Ell Death in the Rat Hippocampus in a Model of Renatal Brain Injury: Time Course and Expression of Eath-related Proteins

bstract—Survival rates have increased dramatically for very remature (gestational week 24–28) infants. However, many f these infants grow up to have profound cognitive, motor nd behavioral impairments due to brain damage. We have eveloped a novel model of prenatal infant gray matter injury. uring the neonatal period, GABA is an excitatory neuroransmitter. GABAA receptor activation results in chloride fflux and membrane depolarization sufficient to open L-type oltage sensitive calcium channels. Our model involves exessive GABAA receptor activation in the newborn rat, with amage due to the resultant excessive calcium influx, not ABAA receptor activation itself. A common feature among umerous insult pathologies in the neonatal brain is an eleation in the intracellular levels of calcium. The goals of the resent study were: 1) to document the time course and mount of cell death (both apoptotic and necrotic), and 2) to nvestigate the effect of GABAA receptor activation on the ime course and expression of three cell death-related proeins (caspase-9, bax and bcl-2) in our model of prenatal brain njury. The magnitude of cell death, using TdT-mediated UTP nick end labeling and Cresyl Violet to quantify the ncidence of apoptotic and necrotic cells, was region depenent (CA1>CA2/3>dentate gyrus) and persisted for at least 5 ays following insult. There was a relative increase in the mount of bax to bcl-2 protein, and increased protein levels f caspase-9, indicative of cell death. These findings are onsistent with mechanisms of cell death seen in other types f early brain insult, and highlight a conserved cascade of vents leading to cell death in the developing brain. © 2004 BRO. Published by Elsevier Ltd. All rights reserved.