Of mice and men: can MMP-9 be a biomarker and a potential target for treatment after traumatic brain injury?

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Traumatic brain injury (TBI) is a highly prevalent cause of death and disability in the US and has become a significant burden to our present healthcare system. Currently there are few biomarkers and clinical diagnostic tests to determine the severity of TBI in humans. In addition, there are few efficacious treatments at this time for TBI that do not have severe side effects. Matrix metalloproteinases (MMPs) represent the most prominent family of endopeptidases that are necessary for normal growth and development but are also involved in the disruption of the blood-brain barrier (BBB), neuronal cell death, neuroinflammation and/or neurodegeneration after TBI. Studies of mouse models from our laboratory and others have shown that there is an elevation of MMPs, specifically gelatinase MMP-9, in the brain tissue of mice with TBI. In the Gu laboratory, we have adopted an electromagnetic (EM) controlled cortical impact (CCI) mouse model along with refined surgical techniques and behavioral testing to mimic a precise, graded TBI. Here we compare our EM CCI mouse model of TBI to cerebrospinal fluid (CSF) from the severe human head trauma cases through examining matrix metalloproteinase-9 (MMP-9), which we have shown to be upregulated after TBI. We also examine the efficacy of selective MMP-9 inhibitors analog to the prototype mechanism-based MMP inhibitor SB-3CT, which is selective to gelatinases (MMP-2/-9). SB-3CT has been shown to attenuate MMP-9 and ameliorate neurological deficits after TBI.