Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury

Christopher C Leonardo, Keith R Pennypacker

Exposure to hypoxic-ischemic insults during the neonatal or perinatal developmental periods produces various forms of pathology. Injuries that occur in response to these events often manifest as severe cognitive and/or motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of hypoxic-ischemic injury, there is a growing need for effective therapies that can be delivered at delayed time points. Much of the research into mechanisms of neural injury has focused on molecular targets associated with excitotoxicity and free oxygen radicals. Despite repeated success in animal models, these compounds have failed to show efficacy in clinical trials. Increasing evidence indicates that hypoxic-ischemic injury in the neonate is progressive, and the resulting neuropathies are linked to the activation of neuroinflammatory processes that occur in response to the initial wave of cell death. Understanding this latter response, therefore, will be critical in the development of novel therapies to block the progression of the injury. In this review, we summarize emerging concepts from rodent models concerning the regulation of various cytokines, chemokines, and matrix metalloproteinases in response to ischemia, and the various ways in which the delayed neuroinflammatory response may contribute to the progressive nature of neonatal hypoxic-ischemic injury in rat. Finally, we discuss data that supports the potential to target these neuroinflammatory signals at clinically relevant time points.