BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia

Hypoxic-ischemic (H-I) injury to the brain in the perinatal period often le ads to significant long-term neurological deficits. In a model of neonatal H-I injury in postnatal day 7 rats, our previous data have shown that cell death with features of apoptosis is prominent between 6 and 24 h after H-I and that neurotrophins, particularly BDNF, can markedly protect against tis sue loss. During brain development, caspase-3 is required for normal levels of programmed cell death. Utilizing an antibody specific for the activated form of caspase-3, CM1,we now show that caspase-3 is specifically activate d in neuronal cell bodies and their processes beginning at 6 h and peaking 24 h following unilateral carotid ligation and exposure to hypoxia in postn atal day 7 rats. Caspase-3 activation began to occur in cortex at 6 h and i n striatum and hippocampus at 12-18 h. Caspase-3 activation was also observ ed in developing oligodendrocytes. Intracerebroventricular injection of BDN F prior to H-I injury almost completely abolished evidence of H-I-induced c aspase-3 activation in vivo. Utilizing a specific molecular marker of an ap optotic pathway, these findings demonstrate that H-I injury to the developi ng brain is a strong apoptotic stimulus leading to caspase-3 activation, th at BDNF can block this process in vivo, and that the ability of BDNF to inh ibit caspase activation and subsequent apoptosis likely accounts in large p art for its protection against neuronal injury in this model. (C) 2000 Acad emic Press.