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 vehicletreated 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.
Bibliographical noteFunding Information:
LJN received two grants from the National Institute of Neurological Disorders and Stroke (http:// www.ninds.nih.gov/) with grant numbers RO1NS077767 and RO1NS050159. BDS received a CJ Martin Early Career Fellowship from the Australian National Health and Medical Research Council with award number 1052505. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank S.A. Canchola, Manager of the Neurobehavioral Core for Rehabilitation Research at UCSF, for assistance with behavioral assays, and Hualiang Pi at University of Notre Dame for doing the gelatin zymography.