title: Early Gelatinase Activity Is Not a Determinant of Long-Term Recovery after Traumatic Brain Injury in the Immature Mouse.
abstract: The gelatinases, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to be key mediators of secondary damage in adult animal models of brain injury. Moreover, an acute increase in these proteases in plasma and brain extracellular fluid of adult patients with moderate-to-severe traumatic brain injuries (TBIs) is associated with poorer clinical outcomes and mortality. Nonetheless, their involvement after TBI in the pediatric brain remains understudied. Using a murine model of TBI at postnatal day 21 (p21), approximating a toddler-aged child, we saw upregulation of active and pro-MMP-9 and MMP-2 by gelatin zymography at 48 h post-injury. We therefore investigated the role of gelatinases on long-term structural and behavioral outcomes after injury after acute inhibition with a selective gelatinase inhibitor, p-OH SB-3CT. After systemic administration, p-OH SB-3CT crossed the blood-brain barrier at therapeutically-relevant concentrations. TBI at p21 induced hyperactivity, deficits in spatial learning and memory, and reduced sociability when mice were assessed at adulthood, alongside pronounced tissue loss in key neuroanatomical regions. Acute and short-term post-injury treatment with p-OH SB-3CT did not ameliorate these long-term behavioral, cognitive, or neuropathological deficits as compared to vehicle-treated controls, suggesting that these deficits were independent of MMP-9 and MMP-2 upregulation. These findings emphasize the vulnerability of the immature brain to the consequences of traumatic injuries. However, early upregulation of gelatinases do not appear to be key determinants of long-term recovery after an early-life injury.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.|Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Bridgette D
authors.initials: BD
authors.lastname: Semple
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.|Department of Physical Therapy and Rehabilitation, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Noble-Haeusslein
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kayleen G
authors.initials: KG
authors.lastname: Tercovich
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Trung T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.affiliation: Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, Division of Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Alpa
authors.initials: A
authors.lastname: Trivedi
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001930:Brain Injuries / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002675:Child, Preschool; D004195:Disease Models, Animal; D015870:Gene Expression; D006573:Heterocyclic Compounds, 1-Ring / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D020127:Recovery of Function / Q000502:physiology; D012934:Social Isolation; D065852:Spatial Memory; D013450:Sulfones / Q000378:metabolism* / Q000494:pharmacology; D015599:Trauma Severity Indices; D017211:Treatment Failure
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9