Biochemical Basis of Hypoxic-Ischemic Encephalopathy

Abstract

Despite improved methods of intrapartum monitoring and advances in neonatal care and treatment, neonatal hypoxic-ischemic injury continues to produce significant morbidity and mortality, often leading to long-term neurologic consequences. Hypoxia creates an imbalance in metabolic demand and cellular energy supply, resulting in the disruption of critical cellular functions and the activation of excitatory neurotransmitters. In addition, the structure, function, and modification of cellular processes, such as the N-methyl-D-aspartate (NMDA) receptor and intracellular calcium regulation, are affected. Nuclear calcium signals control critical nuclear functions, including regulation of transcription factors and cell cycle, gene transcription, DNA replication, and nuclear envelope breakdown. Nitric oxide synthase and the generation of nitric oxide during hypoxia may contribute significantly to altered cell function, disruption in calcium homeostasis, and the activation of caspases, leading to programmed cell death. The biochemical mechanisms involved in hypoxic-ischemic neuronal injury and death are exceedingly complex and interdependent. This discussion focuses primarily on some of the major cellular and molecular mechanisms of hypoxic neuronal injury in the newborn brain.