THE CASCADE OF BRAIN INJURY

Objective: This presentation describes the cascade of molecular events responsible for the evolution of encephalopathy and damage from injuries to the developing brain.

Methods: Hypoxia combined with unilateral carotid artery ligation in neonatal mice or rats provides a model for hypoxic-ischemic injuries in neonates and young infants.

Results: Hypoxia-ischemia triggers neuronal depolarization and opening of NMDA-type glutamate receptors, leading to calcium flooding. This in turn leads to activation of neuronal nitric oxide synthase, production of nitric oxide and oxidative stress in mitochondria due to calcium overload. Drugs that block NMDA receptor/channels or block the production of nitric oxide are protective in the developing brain. The activity of NMDA receptor/channels is enhanced in the immature brain because of their role in activity-dependent plasticity; and excessive blockade can also cause apoptosis. Nitric oxide and oxidative stress in mitochondria activate of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (Parp-1), followed by release of apoptosis inducing factor (AIF) and cytochrome C from mitochondria, leading to apoptosis or necrosis. We found that these cell death pathways may differ according to gender: knocking out Parp-1 is protective against hypoxic-ischemic injury in male, but not female mice (Hagberg, et al, J Neurochem, 2004). This is consistent with the report by Du, et al (JBC, 2004) that there are innate gender-based differences in neuronal cell death pathways, with males more likely to use the NMDA→NO.→Parp-1→AIF pathway than females. Differences in cell death pathways could be responsible for gender differences reported in the vulnerability of human infants.

Conclusion: Hypoxia-ischemia triggers a cascade of molecular events after hypoxic-ischemic brain insults in infants, and these cell death pathways may diverge in males versus females. This information is important for designing neuroprotective strategies.