role of metformin on MMP-9 and neutrophils infiltration. Neutrophils infiltration is the major source of the enhanced MMP-9 in SCI. Our results showed that metformin decreased MMP-9 production and blocked neutrophils infiltration at day 1 after injury, which might be related to ICAM-1 down-regulation. Also, our in vitro study showed that metformin inhibited TNF alpha-induced MMP-9 up-regulation in neutrophils, which might be mediated via an AMPK-dependent pathway. Together, it illustrated that metformin prevented the breakdown of BSCB by inhibiting neutrophils infiltration and MMP-9 production, but not by up-regulating TJ proteins expression. Our study may help to better understand the working mechanism of metformin on SCI.
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