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.
Highlights
Matrix metalloproteinases (MMP)-2 and MMP-9 are members of a family of multi-functional gelatinases
Levels of pro-MMP-2 and pro-MMP-9 were significantly elevated after traumatic brain injuries (TBIs), by ~4.6 fold and ~10 fold (p = 0.0032), respectively (Fig 1B and 1C)
The active enzyme forms were increased in the injured brain compared to shams by ~4.6 fold for both MMP-2 (p = 0.0128) and MMP-9 (p = 0.0200)
Summary
Matrix metalloproteinases (MMP)-2 and MMP-9 are members of a family of multi-functional gelatinases. MMPs play an important role in normal brain development, participating in a wide range of physiological processes including embryological modeling, wound healing, angiogenesis, bone remodeling, ovulation and implantation [1–4]. These proteases are key determinants of secondary damage after traumatic and ischemic insults to the adult brain [5–7]. High levels of MMP-2 and MMP-9 are detected acutely post-injury in plasma, brain extracellular fluid and cerebrospinal fluid of adult patients with moderate-to-severe TBI and subarachnoid hemorrhage [15–17], and are associated with poorer outcomes including a longer stay in the intensive care unit and increased risk of mortality [18–20]
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