Poly(ADP ribose) polymerase cleavage precedes neuronal death in the hippocampus and cerebellum following injury to the developing rat forebrain

Transient unilateral forebrain hypoxia-ischaemia (HI) in 14-day-old rats pr oduces infarction and delayed neuronal death in the frontal cortex. Cell de ath can also be observed in regions distant from the primary injury, a phen omenon known as diaschisis. While apoptosis is involved in selective neuron al death, its role in infarction and diaschisis remains poorly understood, Here, we have investigated the proteolytic cleavage of poly(ADP ribose) pol ymerase (PARP) and the occurrence of apoptosis in the hippocampus and the c erebellum following either HI or traumatic brain injury. We demonstrate tha t: (i) in vitro, PARP is cleaved during apoptosis but not necrosis in cultu red neuronal (N1E) cells and Swiss 3T3 fibroblasts; (ii) following HI, apop totic cells can be detected by 4h after injury in the hippocampus; (iii) in the ipsilateral hippocampus the appearance of cells with apoptotic morphol ogy is preceded by a dramatic increase in PARR cleavage in the same region, starting immediately following HI and persisting for 24 h; (iv) HI also in duces apoptosis in the cerebellum and, as in the hippocampus, the appearanc e of cells with apoptotic morphology is preceded by PARP cleavage that is g reater on the side Ipsilateral to forebrain injury; and (v) similarly, trau matic brain injury to the forebrain leads to PARR cleavage and apoptosis in the cerebellum. We conclude that HI injury or traumatic injury to the deve loping rat forebrain leads to PARP cleavage in directly affected areas and in sites distant from the primary injury that precedes the appearance of ce lls with apoptotic morphology. Our results are consistent with a role for a poptotic cell death in infarction and in diaschisis resulting from forebrai n injury to the developing brain.