MMP-9 Inhibitor GM6001 Prevents the Development of ssTBI-Induced Parkinson’s Disease via the Autophagy Pathway

• Published in: Cellular and molecular neurobiology 2021-11, Vol.41 (8), p.1651-1663
• Main Authors: Lin, Chao, Wu, Wei, Lu, Hua, Li, Wentao, Bao, Zhongyuan, Wang, Yingyi, Zhao, Lin, Guo, Tianwei, Cai, Ning, Li, Zheng, Ji, Jing, Hou, Lijun, You, Yongping, Liu, Ning
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - drug effects; Autophagy - physiology; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - enzymology; Brain - pathology; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - enzymology; Brain Injuries, Traumatic - pathology; Cell Biology; Concussion; Dipeptides - pharmacology; Dipeptides - therapeutic use; Female; Gelatinase B; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Matrix Metalloproteinase Inhibitors - therapeutic use; Maze Learning - drug effects; Maze Learning - physiology; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Movement disorders; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neuroprotection; Neurosciences; Original Research; Parkinson's disease; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - enzymology; Parkinsonian Disorders - pathology; Phagocytosis; Risk factors; Signal Transduction - drug effects; Signal Transduction - physiology; Trauma Severity Indices; Traumatic brain injury
• ISSN: 0272-4340; 1573-6830
• DOI: 10.1007/s10571-020-00933-z

Concussion is a widely recognized environmental risk factor for neurodegenerative diseases, including Parkinson’s disease (PD). Small-vessel disease of the brain has been reported to contribute to neurodegenerative diseases. In this study, we observed BBB disruption in wild-type (WT) mice, but not in matrix metalloproteinase 9 (MMP-9) knockout mice, subjected to single severe traumatic brain injury (ssTBI). Furthermore, treating ssTBI mice with the MMP-9 inhibitor GM6001 effectively maintained BBB integrity, promoted the elimination of damaged mitochondria via mitophagy, and then prevented neuronal death and progressive neurodegeneration. However, we did not observe this neuroprotective effect of MMP-9 inhibition in beclin-1 −/+ mice. Collectively, these findings revealed that concussion led to BBB disruption via MMP-9, and that GM6001 prevented the development of PD via the autophagy pathway.