Cellular Mechanisms of Intrapartum Hypoxic–Ischaemic Cerebral Injury

• The immature brain has a lower overall oxygen demand compared to the mature brain; however, regions undergoing active maturation have significantly higher oxygen needs.
• High oxygen demands in actively maturing regions are critical for enzyme functions involved in neuronal development, ion homeostasis (e.g., Na K-ATPase), and oxidative metabolism.
• Failure to meet regional energy demands during fetal asphyxia leads to rapid energy depletion, initiating cellular injury and cell death cascades.

Role of Glutamate in Brain Development and Injury

• Glutamate is essential for normal neuronal development, including differentiation, dendritic arborization, synapse formation, and plasticity, primarily via NMDA receptors.
• NMDA receptor activation under normal conditions tightly regulates calcium influx, crucial for neuronal growth and maturation.
• Energy-dependent ion pumps maintain control over neuronal membrane potential, essential for normal glutamate receptor function.
• In fetal asphyxia, energy failure disrupts glutamate regulation, leading to excessive presynaptic glutamate release and impaired reuptake, causing glutamate accumulation.
• Sustained glutamate receptor activation leads to excessive calcium influx, triggering excitotoxic neuronal injury and cell death.