Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats

Caspases are believed to play a key role in the delayed neuronal cell death observed in the rat brain after hypoxic-ischemic (HI) insult. Caspase inhi bitors have been developed as antiapoptotic agents. Hippocampal damage afte r HI insult is strongly related to tissue temperature, and systemic hypothe rmia has been introduced clinically for bra-in protection. In this study, w e examined the effects of a caspase inhibitor and systemic hypothermia on n euronal protection in the developing rat brain. Postnatal d 7 rat pups were subjected to the Rice model of hypoxia for I h. Systemic hypothermia was i nduced with a water bath at 29 degreesC. Before HI insult, a pan-caspase in hibitor, boc-aspartyl-(OMe)-fluoromethyl-ketone (BAF), was injected into th e cerebral ventricle. The ipsilateral hippocampus was subjected to caspase assays and histologic assessment. The HI group at 37 degreesC (HI-37 degree sC) showed a peak of caspase-3 activity 16 It after insult. This activity w as significantly reduced in the presence of BAF or hypothermia (HI-29 degre esC group, p < 0.05) or by the combination of HI-29 degreesC + BAY (p < 0.0 1 versus HI-37 degreesC). The number of neuronal cells in the ipsilateral h ippocampal CAI region in the HI-37 degreesC group was significantly decreas ed (62.9% versus control). The number of neuronal cells was maintained in t he HI-37 degreesC + BAF group (82.7%), the HI-29 degreesC group (78.7%), an d the combination group (95.2%) (p < 0.05 versus HI-37 degreesC). A combina tion of systemic hypothermia and BAF produced a strong protective effect ag ainst neuronal damage in the developing rat brain, along with a reduction i n caspase-3 activity.