Triggers of Cell Death in the Developing Brain

Cell death occurs physiologically in the mammalian brain during the period of the growth spurt. In humans, this period starts in the 3rd trimester of gestation and ends by the third year of life. Environmental factors can interact with programmed cell death mechanisms to pathologically increase the numbers of neurons undergoing self elimination (apoptosis) and potentially lead to brain injury. It has been shown that classes of drugs which block glutamate N-methyl-D-aspartate (NMDA) receptors, activate γ- aminobutyric-acid (GABAA) receptors or block voltage gated sodium channels, when administered to immature rodents during susceptible developmental periods, trigger profound apoptotic cell death in the brain. Sedative, anesthetic and anticonvulsant drugs utilize these mechanisms to exert their actions. In addition, short exposures to non-physiologic oxygen levels can also trigger apoptotic cell death in the brains of infant rodents. Pathomechanisms involved in the neurotoxic actions of sedatives, anesthetics, anticonvulsants and oxygen include decreased expression of neurotrophins, inactivation of survival signaling proteins, activation of inflammatory cytokines as well as oxidative stress. These findings raise concerns regarding treatment of pregnant women, infants and young children with sedatives, anesthetics and anticonvulsants and premature infants with oxygen. Modified approaches should be developed for patients within these vulnerable age groups.