title: Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, p-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor-with such desirable pharmacokinetic properties-holds considerable promise as a potential pharmacological treatment of TBI.
authors.affiliation: Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri, United States of America ; Center for Translational Neuroscience, University of Missouri School of Medicine, Columbia, Missouri, United States of America ; MS in Pathology Program, University of Missouri Graduate School, Columbia, Missouri, United States of America.
authors.forename: Orr
authors.initials: O
authors.lastname: Hadass
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Tomlinson
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.forename: Shanyan
authors.initials: S
authors.lastname: Chen
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Purdy
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Walker
authors.forename: Chunyang
authors.initials: C
authors.lastname: Zhang
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Giritharan
authors.forename: Whitley
authors.initials: W
authors.lastname: Purnell
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Robinson
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Shin
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Agnes
authors.initials: A
authors.lastname: Simonyi
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects*; D005453:Fluorescence; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics / Q000494:pharmacology*; D006652:Histological Techniques; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D018782:Maze Learning; D051379:Mice; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D020780:Matrix Metalloproteinase 9