HIE and neuroprotection

Abstract

The neonatal brain is sensitive to hypoxic-ischemic insults that cause selective patterns on damage depending on the type and severity of the insult. An insult that damages the brain is associated with a neonatal encephalopathy that is associated with seizures. This encephalopathy reflects a rise in extracellular glutamate in the brain due to impaired glial pumping of neurotransmitter out of the synapse, which in turn triggers activation of NMDA glutamate receptors. Activation of NMDA receptors causes calcium to flow through the NMDA receptor channel, leading to activation of nNOS and production of nitric oxide (NO). High levels of NO combined with activation of apoptosis inducing factor (AIF) cause dysfunction of mitochondria, leading to a mixture of delayed apoptosis and necrosis. Mild hypothermia continued for three days in a neonatal intensive care unit has become the standard of care in most high income countries, and it is effective if applied soon enough after the insult. However prolonged insults or those remote from the time of delivery do not respond as well and other adjuvant therapies are needed to combine with hypothermia. Erythropoietin is one of these therapies, and another is carbon nanoparticles called dendrimers that can be administered intravenously and can carry drugs through the blood brain barrier and are taken up by activated microglia in the brain. Dendrimers carrying the anti-oxidant N-acetyl-cysteine (NAC) are neuroprotective in models of endotoxin induced brain injury. Follow-up studies demonstrate to efficacy of these strategies on motor and cognitive function in older children.