Neuroprotective strategies in excitotoxic brain injury: potential applications to the preterm brain

Abstract

Neuronal and oligodendroglial cell death owing to increased glutamate levels plays an important role in the pathophysiology of hypoxic-, ischemic- and inflammation-mediated brain injury as well as in disorders such as epilepsy, Alzheimer’s, Parkinson’s or Huntington’s disease. In addition, excitotoxic brain injury is known to be a major contributing factor to brain injury in preterm infants. Excitotoxicity is characterized as excessive glutamatergic activation of postsynaptic receptors that consequently leads to cell injury and cell death. The major excitatory amino acid neurotransmitter is glutamate. Glutamate plays a key role in brain development, affecting progenitor cell differentiation, proliferation, migration and survival. In physiological conditions the presence of glutamate in the synapse is regulated by ATP-dependent glutamate transporters in neurons and glial cells, with astrocytes being responsible for a major part of glutamate uptake in the brain. In pathologic circumstances the function of the transporters is impaired, leading to glutamate accumulation in the synaptic cleft and in turn excessive activation of postsynaptic glutamate receptors with subsequent massive Ca2+ influx, activation of neuronal nitric oxide synthase, translocation of proapoptotic genes to the mitochondria, mitochondrial dysfunction, release of cytochrome C into the cytosol, activation of caspases and subsequent cell death. Based on the pathogenic concept of an overactivation of the excitatory pathways, glutamate receptors have been a longstanding therapeutic target for rational drug design. This article reviews the pathophysiology of excitotoxic brain injury in the example of preterm brain injury, as well as current research on therapeutic antiexcitotoxic strategies.