Early gelatinase activity is not a determinant of long-term recovery after traumatic brain injury in the immature mouse

Bridgette D. Semple; Linda J. Noble-Haeusslein; Major Gooyit; Kayleen G. Tercovich; Zhihong Peng; Trung T. Nguyen; Valerie A. Schroeder; Mark A. Suckow; Mayland Chang; Jacob Raber; Alpa Trivedi

doi:10.1371/journal.pone.0143386

Early gelatinase activity is not a determinant of long-term recovery after traumatic brain injury in the immature mouse

Bridgette D. Semple, Linda J. Noble-Haeusslein, Major Gooyit, Kayleen G. Tercovich, Zhihong Peng, Trung T. Nguyen, Valerie A. Schroeder, Mark A. Suckow, Mayland Chang, Jacob Raber, Alpa Trivedi

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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 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.

Original language	English
Article number	e0143386
Journal	PLoS ONE
Volume	10
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0143386
State	Published - Nov 1 2015

Bibliographical note

Funding 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.

Publisher Copyright:
© 2015 Semple et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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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 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.",

author = "Semple, {Bridgette D.} and Noble-Haeusslein, {Linda J.} and Major Gooyit and Tercovich, {Kayleen G.} and Zhihong Peng and Nguyen, {Trung T.} and Schroeder, {Valerie A.} and Suckow, {Mark A.} and Mayland Chang and Jacob Raber and Alpa Trivedi",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2015 Semple et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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AU - Noble-Haeusslein, Linda J.

AU - Gooyit, Major

AU - Tercovich, Kayleen G.

AU - Peng, Zhihong

AU - Nguyen, Trung T.

AU - Schroeder, Valerie A.

AU - Suckow, Mark A.

AU - Chang, Mayland

AU - Raber, Jacob

AU - Trivedi, Alpa

N1 - Funding 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. Publisher Copyright: © 2015 Semple et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

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Early gelatinase activity is not a determinant of long-term recovery after traumatic brain injury in the immature mouse

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