Improvements in medical care over recent decades have increased the number of premature and low birth weight infants that survive hypoxic-ischemic (H-I) insults. Because there is a rising incidence in diseases associated with these events, it is critical to develop effective therapies to treat the various resulting neuropathies. Extracellular matrix constitutes the majority of brain parenchyma. Lecticans and matrix-degrading proteases including ADAMTSs (a disintegrin and metalloproteinase with thrombospondin repeats) and matrix metalloproteinases (MMPs) exert effects on cell viability and may be associated with either protective or destructive processes after H-I. Both ADAMTSs (Cross et al. 2006; Tian et al. 2007) and MMPs (del Zoppo et al. 2007; Gu et al. 2005; Rosenberg et al. 2001) have been associated with pathological states in brain, yet the relative contributions of lecticans, ADAMTSs and MMPs to inflammation and cell death remain unknown. In the present study, the first series of experiments were conducted to characterize cellular damage and neuroinflammation in the postnatal day 7 rat after exposure to H-I, and to determine if cell death and inflammation were associated with alterations in lectican expression. Data showed that reduced brevican expression occurred 4 days after H-I in lesioned hippocampus. Additionally, reduced versican expression in white matter was concomitant with pre-OL cell death at this endpoint. In contrast, both lecticans were elevated at later endpoints (14, 21 days) that were associated with increased neuroinflammation and cavitary infarction. These data suggest that lectican loss is associated with cell death at the early endpoint, whereas increased lectican deposition over time likely leads to glial scar formation and a reduced capacity for neuroplasticity. Two subsequent series of experiments were conducted to determine the relative contributions of matrix-degrading proteases to injury, and whether proteolytic activity was associated with neuroinflammatory events. The first objective was to determine whether treatment with AG3340, a selective inhibitor of gelatin-degrading MMPs, or the anti-inflammatory compound minocycline, could provide neuroprotection when administered at a delayed time point after insult, and to compare the efficacy of AG3340 with that of the well-known anti-inflammatory compound minocycline. Data showed that both compounds effectively dampened the recruitment of microglia/macrophages to the lesion site when administered 24 hrs after H-I. These effects were associated with reduced neurodegeneration, indicating that these compounds neuroprotect at a clinically relevant time point. The final series of experiments tested whether these compounds could neuroprotect in an ex vivo model of oxygen glucose deprivation (OGD) that lacks peripheral immune cell involvement, thus providing insight into the relative contributions of resident microglia and gelatinase activity to the inflammatory sequelae. Results showed that both compounds blocked the OGD-induced increase in gelatinase activity and were neuroprotective in the absence of peripheral immune cells. Taken together, these data indicate that resident microglia contribute to H-I injury through gelatinase activation. Thus, the present study demonstrates that gelatin-degrading MMPs are important targets to consider when developing therapies to combat neonatal H-I injury.