Mechanism-based inhibition of matrix metalloproteinase-9 provides neuroprotection in a mouse model of traumatic brain injury
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Traumatic brain injury (TBI) is a leading cause of death and disability in the U.S. Following an initial mechanical impact, TBI progresses to a secondary injury phase characterized by events that exacerbate brain damage. Matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes that can cause detrimental outcomes via aberrant proteolysis, disruption of the blood-brain barrier (BBB), and neurodegeneration. In the present study we examined the roles of gelatinases (MMP-2/9) in an experimental mouse model of TBI, as well as the therapeutic potential of SB-3CT, a mechanism-based gelatinase inhibitor. Immunohistochemistry showed elevated nitrosative-oxidative stress within 24 hours of trauma. Gelatin zymography revealed that MMP-9 activity was significantly elevated during the first 7 days post-trauma. SB-3CT treatment for 7 days attenuated MMP-9 activity and thereby reduced histological lesion volumes, laminin degradation, and neuronal damage. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes in TBI mice, including motor function assessed by the beam-walking test, and spatial learning and memory using a Barnes maze. These results demonstrate considerable promise for the mechanism-based type of gelatinase inhibitors as a potential pharmacological treatment of brain injuries.
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