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 (US) |
|---|---|
| Article number | e0143386 |
| Journal | PLoS One |
| Volume | 10 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2015 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Early gelatinase activity is not a determinant of long-term recovery after traumatic brain injury in the immature mouse. / Semple, Bridgette D.; Noble-Haeusslein, Linda J.; Gooyit, Major; Tercovich, Kayleen G.; Peng, Zhihong; Nguyen, Trung T.; Schroeder, Valerie A.; Suckow, Mark A.; Chang, Mayland; Raber, Jacob; Trivedi, Alpa.
In: PLoS One, Vol. 10, No. 11, e0143386, 01.11.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Early gelatinase activity is not a determinant of long-term recovery after traumatic brain injury in the immature mouse
AU - Semple, Bridgette D.
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
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84957534811&partnerID=8YFLogxK
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U2 - 10.1371/journal.pone.0143386
DO - 10.1371/journal.pone.0143386
M3 - Article
C2 - 26588471
AN - SCOPUS:84957534811
VL - 10
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 11
M1 - e0143386
ER -