Pharmacologic Neuroprotective Strategies in Neonatal Brain Injury

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Key points

  • There are many ways to achieve neuroprotection: preconditioning, salvaging, repair.

  • Hypothermia is now standard of care for term hypoxic-ischemic encephalopathy so studies to investigate additional therapies will be added to that treatment.

  • Strategies that target multiple mechanisms and consider age-appropriate mechanisms will be most beneficial.

Mechanisms of brain injury: preterm versus term

The two most common causes of neonatal brain injury in the United States are extreme prematurity and hypoxic-ischemic encephalopathy (HIE). In the United States, 1 in 8 babies is born before term (37–40 weeks), and 1.44% of babies (56,000 per year) are born with a birth weight of 1250 g or less.1 These small, preterm babies are at high risk of death or neurodevelopmental impairment: approximately 20% die before hospital discharge, and 40% of survivors develop long-term intellectual or physical

The injury cascade

Although the cellular targets of HI are different depending on age and severity of insult, the basic cascade of injury occurs in a uniform way regardless of age and continues for a prolonged period of time. Cell death occurs in 2 main phases: primary death from hypoxia and energy depletion, followed by reperfusion and increased free radical (FR) formation, excitotoxicity, and nitric oxide production with secondary energy failure and delayed death (Fig. 1). A tertiary phase was recently

Antiexcitotoxic Agents

The earliest pharmacologic strategies to protect the newborn brain were designed to block the initial phases of injury, excitotoxicity, and oxidative stress. Many of these agents failed because it is impossible to block normal developmental processes, like glutamatergic signaling, without harming the brain. Therefore, therapies designed to block the NMDA receptor resulted in increased, rather than decreased, cell death.22 However, some agents, like magnesium sulfate, used to stop preterm labor,

Growth factors as neuroprotectants

Many growth factors have essential roles during fetal and postnatal brain development. Although the effects of some, such as brain-derived neurotrophic factor (BDNF), are largely restricted to the brain, others such as Epo, VEGF, granulocyte colony–stimulating factor (GCSF), and insulinlike growth factor 1 (IGF-1) have important somatic effects in addition to their roles in neurodevelopment. All of the factors listed earlier have been evaluated as neuroprotectant therapies for adult and

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