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Theranostics 2018; 8(15):4181-4198. doi:10.7150/thno.25707 This issue Cite

Research Paper

Flufenamic acid inhibits secondary hemorrhage and BSCB disruption after spinal cord injury

Yingtao Yao^1,2, Jianyi Xu^1,2, Tingting Yu^1,2, Zhilong Chen^1,2, Zhiyong Xiao³, Jiedong Wang³, Yiqiang Hu³, Yongchao Wu^3✉, Dan Zhu^1,2✉

1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
2. MoE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
3. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

✉ Corresponding authors: Dan Zhu, Ph. D Professor, Britton Chance Center for Biomedical Photonics, Huazhong University of Science and Technology.1037 Luoyu Road, Wuhan 430074, P.R. China. Tel: +86 27 8779 2033; Fax: +86 27 8779 2034; dawnzhhust.edu.cn and Yongchao Wu. Department of Orthopedics, Union Hospital, Huazhong University of Science and Technology. 1277 Jiefang Dadao, Wuhan, 430022 Hubei Province, China. Tel: +86 27 8535 1626; fax: +86 27 8577 6343; email: wuyongchaocom More

Abstract

Acute spinal cord injury (SCI) induces secondary hemorrhage and initial blood-spinal cord barrier (BSCB) disruption. The transient receptor potential melastatin 4 (Trpm4) together with sulfonylurea receptor 1 (Sur1) forms the Sur1-Trpm4 channel complex. The up-regulation of Sur1-Trpm4 after injury plays a crucial role in secondary hemorrhage, which is the most destructive mechanism in secondary injuries of the central nervous system (CNS). The matrix metalloprotease (MMP)-mediated disruption of the BSCB leads to an inflammatory response, neurotoxin production and neuronal cell apoptosis. Thus, preventing secondary hemorrhage and BSCB disruption should be an important goal of therapeutic interventions in SCI.

Methods: Using a moderate contusion injury model at T10 of the spinal cord, flufenamic acid (FFA) was injected intraperitoneally 1 h after SCI and then continuously once per day for one week.

Results: Trpm4 expression is highly up-regulated in capillaries 1 d after SCI. Treatment with flufenamic acid (FFA) inhibited Trpm4 expression, secondary hemorrhage, and capillary fragmentation and promoted angiogenesis. In addition, FFA significantly inhibited the expression of MMP-2 and MMP-9 at 1 d after SCI and significantly attenuated BSCB disruption at 1 d and 3 d after injury. Furthermore, we found that FFA decreased the hemorrhage- and BSCB disruption-induced activation of microglia/macrophages and was associated with smaller lesions, decreased cavity formation, better myelin preservation and less reactive gliosis. Finally, FFA protected motor neurons and improved locomotor functions after SCI.

Conclusion: This study indicates that FFA improves functional recovery, in part, due to the following reasons: (1) it inhibits the expression of Trpm4 to reduce the secondary hemorrhage; and (2) it inhibits the expression of MMP-2 and MMP-9 to block BSCB disruption. Thus, the results of our study suggest that FFA may represent a potential therapeutic agent for promoting functional recovery.

Keywords: spinal cord injury, secondary hemorrhage, blood-spinal cord barrier, Trpm4, matrix metalloproteases

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